Podcasts about modulated

BUFFALO, NY- April 9, 2024 – A new #researchpaper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 6, entitled, “CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction.” Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. The geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes. In this new study, researchers Alcir L. Dafre, Saadia Zahid, Jessica Jorge Probst, Antonio Currais, Jingting Yu, David Schubert, and Pamela Maher from Salk Institute for Biological Studies, National University of Sciences and Technology (NUST) and Federal University of Santa Catarina investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice. “This comprehensive analysis aimed to further understand how CMS121 influences the metabolic landscape, paving the way for potential therapeutic applications beyond its established geroneuroprotective benefits.” Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism. The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121. “The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.” DOI - https://doi.org/10.18632/aging.205673 Corresponding authors - Pamela Maher - pmaher@salk.edu and Alcir L. Dafre - alcir.dafre@ufsc.br Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205673 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US Aging publishes research papers in all fields of aging research including but not limited, aging from yeast to mammals, cellular senescence, age-related diseases such as cancer and Alzheimer's diseases and their prevention and treatment, anti-aging strategies and drug development and especially the role of signal transduction pathways such as mTOR in aging and potential approaches to modulate these signaling pathways to extend lifespan. The journal aims to promote treatment of age-related diseases by slowing down aging, validation of anti-aging drugs by treating age-related diseases, prevention of cancer by inhibiting aging. Cancer and COVID-19 are age-related diseases. Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

Thomas Rockwell, San Diego State University The Salton Basin was free of significant water between about 100 BCE and 950 CE but has filled to the sill elevation of +13 m six times between ca 950 and 1730 CE. Based on a dense array of cone penetrometer (CPT) soundings across a small sag pond, the Imperial fault is interpreted to have experienced an increase in earthquake rate and accelerated slip in the few hundred years after re-inundation, an observation that is also seen on the southern San Andreas and San Jacinto faults. This regional basin-wide signal of transient accelerated slip in interpreted to result from the effects of increased pore pressure on fault strength resulting from the ~100 m of water load during full lake inundations. If the relationship between co-seismic subsidence in the sag depression and horizontal slip through the sag is even close to constant, the slip rate on the Imperial fault may have exceeded the plate rate for a few hundred years due to excess stored elastic strain that accumulated during the extended dry period prior to ca 950 CE.

Mong-Han Huang, University of Maryland The Ross Ice Shelf (RIS) in Antarctica is the largest ice shelf in the world. As the RIS flows toward the Ross Sea, a buildup of tensile stress due to increasing ice flow velocity develops a series of flow-perpendicular rift zones. Although these rifts are essential in contributing to future calving and reduction in size of the ice shelf, their material properties and mechanical response to external stress in the rift zone scale (~10-100 km) are poorly understood, partly due to a lack of high spatial-temporal scale in-situ observations to characterize key rift processes. Using a deployment of seismometers and GPS stations from the NSF DRRIS project and recently by our team, we further explore the link between seismicity, tidal cycles, and air temperature at two rifts of different ages. We found that icequakes along the major rift zones on RIS are modulated with the oscillating tidal stressing rate, and icequakes have a stronger modulation with stress rate in older rifts. We adopted the theory proposed by Heimisson and Avouac (2020) about seismicity rate due to oscillating stresses for icequakes. On RIS, the characteristic time scale from elevated icequake seismicity rate to background rate is much shorter than the periodicity of the tidal stresses, and therefore the seismicity rate is proportional to the stressing rate. This also suggests that how stress varies in time, rather than the total quantity of stress, has a higher contribution to brittle fractures in ice shelves. Constraining the current behavior of ice shelf rifts and their modulation by oscillating stresses will help inform their future stability in a changing climate.

References Nat Commun. 2022; 13: 4435. Virchows Archiv: European Journal of Pathology, 2020. Vol. 476, Issue 2 Cell Death Differ. 2015 Apr; 22(5): 703–718 Pentangle.1971. Hunting Song. https://youtu.be/CwvpMGc_J-w?si=s6pS2agc5s1N0H2z Falconieri , Cima, Uccellini, Turini, Merula, et al. 1600-1650. Early Italian Baroque Ensemble. https://music.youtube.com/playlist?list=OLAK5uy_mQznM05seareQTK-s3j-1VgS4DHblD5po&si=3mJts6TW3-T2g7k5 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

Becky Winslow, BS, PharmD Host and Pharmacogenomics Medical Science Liaison; Behnaz Sarrami, MS, PharmD, Host and Pharmacogenomics Medical Science Liaison; Thierry Dervieux, PharmD, PhD, Chief Scientific Officer at Prometheus Laboratories Disclaimer: Behnaz Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of Castle Biosciences, Inc. Becky Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of any other entity.   Transcription:  1 00:00:06,190 --> 00:00:19,620 You're listening to the Pharmacy podcast Network in a world where one size fits all medications dominate the pharmaceutical industry. 2 00:00:20,079 --> 00:00:24,750 Precision medicine brings a ray of hope for those seeking customized health care. 3 00:00:25,350 --> 00:00:32,830 Pharmacists have a unique opportunity to help people in need of specialized testing to ensure medications work as intended. 4 00:00:33,540 --> 00:00:44,680 Welcome to PGX for pharmacists where we unravel the wonders of precision medicine and its potential to revolutionize the way we approach pharmacy care. 5 00:00:45,169 --> 00:00:52,790 Get ready to uncover the secrets behind pharmacogenomics and how it's transforming lives one genome at a time. 6 00:00:52,799 --> 00:00:53,189 Hello, 7 00:00:53,200 --> 00:00:53,950 everyone. 8 00:00:54,159 --> 00:00:55,080 I'm your host, 9 00:00:55,090 --> 00:00:56,389 Doctor Becky Winslow. 10 00:00:56,409 --> 00:01:09,860 And you're listening to the PGX for Pharmacist podcast that we magazine recognized in 2021 as the ninth most listened to genetics podcasts in the world on the PGX for Pharmacist podcast. 11 00:01:09,870 --> 00:01:16,690 We explore all things pharmacogenomics related and our mission is to educate and advocate for PGX. 12 00:01:16,769 --> 00:01:23,849 We accomplish this mission through exclusive interviews with highly qualified and well experienced pharmacogenomics. 13 00:01:23,860 --> 00:01:29,720 Industry leaders such as today's special guest and my name is Baas Sami, 14 00:01:29,730 --> 00:01:32,739 the co-host of PGX for Pharms podcast, 15 00:01:32,750 --> 00:01:33,860 Pharmacogenomics, 16 00:01:33,870 --> 00:01:36,819 medical science liaison and a mentor to pharmacist. 17 00:01:36,889 --> 00:01:40,239 Connect with us on linkedin and let's get a conversation going. 18 00:01:40,269 --> 00:01:46,720 We want to hear from you and how you're impacting pharmacogenomic stakeholders and what you have learned throughout your journey. 19 00:01:48,510 --> 00:01:49,010 Ok. 20 00:01:49,019 --> 00:01:50,819 So without any further ado, 21 00:01:50,839 --> 00:01:54,769 I'm extremely pleased to introduce to our audience. 22 00:01:54,919 --> 00:01:56,059 Doctor Theory Devo, 23 00:01:57,239 --> 00:02:01,129 the Chief Scientific Officer at Prometheus Laboratories, 24 00:02:01,139 --> 00:02:08,139 and Perme Prometheus Laboratories is a reference clinical laboratory that's focused on the diagnosis, 25 00:02:08,149 --> 00:02:13,330 prognosis and monitoring of immune mediated inflammatory diseases. 26 00:02:13,970 --> 00:02:14,229 So, 27 00:02:14,240 --> 00:02:14,649 thank you, 28 00:02:14,660 --> 00:02:17,759 Doctor De for joining us on the podcast. 29 00:02:17,770 --> 00:02:18,589 Today. 30 00:02:18,600 --> 00:02:23,190 I'm excited to share your and Prometheus's story with our audience. 31 00:02:23,649 --> 00:02:25,630 Um in particular, 32 00:02:25,639 --> 00:02:45,369 I'm excited about you sharing your career journey as a farm D phd and Chief scientific officer and designer of the Predictor PK AD A which is a precision guided dosing test for the optimization of Humira Remicade and their bio cylinders. 33 00:02:46,119 --> 00:02:46,449 So, 34 00:02:46,460 --> 00:03:04,220 one of Bana's and my main goals for this episode of the PGX for Pharmacist podcast is to expand our audience's notion of what a PGX test looks like and to inspire them to think bigger than the traditional box PGX test. 35 00:03:04,229 --> 00:03:08,020 Most of them or most of you are uh familiar with. 36 00:03:09,020 --> 00:03:09,429 So, 37 00:03:09,440 --> 00:03:22,179 Doctor D uh I'd like to start the podcast by having our guests um introduce themselves and elaborate on how you are a pharmacogenomics expert. 38 00:03:23,619 --> 00:03:23,800 Yeah, 39 00:03:23,809 --> 00:03:24,250 thank you, 40 00:03:24,259 --> 00:03:25,759 Becky for having me. 41 00:03:25,770 --> 00:03:26,850 Uh uh Yes. 42 00:03:26,860 --> 00:03:27,289 So I am a, 43 00:03:27,300 --> 00:03:30,820 I am a pharmacist uh with uh a family who is a, 44 00:03:30,830 --> 00:03:33,039 a doctorate in pharmacokinetics. 45 00:03:33,539 --> 00:03:44,520 Uh I completed my studies in France and I came as a postdoc uh fellow uh to work in the United States about 20 years ago to work on the pharmacogenomic of anti cancer agents, 46 00:03:44,929 --> 00:03:49,160 uh primarily uh six Maturin as well as methotrexate. 47 00:03:49,169 --> 00:03:50,550 After my post doc, 48 00:03:50,770 --> 00:03:52,960 uh I moved uh in industry for promet. 49 00:03:53,490 --> 00:04:01,429 So I have a large experience in uh uh the implementation of pharmacogenetics testing in immune mediated inflammatory disease. 50 00:04:01,509 --> 00:04:12,550 Our lab Rome was the first uh clinical laboratory in the United States to offer the fin uh metyl transfer genotyping as well as the thin metabolites. 51 00:04:12,559 --> 00:04:13,029 So, 52 00:04:13,050 --> 00:04:21,989 uh uh of uh of 70 publications in the field and uh I'm very uh very excited to have uh to be on the postcard with you uh uh today. 53 00:04:23,660 --> 00:04:24,220 All right. 54 00:04:24,230 --> 00:04:27,359 So thank you for qualifying yourself as an expert. 55 00:04:27,369 --> 00:04:27,619 So, 56 00:04:27,630 --> 00:04:32,839 let's jump right in and delve into your current PGX work. 57 00:04:32,850 --> 00:04:33,279 So, 58 00:04:33,489 --> 00:04:36,540 if you'll tell us um a little about Prometheus, 59 00:04:36,549 --> 00:04:38,000 specifically, 60 00:04:38,010 --> 00:04:40,350 what is Prometheus's mission? 61 00:04:40,359 --> 00:04:43,799 And how are you guys going about accomplishing your mission? 62 00:04:44,760 --> 00:04:44,980 Yeah, 63 00:04:44,989 --> 00:04:45,700 sure. 64 00:04:45,709 --> 00:04:47,459 Uh So Promet is a, 65 00:04:47,470 --> 00:04:52,790 is a reference uh clinical laboratory based in Southern California in San Diego. 66 00:04:53,230 --> 00:04:56,809 Uh The company has been there for uh over 25 years. 67 00:04:56,820 --> 00:05:03,950 We are uh specialize in the differential diagnosis of autoimmune G I disease uh disorders, 68 00:05:04,059 --> 00:05:06,019 uh gastrointestinal disorder, 69 00:05:06,230 --> 00:05:08,619 uh and inflammatory bowel disease. 70 00:05:08,980 --> 00:05:10,299 And over the years, 71 00:05:10,309 --> 00:05:16,600 we have developed a portfolio of a differentiated solution to facilitate the diagnosis, 72 00:05:16,609 --> 00:05:17,470 the prognosis, 73 00:05:17,480 --> 00:05:18,429 the monitoring, 74 00:05:18,660 --> 00:05:21,910 as well as therapy selection with pharmacogenetics testing, 75 00:05:21,920 --> 00:05:24,730 which we are offering to our clinical laboratory. 76 00:05:24,829 --> 00:05:26,350 And most importantly, 77 00:05:26,410 --> 00:05:27,299 uh recently, 78 00:05:27,309 --> 00:05:35,660 we are uh uh developing some uh uh testing solution with the credit topic care test to optimize treatment to uh biologics. 79 00:05:36,470 --> 00:05:37,130 Ok. 80 00:05:37,140 --> 00:05:37,329 Well, 81 00:05:37,339 --> 00:05:37,450 that, 82 00:05:37,459 --> 00:05:38,049 that's great. 83 00:05:38,059 --> 00:05:46,100 Can you also tell us uh about the Prois Library of Precision Medicine Tests for inflammatory bowel disease for patients? 84 00:05:46,109 --> 00:05:49,230 how they benefit medication therapy management. 85 00:05:49,239 --> 00:05:56,429 Stakeholders across the IB DS patients journey from diagnosis to treatment to disease, 86 00:05:56,440 --> 00:06:02,049 monitoring through remission and how they differ from other lab tests for IBD and his treatments. 87 00:06:02,709 --> 00:06:03,209 Yes. 88 00:06:03,220 --> 00:06:03,369 So, 89 00:06:03,380 --> 00:06:04,399 so we uh our, 90 00:06:04,410 --> 00:06:10,100 our clinical laboratory offers some uh highly specialized test to facilitate the, 91 00:06:10,109 --> 00:06:16,779 the diagnostic of uh to facilitate the differential diagnosis of uh uh inflammatory bowel disease. 92 00:06:16,790 --> 00:06:22,359 So we are following uh testing solution with uh serological testing, 93 00:06:22,529 --> 00:06:23,799 for example, 94 00:06:23,809 --> 00:06:38,410 uh uh piana as as as well as uh macro microbial uh uh antibodies that are present uh uh in Crohn's disease as well as uh over uh auto uh auto antibodies that are present in er colitis. 95 00:06:39,339 --> 00:06:43,684 These are conditions that are uh uh somewhat difficult to treat. 96 00:06:43,704 --> 00:06:49,994 Uh And uh we are uh uh offering those tests to uh help uh gastroenterologist. 97 00:06:50,015 --> 00:06:51,114 Uh uh first of all, 98 00:06:51,125 --> 00:07:03,434 to establish a differential diagnosis of IBD as compared to other uh condition typically uh uh irritable bowel syndrome as well as over gastrointestinal disorder. 99 00:07:03,445 --> 00:07:05,635 When the diagnostic is established, 100 00:07:05,910 --> 00:07:31,839 uh we offer uh testing to uh establish a prognosis where we're gonna in inform the clinician that the patient has a more aggressive uh disease that will require more aggressive treatment where uh we can uh provide the testing solution to initiate uh uh the most appropriate therapy for uh for the patient uh with uh a testing where we are uh basically uh you know, 101 00:07:31,850 --> 00:07:36,559 establish de determining some genotyping with the fit transferal genotyping. 102 00:07:36,570 --> 00:07:37,279 For example, 103 00:07:37,290 --> 00:07:40,250 where we can uh indicate that the patient is, 104 00:07:40,260 --> 00:07:45,079 is likely uh to present with a side effect to those medication. 105 00:07:45,399 --> 00:07:46,170 And once you know, 106 00:07:46,179 --> 00:07:47,799 the the treatment is initiative, 107 00:07:47,809 --> 00:08:16,089 we have a portfolio of solution uh to facilitate the monitoring of the disease of the inflammatory bowel disease as well as the dosing optimization with uh uh the answer test which uh measure blood level uh for uh uh monoclonal antibodies that are indicated in the treatment of IB start with starting with Infliximab Adalimumab as well as uh Tein and vidal. 108 00:08:16,980 --> 00:08:24,040 So we have a comprehensive portfolio to uh to surround the clinician with uh a variety of testing solution. 109 00:08:24,049 --> 00:08:30,250 With our goal being to improve the uh the outcome uh of patients with uh with diabetes. 110 00:08:30,260 --> 00:08:34,520 And I think that the pharmacist has a very important role to play from that perspective. 111 00:08:35,179 --> 00:08:36,039 So theory, 112 00:08:36,049 --> 00:08:40,239 could you elaborate for us more on the predictor test? 113 00:08:40,249 --> 00:08:42,758 Um especially since you designed that test, 114 00:08:42,768 --> 00:08:44,218 we'd really like to know, 115 00:08:44,489 --> 00:08:45,039 um you know, 116 00:08:45,049 --> 00:08:49,638 what did that take and what role does it play in your suite of testing? 117 00:08:51,049 --> 00:08:51,270 Yeah. 118 00:08:51,280 --> 00:08:51,890 Sure. 119 00:08:51,900 --> 00:08:52,510 So the, 120 00:08:52,520 --> 00:08:52,570 the, 121 00:08:52,580 --> 00:08:52,989 the, 122 00:08:53,000 --> 00:08:53,229 the, 123 00:08:53,239 --> 00:08:59,960 the predictor test is uh uh is uh is utilized when the patient is receiving treatment. 124 00:09:00,280 --> 00:09:18,190 It's been speci specifically designed to optimize uh biological uh uh disease modifiers such as Infliximab adalimumab that are co therapies in the treatment of inflammatory bowel disease as well as other immune uh mediated inflammatory. 125 00:09:18,200 --> 00:09:21,549 This is what the test does is to you connect the blood specimen, 126 00:09:22,229 --> 00:09:23,049 uh you know, 127 00:09:23,059 --> 00:09:24,750 with dosing information. 128 00:09:25,039 --> 00:09:41,989 And what we do is to uh uh provide guidance uh to clinician with uh respect of the best dose to give in order to achieve the best the level which is the most consistent with uh uh the disease control that needs to be achieved for the patient. 129 00:09:42,169 --> 00:09:43,729 Typically a vast majority, 130 00:09:43,739 --> 00:09:46,159 about two third of a third to two third, 131 00:09:46,169 --> 00:09:54,669 a third of patient uh tend to be uh uh unresponsive uh to this uh very expensive medication. 132 00:09:54,989 --> 00:09:57,960 Uh Not because they don't have the uh you know, 133 00:09:57,969 --> 00:09:59,289 typically because they have a, 134 00:09:59,299 --> 00:09:59,590 you know, 135 00:09:59,599 --> 00:10:05,599 pharmacokinetic uh suboptimal pharmacokinetic uh that makes them uh you know, 136 00:10:05,609 --> 00:10:09,440 unresponsive because uh not enough drug has been given. 137 00:10:09,450 --> 00:10:18,469 So what we do with a predictor test is to basically estimate the pa the pharmacokinetic uh parameter for the patient. 138 00:10:18,750 --> 00:10:24,729 And from then uh re report the best dose uh to give in order to achieve the, 139 00:10:24,760 --> 00:10:31,570 the level which is consistent with the uh the most uh uh effective disease control to be achieved for the patient. 140 00:10:32,169 --> 00:10:33,059 So we are offering, 141 00:10:33,070 --> 00:10:38,049 we have developed a test for the Infliximab as well as Adalimumab which is Humira, 142 00:10:38,909 --> 00:10:41,309 but these are antimony causes factor. 143 00:10:41,460 --> 00:10:49,549 And we are also developing the test for vidur as well as uh is that are widely used also in the treatment of, 144 00:10:49,559 --> 00:10:51,969 of uh inflammatory bubble disease. 145 00:10:51,979 --> 00:10:52,669 Wow, 146 00:10:52,679 --> 00:10:55,450 uh for MET is a suite of tests. 147 00:10:55,460 --> 00:11:00,940 Goes well beyond um the PGX testing that our audience is most familiar with, 148 00:11:01,299 --> 00:11:08,679 uh which typically only includes snips for cyp genes and some pharmacodynamic genes. 149 00:11:08,690 --> 00:11:31,424 This is really exciting um genes and biomarkers related to immunology are not commonly found in what I call the box PGX tests such as those uh made by large uh laboratory manufacturing companies um where the panel has a set number of genes and uh you know, 150 00:11:31,434 --> 00:11:36,054 it was developed by a larger laboratory for maybe smaller laboratories use. 151 00:11:36,729 --> 00:11:39,010 So my understanding, 152 00:11:39,020 --> 00:11:53,729 having talked with you extensively theory is that immunology has fewer PGX test available because it's actually more difficult say than oncology to research and develop tests. 153 00:11:53,739 --> 00:11:54,119 So, 154 00:11:54,130 --> 00:12:00,729 could you elaborate for our audience on the difficulties that are associated with immunology, 155 00:12:00,739 --> 00:12:05,830 research and developing tests uh for immunology versus say oncology? 156 00:12:06,330 --> 00:12:06,530 Yeah, 157 00:12:06,539 --> 00:12:07,049 sure. 158 00:12:07,059 --> 00:12:09,969 So in uh in immunology, 159 00:12:09,979 --> 00:12:11,590 as compared to oncology, 160 00:12:11,599 --> 00:12:17,169 there is no such a thing such as a somatic mutation where for example, 161 00:12:17,179 --> 00:12:18,429 you're gonna have a behalf, 162 00:12:18,440 --> 00:12:18,659 you know, 163 00:12:18,669 --> 00:12:20,349 that indicates that the patient, 164 00:12:20,679 --> 00:12:20,919 you know, 165 00:12:20,929 --> 00:12:25,239 is likely to benefit or not from some treatment in immunology. 166 00:12:25,250 --> 00:12:26,750 This is far more complicated, 167 00:12:26,760 --> 00:12:28,830 complicated for the reason, 168 00:12:29,239 --> 00:12:31,020 starting with uh the fact that, 169 00:12:31,030 --> 00:12:31,179 you know, 170 00:12:31,190 --> 00:12:36,219 the response to this uh medication uh are multifactorial. 171 00:12:36,260 --> 00:12:37,820 And the fact that uh you know, 172 00:12:37,830 --> 00:12:39,380 the mutation that uh the, 173 00:12:39,390 --> 00:12:39,619 the, 174 00:12:39,630 --> 00:12:45,190 the single nucleotide polymorphism in the GM line which uh uh you know, 175 00:12:45,200 --> 00:12:52,429 can potentially associate with uh with outcome uh uh uh uh a lo in advance, 176 00:12:52,440 --> 00:12:58,359 meaning that uh they're gonna have a weak association uh with a response to those medications. 177 00:12:58,369 --> 00:13:09,609 So there is a necessity in immunology to combine multiple genetic polymorphism together in order to achieve uh some uh performances characteristics that will make uh you know, 178 00:13:09,619 --> 00:13:09,859 the, 179 00:13:09,869 --> 00:13:10,380 the, 180 00:13:10,390 --> 00:13:10,520 the, 181 00:13:10,530 --> 00:13:13,219 the clinician uh you know, 182 00:13:13,419 --> 00:13:15,619 uh order the test and most importantly, 183 00:13:15,630 --> 00:13:15,840 the, 184 00:13:15,849 --> 00:13:16,179 the, 185 00:13:16,190 --> 00:13:17,739 the payer to pay for the test. 186 00:13:17,750 --> 00:13:20,469 So this field has been uh you know, 187 00:13:20,479 --> 00:13:20,679 is, 188 00:13:20,690 --> 00:13:21,705 is moving for, 189 00:13:21,715 --> 00:13:21,994 you know, 190 00:13:22,005 --> 00:13:24,575 there are some tests that are being developed right now. 191 00:13:24,924 --> 00:13:39,034 But the biggest challenge is to be able to achieve again the the threshold of uh of performance that makes the test is variable enough uh to be uh again ordered by the clinician and the utilize uh to the benefit of the patient. 192 00:13:39,659 --> 00:13:41,200 I couldn't agree with you more. 193 00:13:41,210 --> 00:13:53,489 Um I've worked on the payer side or market access side of pharmacogenomics and even uh with a box test for which there's um a lot of research data available, 194 00:13:53,500 --> 00:13:55,119 even with those, 195 00:13:55,130 --> 00:13:59,760 it's sometimes difficult uh to get payers um to see the value. 196 00:13:59,770 --> 00:14:01,640 So I absolutely agree with you. 197 00:14:01,940 --> 00:14:03,679 Um The fact that you guys are, 198 00:14:03,690 --> 00:14:11,789 are uh investing in producing the data necessary says a lot about your laboratory. 199 00:14:11,979 --> 00:14:12,559 Um you know, 200 00:14:12,570 --> 00:14:15,380 and how committed you are to this testing and, 201 00:14:15,390 --> 00:14:17,320 and how you believe in the testing. 202 00:14:18,039 --> 00:14:23,640 So I just want to make sure that our audience recognizes that, 203 00:14:24,359 --> 00:14:24,619 you know, 204 00:14:24,630 --> 00:14:31,820 Prometheus doesn't simply provide tests to determine if drugs for IBD will be effective and safe. 205 00:14:32,190 --> 00:14:36,900 Um And maybe what the dose of the drug should be for the patient, 206 00:14:36,909 --> 00:14:40,219 but you have that whole suite of tests. 207 00:14:40,229 --> 00:14:47,380 Um the diagnostic test for the differential diagnosis all the way through remission. 208 00:14:48,030 --> 00:14:53,390 So can you elaborate you elaborated on it some in the previous question? 209 00:14:53,400 --> 00:15:01,229 But um can you tell us the difference between how you had to actually develop the test? 210 00:15:01,520 --> 00:15:02,530 Um You didn't, 211 00:15:02,539 --> 00:15:03,059 in other words, 212 00:15:03,070 --> 00:15:10,659 purchase a test from another manufacturer with the biomarkers that you include in your testing. 213 00:15:10,669 --> 00:15:16,830 Can you elaborate on how much more difficult it is to to develop a test from scratch? 214 00:15:18,169 --> 00:15:18,320 Yeah, 215 00:15:18,330 --> 00:15:18,659 sure. 216 00:15:18,669 --> 00:15:18,809 I mean, 217 00:15:18,820 --> 00:15:22,070 this is this is challenging for multiple and first of all, 218 00:15:22,080 --> 00:15:23,130 you need to have the, 219 00:15:23,419 --> 00:15:27,450 you need to have a clinical data set available with specimen available. 220 00:15:27,460 --> 00:15:28,159 Uh you know, 221 00:15:28,169 --> 00:15:28,780 in front, 222 00:15:28,859 --> 00:15:29,770 obviously, 223 00:15:29,859 --> 00:15:30,890 available. 224 00:15:31,200 --> 00:15:35,890 Uh So we are leveraging a pro meters a large bi bank of specimen. 225 00:15:36,299 --> 00:15:37,190 Uh as I said, 226 00:15:37,200 --> 00:15:39,719 Prometheus has been founded 25 years ago. 227 00:15:39,729 --> 00:15:40,599 So over the, 228 00:15:40,760 --> 00:15:41,919 the past two decades, 229 00:15:41,929 --> 00:15:54,849 we have been able to assemble a large uh substrate of data and specimen which we are uh uh using to uh uh establish our proof of concept if you will. 230 00:15:54,859 --> 00:16:07,559 And then when we have uh identify some genetic polymorphism that are uh adequately uh associated with uh uh disease outcome and disease progression as well as uh toxicity. 231 00:16:07,969 --> 00:16:11,469 Then we are entering validation phase where we are uh you know, 232 00:16:11,570 --> 00:16:14,789 using validation cohorts where we are again, 233 00:16:14,969 --> 00:16:22,630 combining multiple modalities together uh patient demographic as well as genetic marker together with theological marker. 234 00:16:22,640 --> 00:16:23,190 Actually, 235 00:16:23,500 --> 00:16:27,419 to come up with some Multivariate models that are uh again, 236 00:16:27,429 --> 00:16:39,250 bringing the performances characteristics of the pharmacogenomic test or its combination with our marker to the level where it's supposed to be in the first place to meet uh uh payer. 237 00:16:39,650 --> 00:16:41,190 And uh obviously, 238 00:16:41,200 --> 00:16:41,760 again, 239 00:16:41,770 --> 00:16:45,320 the patient uh to the benefit of the patient and to, 240 00:16:45,330 --> 00:16:46,619 to improve its outcome, 241 00:16:46,739 --> 00:16:47,429 the outcome. 242 00:16:48,340 --> 00:16:53,380 I think what you're describing really is the future of pharmacogenomics. 243 00:16:53,390 --> 00:16:54,599 Um In other words, 244 00:16:54,609 --> 00:17:03,419 not singing out pharmacogenomics as you know the end all and be all in the treatment paradigm. 245 00:17:03,559 --> 00:17:08,040 But using a PGX test in combination with, 246 00:17:08,050 --> 00:17:09,069 like you mentioned, 247 00:17:09,250 --> 00:17:11,160 other serological tests, 248 00:17:11,170 --> 00:17:12,959 maybe other genetic tests. 249 00:17:13,290 --> 00:17:14,890 Um But you know, 250 00:17:14,900 --> 00:17:25,869 I think what we want our audience to really wrap their heads around is that PGX is just a piece of that larger puzzle um from diagnosis to treatment to, 251 00:17:25,880 --> 00:17:26,910 to remission. 252 00:17:27,239 --> 00:17:29,880 So I think you guys are absolutely, 253 00:17:29,890 --> 00:17:31,579 you're already in the future. 254 00:17:31,589 --> 00:17:32,849 In other words, 255 00:17:32,859 --> 00:17:33,130 you know, 256 00:17:33,140 --> 00:17:39,689 you're already providing all these different uh tests um like you mentioned to, 257 00:17:39,699 --> 00:17:44,310 to facilitate from diagnosis to remission to remission. 258 00:17:44,660 --> 00:17:45,520 That's correct. 259 00:17:45,530 --> 00:17:45,829 Yeah. 260 00:17:46,349 --> 00:17:55,089 So um you've given us so much great information about uh the tests that that you guys offer. 261 00:17:55,329 --> 00:18:02,060 Can you explain to our audience um your newest test? 262 00:18:02,069 --> 00:18:03,859 Uh the responder test. 263 00:18:04,150 --> 00:18:12,979 And um what role it will play in the paradigm from the diagnosis of IBD to remission? 264 00:18:14,050 --> 00:18:14,260 Yeah, 265 00:18:14,270 --> 00:18:14,760 sure. 266 00:18:14,770 --> 00:18:15,569 So we, 267 00:18:15,579 --> 00:18:18,069 we are doing things a little bit different than other. 268 00:18:18,079 --> 00:18:19,489 We do believe that uh you know, 269 00:18:19,500 --> 00:18:21,449 the it has to be simple. 270 00:18:21,459 --> 00:18:24,189 Uh uh We can obviously construct some very, 271 00:18:24,199 --> 00:18:33,530 very complex algorithm and there are some tests that do that with a very sophisticated machine learning based tools that are available using neural networks, 272 00:18:33,540 --> 00:18:33,729 you know, 273 00:18:33,739 --> 00:18:34,790 those sorts of things. 274 00:18:34,800 --> 00:18:39,729 But we have taken on a different approach where with the responder test, 275 00:18:39,739 --> 00:18:40,329 we are basically, 276 00:18:40,339 --> 00:18:45,160 we are taking an approach which is very simple to address the first and foremost. 277 00:18:45,170 --> 00:18:53,020 Most important aspect of responding uh predicting response to uh to medication is the pharmacokinetics. 278 00:18:53,280 --> 00:19:03,250 Uh You cannot be responding to a drug if the drug is not given and you obviously cannot respond to a drug if the drug is not metabolized adequately. 279 00:19:03,359 --> 00:19:06,349 And this is what we are doing with the responder test. 280 00:19:06,579 --> 00:19:09,010 We are addressing some uh uh you know, 281 00:19:09,020 --> 00:19:11,630 fundamental issues with those uh biologist, 282 00:19:11,640 --> 00:19:12,410 for example, 283 00:19:12,660 --> 00:19:15,170 uh the anti tumor necrosis factors. 284 00:19:15,180 --> 00:19:15,650 So, 285 00:19:15,750 --> 00:19:19,199 such as uh Infliximab and Adalimumab, 286 00:19:19,209 --> 00:19:23,050 it is well known uh that uh uh those drugs, 287 00:19:23,060 --> 00:19:25,689 first of all are prone to immunization. 288 00:19:25,989 --> 00:19:36,949 Uh Meaning that uh uh the drug itself uh is recognized by the immune system uh and digested by the antigen presenting cells. 289 00:19:36,959 --> 00:19:42,209 If you will uh where you gonna have uh uh an immune uh uh response, 290 00:19:42,380 --> 00:19:56,979 uh mounted a cancer drug to produce uh immunogen that will severely impact its pharmacokinetics where the labels will be inadequate to produce uh the desired uh anti-inflammatory effects. 291 00:19:56,989 --> 00:19:57,150 So, 292 00:19:57,160 --> 00:19:58,890 we are with the risk conductors, 293 00:19:58,900 --> 00:20:01,040 we are combining two things together. 294 00:20:01,189 --> 00:20:07,959 First of all is the genetic test itself which uh predicts the risk of immun immunization. 295 00:20:07,969 --> 00:20:18,010 The name of the test is on HL A uh DQ A 105 ali uh that uh uh promotes the presentation of the, 296 00:20:18,020 --> 00:20:19,130 of the, 297 00:20:19,140 --> 00:20:19,910 of Infliximab, 298 00:20:20,010 --> 00:20:20,750 for example, 299 00:20:20,760 --> 00:20:32,130 to the T cell repertoire in order to uh promote the Ronon expansion and the formation of the anti antibodies together with uh another dimension which is the clearance, 300 00:20:32,140 --> 00:20:33,670 which is as important. 301 00:20:33,949 --> 00:20:36,209 Uh One of the key issue is the, 302 00:20:36,219 --> 00:20:36,770 the, 303 00:20:36,780 --> 00:20:41,239 the monoclonal antibodies and uh such as Infliximab or Adalimumab. 304 00:20:41,329 --> 00:20:42,280 But in fact, 305 00:20:42,290 --> 00:20:45,890 a neon antibodies that those drugs are uh you know, 306 00:20:45,900 --> 00:20:49,010 cleared and consumed uh from the, 307 00:20:49,020 --> 00:20:50,949 from the central compartment if you will, 308 00:20:50,959 --> 00:20:54,520 since we are doing a little bit of uh uh pharmacokinetics here. 309 00:20:54,530 --> 00:20:56,020 And uh uh you know, 310 00:20:56,030 --> 00:21:06,670 if the patient present who is uh a high degree of inflammatory burden is gonna have uh the patient will have a high clearance and that's gonna worsen uh in the, 311 00:21:06,680 --> 00:21:13,939 in the presence again of the HL AD Q A 105 genetic marker that uh associate with uh immunization. 312 00:21:13,949 --> 00:21:16,859 So I but this is a combination of both, 313 00:21:17,199 --> 00:21:19,359 these are the predictive factors of pharmacokinetic, 314 00:21:20,359 --> 00:21:38,209 which we combine together where the patient presenting with a risk of immunization as well as accelerated clearance due to the fact that the patient has high inflammation or due to the fact that they are so intrinsic pharmacokinetic properties that makes that the patient, 315 00:21:38,219 --> 00:21:38,300 you know, 316 00:21:38,310 --> 00:21:39,479 will clear the drug very, 317 00:21:39,489 --> 00:21:40,260 very fast. 318 00:21:40,560 --> 00:21:41,670 For example, 319 00:21:41,680 --> 00:21:46,819 due to the inefficient uh recirculation of the drug itself with the new, 320 00:21:46,869 --> 00:21:46,930 the, 321 00:21:46,939 --> 00:21:50,599 the the in the reticular on the system. 322 00:21:50,920 --> 00:21:51,619 Together, 323 00:21:51,630 --> 00:22:02,109 those patients presenting with uh uh together these uh poor prognostic factor of pharmacokinetic origin will tend to be severely underdose, 324 00:22:02,380 --> 00:22:06,719 will not be responding to the drug uh adequately as and they, 325 00:22:06,729 --> 00:22:10,719 and they probably should in the first place if you are able to address uh you know, 326 00:22:10,729 --> 00:22:12,270 the the the exposure. 327 00:22:12,439 --> 00:22:14,079 So what we do with this test, 328 00:22:14,089 --> 00:22:21,640 we will be able to inform uh the clinic that the patient is at risk of achieving, 329 00:22:21,650 --> 00:22:30,829 of achieving suboptimal pharmacokinetics and therefore being able to adjust the dose uh uh to start with more adequately. 330 00:22:30,839 --> 00:22:38,650 So that the the the proper uh exposure is achieved uh during induction to again to, 331 00:22:38,660 --> 00:22:39,040 to, 332 00:22:39,050 --> 00:22:39,380 to, 333 00:22:39,390 --> 00:22:40,890 to achieve a better outcome. 334 00:22:41,040 --> 00:22:47,270 And I think the pharmacist will have a very important role to play here in terms of absolutely, 335 00:22:47,280 --> 00:22:51,239 that information is priceless in the management of these medications. 336 00:22:51,250 --> 00:22:54,930 So thanks for elaborating on that. 337 00:22:56,010 --> 00:22:59,040 And if I may add in our previous conversation, 338 00:22:59,050 --> 00:23:00,810 uh before the recording of podcast, 339 00:23:00,819 --> 00:23:08,869 we had discussed um you guys' robust platform for collaborating with payers to obtain market access and reimbursements for the test. 340 00:23:09,109 --> 00:23:14,109 But without stealing the Thunder from uh Prometheus market access and reimbursement team, 341 00:23:14,199 --> 00:23:22,619 can you please uh briefly detail how Prometheus has proactively worked with payers to solve the problem. 342 00:23:22,920 --> 00:23:27,349 Um the population health problem by building the evidence payers want, 343 00:23:27,359 --> 00:23:41,170 want to see um about your test before you go to the market and then build the test and then hope the payers will see the value and the result and then that will improve the market access and reimbursement for your um precision medicine test. 344 00:23:42,160 --> 00:23:42,339 Yeah. 345 00:23:42,349 --> 00:23:43,180 So briefly I can, 346 00:23:43,189 --> 00:23:43,579 I'm, 347 00:23:43,589 --> 00:23:46,619 I'm probably not the right person to answer that question. 348 00:23:46,630 --> 00:23:47,369 We have a very, 349 00:23:47,380 --> 00:23:52,400 very efficient market access group uh uh pro meters that does a splendid job. 350 00:23:52,410 --> 00:23:59,780 But uh uh uh what I can tell you that we have an evidence uh uh development plan in place where we, 351 00:23:59,790 --> 00:24:14,000 we are establishing the clinical utility of our testing solution by demonstrating uh the payer value uh with respect of uh patient management and uh uh and the, 352 00:24:14,010 --> 00:24:16,630 and the impact of our technology on the, 353 00:24:16,640 --> 00:24:18,119 on physician behavior. 354 00:24:18,430 --> 00:24:21,319 Uh We have uh uh already uh you know, 355 00:24:21,329 --> 00:24:25,160 commercialized uh two of those tests for which we have initiated, 356 00:24:25,170 --> 00:24:29,040 initiated the Power studies uh that uh uh you know, 357 00:24:29,050 --> 00:24:32,000 already provide uh you know, 358 00:24:32,104 --> 00:24:34,484 differentiated and the value to, 359 00:24:34,494 --> 00:24:35,915 to the payer where we are, 360 00:24:35,925 --> 00:24:36,025 the, 361 00:24:36,035 --> 00:24:46,005 the clinicians are basically using our technology to make treatment decision uh as well as uh some prospective clinicality study which we are initiating, 362 00:24:46,145 --> 00:24:47,555 initiating to. 363 00:24:47,564 --> 00:24:48,574 Um uh again, 364 00:24:48,584 --> 00:24:49,425 demonstrate the, 365 00:24:49,435 --> 00:24:49,915 the, 366 00:24:49,925 --> 00:24:50,244 the, 367 00:24:50,255 --> 00:24:53,594 the payer value you uh uh we can certainly follow up with, 368 00:24:53,604 --> 00:24:58,755 uh you can certainly follow up with our market access group uh uh as appropriate there. 369 00:24:58,765 --> 00:25:00,765 Uh They can fill you with more information. 370 00:25:01,349 --> 00:25:01,589 No, 371 00:25:01,599 --> 00:25:02,520 that totally makes sense. 372 00:25:02,530 --> 00:25:03,310 That totally makes sense. 373 00:25:03,319 --> 00:25:10,890 But um we're excited that you're also farm d So how did you get to this role of outside the box path? 374 00:25:10,900 --> 00:25:11,550 There? 375 00:25:11,640 --> 00:25:17,530 There may be a pharmacist student or pharmacist wanting to switch or transition into a role such as yours, 376 00:25:17,540 --> 00:25:19,609 which is a Chief Scientific Officer. 377 00:25:19,619 --> 00:25:20,609 I want to learn more. 378 00:25:20,619 --> 00:25:23,920 So how would you um can you talk a little bit about that? 379 00:25:24,560 --> 00:25:24,780 Well, 380 00:25:24,790 --> 00:25:26,270 we are clinical laboratories. 381 00:25:26,280 --> 00:25:29,400 So in order to uh uh to be in my role, 382 00:25:29,410 --> 00:25:34,020 you need to have uh uh you need to have expertise in clinical laboratory science. 383 00:25:34,030 --> 00:25:36,140 So for the students is basically, 384 00:25:36,150 --> 00:25:36,300 you know, 385 00:25:36,310 --> 00:25:40,770 to do the family degree and then complete the family degree with uh a doctorate, 386 00:25:40,780 --> 00:25:40,930 you know, 387 00:25:40,939 --> 00:25:44,260 which is uh focus on clinical laboratory science. 388 00:25:44,270 --> 00:25:46,079 So you can achieve uh uh you know, 389 00:25:46,089 --> 00:25:47,640 the all the elements you need to be, 390 00:25:47,650 --> 00:25:48,219 for example, 391 00:25:48,229 --> 00:25:53,189 board certified uh as uh as as medical laboratory director. 392 00:25:53,199 --> 00:25:55,160 So you can uh uh so, 393 00:25:55,170 --> 00:25:55,589 uh yeah, 394 00:25:55,599 --> 00:25:56,030 this is, 395 00:25:56,040 --> 00:25:56,400 this is, 396 00:25:56,410 --> 00:25:57,209 this is uh you know, 397 00:25:57,219 --> 00:25:59,160 a great opportunity I think for pharmacies, 398 00:25:59,170 --> 00:26:10,800 there is an absolute need to uh have the clinical pharmacist provide uh uh drug information to healthcare professional as well as uh assist patient with the monitoring of their disease, 399 00:26:10,810 --> 00:26:15,229 the effectiveness of the therapy and um and uh you know, 400 00:26:15,239 --> 00:26:16,060 monitoring the, 401 00:26:16,069 --> 00:26:20,969 the side effect and the toxicity from uh from those uh those medication. 402 00:26:24,650 --> 00:26:24,959 Well, 403 00:26:24,969 --> 00:26:32,119 the I know our audience is going to have uh additional questions for you. 404 00:26:32,130 --> 00:26:32,540 I mean, 405 00:26:32,989 --> 00:26:35,609 you've provided them with so much great information, 406 00:26:35,619 --> 00:26:44,959 but it's only the beginning of what they could possibly learn um about um the testing that you do for IBD and, 407 00:26:44,969 --> 00:26:46,729 and even your career path. 408 00:26:47,050 --> 00:26:47,530 So, 409 00:26:47,540 --> 00:26:49,300 if you wouldn't mind telling us, 410 00:26:49,310 --> 00:26:51,359 um because we have to wrap up, 411 00:26:51,369 --> 00:26:52,670 unfortunately, 412 00:26:53,150 --> 00:26:55,810 this episode of the podcast, 413 00:26:55,819 --> 00:27:00,250 uh could you tell us how our audience members might be able to contact you directly. 414 00:27:01,260 --> 00:27:01,449 Yeah, 415 00:27:01,459 --> 00:27:07,079 I can be contacted on my uh on my email at TT W at como slab dot com. 416 00:27:07,949 --> 00:27:08,810 All right. 417 00:27:09,069 --> 00:27:09,300 Well, 418 00:27:09,310 --> 00:27:14,290 thank you again so much uh for joining us on this episode. 419 00:27:14,300 --> 00:27:15,290 We really, 420 00:27:15,300 --> 00:27:29,530 really hope that our listeners um ideas of not only what PGX can be but how PGX can be utilized in a comprehensive testing suite. 421 00:27:29,709 --> 00:27:35,670 We really hope that our a our audience will um listen in and learn this information. 422 00:27:36,280 --> 00:27:37,869 Um And to our audience, 423 00:27:37,880 --> 00:27:39,439 thank you for tuning in. 424 00:27:39,449 --> 00:27:42,619 We really hope that you've learned from this episode. 425 00:27:43,130 --> 00:27:46,339 Uh We do a whole lot of PG Xing here on this podcast. 426 00:27:46,349 --> 00:27:48,380 We talk about PGX Science, 427 00:27:48,390 --> 00:27:52,030 clinical application and the business of PGX. 428 00:27:52,260 --> 00:27:54,880 So we'd love to hear about from you. 429 00:27:55,099 --> 00:27:56,479 I love to hear from you. 430 00:27:56,489 --> 00:27:58,439 Um What can we teach you? 431 00:27:58,449 --> 00:28:00,920 What more can we teach you through our podcast? 432 00:28:00,930 --> 00:28:12,349 So please drop us a message on linkedin and let us know and please share this link to this podcast link episode with everyone so they can tune in and listen to the PGX for promises podcast. 433 00:28:12,520 --> 00:28:15,369 Leave us a review on Apple podcast or Spotify. 434 00:28:15,459 --> 00:28:18,130 And you can also visit us on PGX four, 435 00:28:18,140 --> 00:28:22,989 the number four Rx dot com to listen to all our other episodes. 436 00:28:23,000 --> 00:28:23,079 Well, 437 00:28:23,089 --> 00:28:23,790 thank you. 438 00:28:24,199 --> 00:28:28,750 Thanks for your interest in PGX and for spending some time with us. 439 00:28:28,760 --> 00:28:35,670 Please share this podcast and leave us a review on Apple podcasts or Spotify for all of our episodes. 440 00:28:35,680 --> 00:28:39,390 Please visit PGX for Rx dot com. 441 00:28:39,569 --> 00:28:43,380 That's PGX for Rx dot com.  

Becky Winslow, BS, PharmD Host and Pharmacogenomics Medical Science Liaison; Behnaz Sarrami, MS, PharmD, Host and Pharmacogenomics Medical Science Liaison; Thierry Dervieux, PharmD, PhD, Chief Scientific Officer at Prometheus Laboratories In this episode of the PGX for Pharmacists Podcast, Dr. Thierry Dervieux, Dr. Behnaz Sarrami, and I discuss Dr. Dervieux's career as a PharmD, PhD, and chief scientific officer who has designed a pharmacogenomics test prescribers may use to optimize biosimilars for autoimmune gastrointestinal diseases. Dr. Dervieux will illustrate to our audience pharmacogenomics' potential beyond Tier 1 and 2 genetic testing by describing the clinical validity and utility of his laboratory's suite of tests in the autoimmune gastrointestinal disease diagnosis and treatment market. Behnaz and I hope this episode will inspire pharmacists interested in pharmacogenomics to think beyond the boxed PGx test most laboratories offer when they think about PGx and consider all the biological systems in which genetics impacts drugs' efficacy and safety. Disclaimer: Behnaz Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of Castle Biosciences, Inc. Becky Disclaimer: These are my personal views and opinions, and I am not speaking on behalf of any other entity.   Transcription: 1 00:00:06,190 --> 00:00:19,620 You're listening to the Pharmacy podcast Network in a world where one size fits all medications dominate the pharmaceutical industry. 2 00:00:20,079 --> 00:00:24,750 Precision medicine brings a ray of hope for those seeking customized health care. 3 00:00:25,350 --> 00:00:32,830 Pharmacists have a unique opportunity to help people in need of specialized testing to ensure medications work as intended. 4 00:00:33,540 --> 00:00:44,680 Welcome to PGX for pharmacists where we unravel the wonders of precision medicine and its potential to revolutionize the way we approach pharmacy care. 5 00:00:45,169 --> 00:00:52,790 Get ready to uncover the secrets behind pharmacogenomics and how it's transforming lives one genome at a time. 6 00:00:52,799 --> 00:00:53,189 Hello, 7 00:00:53,200 --> 00:00:53,950 everyone. 8 00:00:54,159 --> 00:00:55,080 I'm your host, 9 00:00:55,090 --> 00:00:56,389 Doctor Becky Winslow. 10 00:00:56,409 --> 00:01:09,860 And you're listening to the PGX for Pharmacist podcast that we magazine recognized in 2021 as the ninth most listened to genetics podcasts in the world on the PGX for Pharmacist podcast. 11 00:01:09,870 --> 00:01:16,690 We explore all things pharmacogenomics related and our mission is to educate and advocate for PGX. 12 00:01:16,769 --> 00:01:23,849 We accomplish this mission through exclusive interviews with highly qualified and well experienced pharmacogenomics. 13 00:01:23,860 --> 00:01:29,720 Industry leaders such as today's special guest and my name is Baas Sami, 14 00:01:29,730 --> 00:01:32,739 the co-host of PGX for Pharms podcast, 15 00:01:32,750 --> 00:01:33,860 Pharmacogenomics, 16 00:01:33,870 --> 00:01:36,819 medical science liaison and a mentor to pharmacist. 17 00:01:36,889 --> 00:01:40,239 Connect with us on linkedin and let's get a conversation going. 18 00:01:40,269 --> 00:01:46,720 We want to hear from you and how you're impacting pharmacogenomic stakeholders and what you have learned throughout your journey. 19 00:01:48,510 --> 00:01:49,010 Ok. 20 00:01:49,019 --> 00:01:50,819 So without any further ado, 21 00:01:50,839 --> 00:01:54,769 I'm extremely pleased to introduce to our audience. 22 00:01:54,919 --> 00:01:56,059 Doctor Theory Devo, 23 00:01:57,239 --> 00:02:01,129 the Chief Scientific Officer at Prometheus Laboratories, 24 00:02:01,139 --> 00:02:08,139 and Perme Prometheus Laboratories is a reference clinical laboratory that's focused on the diagnosis, 25 00:02:08,149 --> 00:02:13,330 prognosis and monitoring of immune mediated inflammatory diseases. 26 00:02:13,970 --> 00:02:14,229 So, 27 00:02:14,240 --> 00:02:14,649 thank you, 28 00:02:14,660 --> 00:02:17,759 Doctor De for joining us on the podcast. 29 00:02:17,770 --> 00:02:18,589 Today. 30 00:02:18,600 --> 00:02:23,190 I'm excited to share your and Prometheus's story with our audience. 31 00:02:23,649 --> 00:02:25,630 Um in particular, 32 00:02:25,639 --> 00:02:45,369 I'm excited about you sharing your career journey as a farm D phd and Chief scientific officer and designer of the Predictor PK AD A which is a precision guided dosing test for the optimization of Humira Remicade and their bio cylinders. 33 00:02:46,119 --> 00:02:46,449 So, 34 00:02:46,460 --> 00:03:04,220 one of Bana's and my main goals for this episode of the PGX for Pharmacist podcast is to expand our audience's notion of what a PGX test looks like and to inspire them to think bigger than the traditional box PGX test. 35 00:03:04,229 --> 00:03:08,020 Most of them or most of you are uh familiar with. 36 00:03:09,020 --> 00:03:09,429 So, 37 00:03:09,440 --> 00:03:22,179 Doctor D uh I'd like to start the podcast by having our guests um introduce themselves and elaborate on how you are a pharmacogenomics expert. 38 00:03:23,619 --> 00:03:23,800 Yeah, 39 00:03:23,809 --> 00:03:24,250 thank you, 40 00:03:24,259 --> 00:03:25,759 Becky for having me. 41 00:03:25,770 --> 00:03:26,850 Uh uh Yes. 42 00:03:26,860 --> 00:03:27,289 So I am a, 43 00:03:27,300 --> 00:03:30,820 I am a pharmacist uh with uh a family who is a, 44 00:03:30,830 --> 00:03:33,039 a doctorate in pharmacokinetics. 45 00:03:33,539 --> 00:03:44,520 Uh I completed my studies in France and I came as a postdoc uh fellow uh to work in the United States about 20 years ago to work on the pharmacogenomic of anti cancer agents, 46 00:03:44,929 --> 00:03:49,160 uh primarily uh six Maturin as well as methotrexate. 47 00:03:49,169 --> 00:03:50,550 After my post doc, 48 00:03:50,770 --> 00:03:52,960 uh I moved uh in industry for promet. 49 00:03:53,490 --> 00:04:01,429 So I have a large experience in uh uh the implementation of pharmacogenetics testing in immune mediated inflammatory disease. 50 00:04:01,509 --> 00:04:12,550 Our lab Rome was the first uh clinical laboratory in the United States to offer the fin uh metyl transfer genotyping as well as the thin metabolites. 51 00:04:12,559 --> 00:04:13,029 So, 52 00:04:13,050 --> 00:04:21,989 uh uh of uh of 70 publications in the field and uh I'm very uh very excited to have uh to be on the postcard with you uh uh today. 53 00:04:23,660 --> 00:04:24,220 All right. 54 00:04:24,230 --> 00:04:27,359 So thank you for qualifying yourself as an expert. 55 00:04:27,369 --> 00:04:27,619 So, 56 00:04:27,630 --> 00:04:32,839 let's jump right in and delve into your current PGX work. 57 00:04:32,850 --> 00:04:33,279 So, 58 00:04:33,489 --> 00:04:36,540 if you'll tell us um a little about Prometheus, 59 00:04:36,549 --> 00:04:38,000 specifically, 60 00:04:38,010 --> 00:04:40,350 what is Prometheus's mission? 61 00:04:40,359 --> 00:04:43,799 And how are you guys going about accomplishing your mission? 62 00:04:44,760 --> 00:04:44,980 Yeah, 63 00:04:44,989 --> 00:04:45,700 sure. 64 00:04:45,709 --> 00:04:47,459 Uh So Promet is a, 65 00:04:47,470 --> 00:04:52,790 is a reference uh clinical laboratory based in Southern California in San Diego. 66 00:04:53,230 --> 00:04:56,809 Uh The company has been there for uh over 25 years. 67 00:04:56,820 --> 00:05:03,950 We are uh specialize in the differential diagnosis of autoimmune G I disease uh disorders, 68 00:05:04,059 --> 00:05:06,019 uh gastrointestinal disorder, 69 00:05:06,230 --> 00:05:08,619 uh and inflammatory bowel disease. 70 00:05:08,980 --> 00:05:10,299 And over the years, 71 00:05:10,309 --> 00:05:16,600 we have developed a portfolio of a differentiated solution to facilitate the diagnosis, 72 00:05:16,609 --> 00:05:17,470 the prognosis, 73 00:05:17,480 --> 00:05:18,429 the monitoring, 74 00:05:18,660 --> 00:05:21,910 as well as therapy selection with pharmacogenetics testing, 75 00:05:21,920 --> 00:05:24,730 which we are offering to our clinical laboratory. 76 00:05:24,829 --> 00:05:26,350 And most importantly, 77 00:05:26,410 --> 00:05:27,299 uh recently, 78 00:05:27,309 --> 00:05:35,660 we are uh uh developing some uh uh testing solution with the credit topic care test to optimize treatment to uh biologics. 79 00:05:36,470 --> 00:05:37,130 Ok. 80 00:05:37,140 --> 00:05:37,329 Well, 81 00:05:37,339 --> 00:05:37,450 that, 82 00:05:37,459 --> 00:05:38,049 that's great. 83 00:05:38,059 --> 00:05:46,100 Can you also tell us uh about the Prois Library of Precision Medicine Tests for inflammatory bowel disease for patients? 84 00:05:46,109 --> 00:05:49,230 how they benefit medication therapy management. 85 00:05:49,239 --> 00:05:56,429 Stakeholders across the IB DS patients journey from diagnosis to treatment to disease, 86 00:05:56,440 --> 00:06:02,049 monitoring through remission and how they differ from other lab tests for IBD and his treatments. 87 00:06:02,709 --> 00:06:03,209 Yes. 88 00:06:03,220 --> 00:06:03,369 So, 89 00:06:03,380 --> 00:06:04,399 so we uh our, 90 00:06:04,410 --> 00:06:10,100 our clinical laboratory offers some uh highly specialized test to facilitate the, 91 00:06:10,109 --> 00:06:16,779 the diagnostic of uh to facilitate the differential diagnosis of uh uh inflammatory bowel disease. 92 00:06:16,790 --> 00:06:22,359 So we are following uh testing solution with uh serological testing, 93 00:06:22,529 --> 00:06:23,799 for example, 94 00:06:23,809 --> 00:06:38,410 uh uh piana as as as well as uh macro microbial uh uh antibodies that are present uh uh in Crohn's disease as well as uh over uh auto uh auto antibodies that are present in er colitis. 95 00:06:39,339 --> 00:06:43,684 These are conditions that are uh uh somewhat difficult to treat. 96 00:06:43,704 --> 00:06:49,994 Uh And uh we are uh uh offering those tests to uh help uh gastroenterologist. 97 00:06:50,015 --> 00:06:51,114 Uh uh first of all, 98 00:06:51,125 --> 00:07:03,434 to establish a differential diagnosis of IBD as compared to other uh condition typically uh uh irritable bowel syndrome as well as over gastrointestinal disorder. 99 00:07:03,445 --> 00:07:05,635 When the diagnostic is established, 100 00:07:05,910 --> 00:07:31,839 uh we offer uh testing to uh establish a prognosis where we're gonna in inform the clinician that the patient has a more aggressive uh disease that will require more aggressive treatment where uh we can uh provide the testing solution to initiate uh uh the most appropriate therapy for uh for the patient uh with uh a testing where we are uh basically uh you know, 101 00:07:31,850 --> 00:07:36,559 establish de determining some genotyping with the fit transferal genotyping. 102 00:07:36,570 --> 00:07:37,279 For example, 103 00:07:37,290 --> 00:07:40,250 where we can uh indicate that the patient is, 104 00:07:40,260 --> 00:07:45,079 is likely uh to present with a side effect to those medication. 105 00:07:45,399 --> 00:07:46,170 And once you know, 106 00:07:46,179 --> 00:07:47,799 the the treatment is initiative, 107 00:07:47,809 --> 00:08:16,089 we have a portfolio of solution uh to facilitate the monitoring of the disease of the inflammatory bowel disease as well as the dosing optimization with uh uh the answer test which uh measure blood level uh for uh uh monoclonal antibodies that are indicated in the treatment of IB start with starting with Infliximab Adalimumab as well as uh Tein and vidal. 108 00:08:16,980 --> 00:08:24,040 So we have a comprehensive portfolio to uh to surround the clinician with uh a variety of testing solution. 109 00:08:24,049 --> 00:08:30,250 With our goal being to improve the uh the outcome uh of patients with uh with diabetes. 110 00:08:30,260 --> 00:08:34,520 And I think that the pharmacist has a very important role to play from that perspective. 111 00:08:35,179 --> 00:08:36,039 So theory, 112 00:08:36,049 --> 00:08:40,239 could you elaborate for us more on the predictor test? 113 00:08:40,249 --> 00:08:42,758 Um especially since you designed that test, 114 00:08:42,768 --> 00:08:44,218 we'd really like to know, 115 00:08:44,489 --> 00:08:45,039 um you know, 116 00:08:45,049 --> 00:08:49,638 what did that take and what role does it play in your suite of testing? 117 00:08:51,049 --> 00:08:51,270 Yeah. 118 00:08:51,280 --> 00:08:51,890 Sure. 119 00:08:51,900 --> 00:08:52,510 So the, 120 00:08:52,520 --> 00:08:52,570 the, 121 00:08:52,580 --> 00:08:52,989 the, 122 00:08:53,000 --> 00:08:53,229 the, 123 00:08:53,239 --> 00:08:59,960 the predictor test is uh uh is uh is utilized when the patient is receiving treatment. 124 00:09:00,280 --> 00:09:18,190 It's been speci specifically designed to optimize uh biological uh uh disease modifiers such as Infliximab adalimumab that are co therapies in the treatment of inflammatory bowel disease as well as other immune uh mediated inflammatory. 125 00:09:18,200 --> 00:09:21,549 This is what the test does is to you connect the blood specimen, 126 00:09:22,229 --> 00:09:23,049 uh you know, 127 00:09:23,059 --> 00:09:24,750 with dosing information. 128 00:09:25,039 --> 00:09:41,989 And what we do is to uh uh provide guidance uh to clinician with uh respect of the best dose to give in order to achieve the best the level which is the most consistent with uh uh the disease control that needs to be achieved for the patient. 129 00:09:42,169 --> 00:09:43,729 Typically a vast majority, 130 00:09:43,739 --> 00:09:46,159 about two third of a third to two third, 131 00:09:46,169 --> 00:09:54,669 a third of patient uh tend to be uh uh unresponsive uh to this uh very expensive medication. 132 00:09:54,989 --> 00:09:57,960 Uh Not because they don't have the uh you know, 133 00:09:57,969 --> 00:09:59,289 typically because they have a, 134 00:09:59,299 --> 00:09:59,590 you know, 135 00:09:59,599 --> 00:10:05,599 pharmacokinetic uh suboptimal pharmacokinetic uh that makes them uh you know, 136 00:10:05,609 --> 00:10:09,440 unresponsive because uh not enough drug has been given. 137 00:10:09,450 --> 00:10:18,469 So what we do with a predictor test is to basically estimate the pa the pharmacokinetic uh parameter for the patient. 138 00:10:18,750 --> 00:10:24,729 And from then uh re report the best dose uh to give in order to achieve the, 139 00:10:24,760 --> 00:10:31,570 the level which is consistent with the uh the most uh uh effective disease control to be achieved for the patient. 140 00:10:32,169 --> 00:10:33,059 So we are offering, 141 00:10:33,070 --> 00:10:38,049 we have developed a test for the Infliximab as well as Adalimumab which is Humira, 142 00:10:38,909 --> 00:10:41,309 but these are antimony causes factor. 143 00:10:41,460 --> 00:10:49,549 And we are also developing the test for vidur as well as uh is that are widely used also in the treatment of, 144 00:10:49,559 --> 00:10:51,969 of uh inflammatory bubble disease. 145 00:10:51,979 --> 00:10:52,669 Wow, 146 00:10:52,679 --> 00:10:55,450 uh for MET is a suite of tests. 147 00:10:55,460 --> 00:11:00,940 Goes well beyond um the PGX testing that our audience is most familiar with, 148 00:11:01,299 --> 00:11:08,679 uh which typically only includes snips for cyp genes and some pharmacodynamic genes. 149 00:11:08,690 --> 00:11:31,424 This is really exciting um genes and biomarkers related to immunology are not commonly found in what I call the box PGX tests such as those uh made by large uh laboratory manufacturing companies um where the panel has a set number of genes and uh you know, 150 00:11:31,434 --> 00:11:36,054 it was developed by a larger laboratory for maybe smaller laboratories use. 151 00:11:36,729 --> 00:11:39,010 So my understanding, 152 00:11:39,020 --> 00:11:53,729 having talked with you extensively theory is that immunology has fewer PGX test available because it's actually more difficult say than oncology to research and develop tests. 153 00:11:53,739 --> 00:11:54,119 So, 154 00:11:54,130 --> 00:12:00,729 could you elaborate for our audience on the difficulties that are associated with immunology, 155 00:12:00,739 --> 00:12:05,830 research and developing tests uh for immunology versus say oncology? 156 00:12:06,330 --> 00:12:06,530 Yeah, 157 00:12:06,539 --> 00:12:07,049 sure. 158 00:12:07,059 --> 00:12:09,969 So in uh in immunology, 159 00:12:09,979 --> 00:12:11,590 as compared to oncology, 160 00:12:11,599 --> 00:12:17,169 there is no such a thing such as a somatic mutation where for example, 161 00:12:17,179 --> 00:12:18,429 you're gonna have a behalf, 162 00:12:18,440 --> 00:12:18,659 you know, 163 00:12:18,669 --> 00:12:20,349 that indicates that the patient, 164 00:12:20,679 --> 00:12:20,919 you know, 165 00:12:20,929 --> 00:12:25,239 is likely to benefit or not from some treatment in immunology. 166 00:12:25,250 --> 00:12:26,750 This is far more complicated, 167 00:12:26,760 --> 00:12:28,830 complicated for the reason, 168 00:12:29,239 --> 00:12:31,020 starting with uh the fact that, 169 00:12:31,030 --> 00:12:31,179 you know, 170 00:12:31,190 --> 00:12:36,219 the response to this uh medication uh are multifactorial. 171 00:12:36,260 --> 00:12:37,820 And the fact that uh you know, 172 00:12:37,830 --> 00:12:39,380 the mutation that uh the, 173 00:12:39,390 --> 00:12:39,619 the, 174 00:12:39,630 --> 00:12:45,190 the single nucleotide polymorphism in the GM line which uh uh you know, 175 00:12:45,200 --> 00:12:52,429 can potentially associate with uh with outcome uh uh uh uh a lo in advance, 176 00:12:52,440 --> 00:12:58,359 meaning that uh they're gonna have a weak association uh with a response to those medications. 177 00:12:58,369 --> 00:13:09,609 So there is a necessity in immunology to combine multiple genetic polymorphism together in order to achieve uh some uh performances characteristics that will make uh you know, 178 00:13:09,619 --> 00:13:09,859 the, 179 00:13:09,869 --> 00:13:10,380 the, 180 00:13:10,390 --> 00:13:10,520 the, 181 00:13:10,530 --> 00:13:13,219 the clinician uh you know, 182 00:13:13,419 --> 00:13:15,619 uh order the test and most importantly, 183 00:13:15,630 --> 00:13:15,840 the, 184 00:13:15,849 --> 00:13:16,179 the, 185 00:13:16,190 --> 00:13:17,739 the payer to pay for the test. 186 00:13:17,750 --> 00:13:20,469 So this field has been uh you know, 187 00:13:20,479 --> 00:13:20,679 is, 188 00:13:20,690 --> 00:13:21,705 is moving for, 189 00:13:21,715 --> 00:13:21,994 you know, 190 00:13:22,005 --> 00:13:24,575 there are some tests that are being developed right now. 191 00:13:24,924 --> 00:13:39,034 But the biggest challenge is to be able to achieve again the the threshold of uh of performance that makes the test is variable enough uh to be uh again ordered by the clinician and the utilize uh to the benefit of the patient. 192 00:13:39,659 --> 00:13:41,200 I couldn't agree with you more. 193 00:13:41,210 --> 00:13:53,489 Um I've worked on the payer side or market access side of pharmacogenomics and even uh with a box test for which there's um a lot of research data available, 194 00:13:53,500 --> 00:13:55,119 even with those, 195 00:13:55,130 --> 00:13:59,760 it's sometimes difficult uh to get payers um to see the value. 196 00:13:59,770 --> 00:14:01,640 So I absolutely agree with you. 197 00:14:01,940 --> 00:14:03,679 Um The fact that you guys are, 198 00:14:03,690 --> 00:14:11,789 are uh investing in producing the data necessary says a lot about your laboratory. 199 00:14:11,979 --> 00:14:12,559 Um you know, 200 00:14:12,570 --> 00:14:15,380 and how committed you are to this testing and, 201 00:14:15,390 --> 00:14:17,320 and how you believe in the testing. 202 00:14:18,039 --> 00:14:23,640 So I just want to make sure that our audience recognizes that, 203 00:14:24,359 --> 00:14:24,619 you know, 204 00:14:24,630 --> 00:14:31,820 Prometheus doesn't simply provide tests to determine if drugs for IBD will be effective and safe. 205 00:14:32,190 --> 00:14:36,900 Um And maybe what the dose of the drug should be for the patient, 206 00:14:36,909 --> 00:14:40,219 but you have that whole suite of tests. 207 00:14:40,229 --> 00:14:47,380 Um the diagnostic test for the differential diagnosis all the way through remission. 208 00:14:48,030 --> 00:14:53,390 So can you elaborate you elaborated on it some in the previous question? 209 00:14:53,400 --> 00:15:01,229 But um can you tell us the difference between how you had to actually develop the test? 210 00:15:01,520 --> 00:15:02,530 Um You didn't, 211 00:15:02,539 --> 00:15:03,059 in other words, 212 00:15:03,070 --> 00:15:10,659 purchase a test from another manufacturer with the biomarkers that you include in your testing. 213 00:15:10,669 --> 00:15:16,830 Can you elaborate on how much more difficult it is to to develop a test from scratch? 214 00:15:18,169 --> 00:15:18,320 Yeah, 215 00:15:18,330 --> 00:15:18,659 sure. 216 00:15:18,669 --> 00:15:18,809 I mean, 217 00:15:18,820 --> 00:15:22,070 this is this is challenging for multiple and first of all, 218 00:15:22,080 --> 00:15:23,130 you need to have the, 219 00:15:23,419 --> 00:15:27,450 you need to have a clinical data set available with specimen available. 220 00:15:27,460 --> 00:15:28,159 Uh you know, 221 00:15:28,169 --> 00:15:28,780 in front, 222 00:15:28,859 --> 00:15:29,770 obviously, 223 00:15:29,859 --> 00:15:30,890 available. 224 00:15:31,200 --> 00:15:35,890 Uh So we are leveraging a pro meters a large bi bank of specimen. 225 00:15:36,299 --> 00:15:37,190 Uh as I said, 226 00:15:37,200 --> 00:15:39,719 Prometheus has been founded 25 years ago. 227 00:15:39,729 --> 00:15:40,599 So over the, 228 00:15:40,760 --> 00:15:41,919 the past two decades, 229 00:15:41,929 --> 00:15:54,849 we have been able to assemble a large uh substrate of data and specimen which we are uh uh using to uh uh establish our proof of concept if you will. 230 00:15:54,859 --> 00:16:07,559 And then when we have uh identify some genetic polymorphism that are uh adequately uh associated with uh uh disease outcome and disease progression as well as uh toxicity. 231 00:16:07,969 --> 00:16:11,469 Then we are entering validation phase where we are uh you know, 232 00:16:11,570 --> 00:16:14,789 using validation cohorts where we are again, 233 00:16:14,969 --> 00:16:22,630 combining multiple modalities together uh patient demographic as well as genetic marker together with theological marker. 234 00:16:22,640 --> 00:16:23,190 Actually, 235 00:16:23,500 --> 00:16:27,419 to come up with some Multivariate models that are uh again, 236 00:16:27,429 --> 00:16:39,250 bringing the performances characteristics of the pharmacogenomic test or its combination with our marker to the level where it's supposed to be in the first place to meet uh uh payer. 237 00:16:39,650 --> 00:16:41,190 And uh obviously, 238 00:16:41,200 --> 00:16:41,760 again, 239 00:16:41,770 --> 00:16:45,320 the patient uh to the benefit of the patient and to, 240 00:16:45,330 --> 00:16:46,619 to improve its outcome, 241 00:16:46,739 --> 00:16:47,429 the outcome. 242 00:16:48,340 --> 00:16:53,380 I think what you're describing really is the future of pharmacogenomics. 243 00:16:53,390 --> 00:16:54,599 Um In other words, 244 00:16:54,609 --> 00:17:03,419 not singing out pharmacogenomics as you know the end all and be all in the treatment paradigm. 245 00:17:03,559 --> 00:17:08,040 But using a PGX test in combination with, 246 00:17:08,050 --> 00:17:09,069 like you mentioned, 247 00:17:09,250 --> 00:17:11,160 other serological tests, 248 00:17:11,170 --> 00:17:12,959 maybe other genetic tests. 249 00:17:13,290 --> 00:17:14,890 Um But you know, 250 00:17:14,900 --> 00:17:25,869 I think what we want our audience to really wrap their heads around is that PGX is just a piece of that larger puzzle um from diagnosis to treatment to, 251 00:17:25,880 --> 00:17:26,910 to remission. 252 00:17:27,239 --> 00:17:29,880 So I think you guys are absolutely, 253 00:17:29,890 --> 00:17:31,579 you're already in the future. 254 00:17:31,589 --> 00:17:32,849 In other words, 255 00:17:32,859 --> 00:17:33,130 you know, 256 00:17:33,140 --> 00:17:39,689 you're already providing all these different uh tests um like you mentioned to, 257 00:17:39,699 --> 00:17:44,310 to facilitate from diagnosis to remission to remission. 258 00:17:44,660 --> 00:17:45,520 That's correct. 259 00:17:45,530 --> 00:17:45,829 Yeah. 260 00:17:46,349 --> 00:17:55,089 So um you've given us so much great information about uh the tests that that you guys offer. 261 00:17:55,329 --> 00:18:02,060 Can you explain to our audience um your newest test? 262 00:18:02,069 --> 00:18:03,859 Uh the responder test. 263 00:18:04,150 --> 00:18:12,979 And um what role it will play in the paradigm from the diagnosis of IBD to remission? 264 00:18:14,050 --> 00:18:14,260 Yeah, 265 00:18:14,270 --> 00:18:14,760 sure. 266 00:18:14,770 --> 00:18:15,569 So we, 267 00:18:15,579 --> 00:18:18,069 we are doing things a little bit different than other. 268 00:18:18,079 --> 00:18:19,489 We do believe that uh you know, 269 00:18:19,500 --> 00:18:21,449 the it has to be simple. 270 00:18:21,459 --> 00:18:24,189 Uh uh We can obviously construct some very, 271 00:18:24,199 --> 00:18:33,530 very complex algorithm and there are some tests that do that with a very sophisticated machine learning based tools that are available using neural networks, 272 00:18:33,540 --> 00:18:33,729 you know, 273 00:18:33,739 --> 00:18:34,790 those sorts of things. 274 00:18:34,800 --> 00:18:39,729 But we have taken on a different approach where with the responder test, 275 00:18:39,739 --> 00:18:40,329 we are basically, 276 00:18:40,339 --> 00:18:45,160 we are taking an approach which is very simple to address the first and foremost. 277 00:18:45,170 --> 00:18:53,020 Most important aspect of responding uh predicting response to uh to medication is the pharmacokinetics. 278 00:18:53,280 --> 00:19:03,250 Uh You cannot be responding to a drug if the drug is not given and you obviously cannot respond to a drug if the drug is not metabolized adequately. 279 00:19:03,359 --> 00:19:06,349 And this is what we are doing with the responder test. 280 00:19:06,579 --> 00:19:09,010 We are addressing some uh uh you know, 281 00:19:09,020 --> 00:19:11,630 fundamental issues with those uh biologist, 282 00:19:11,640 --> 00:19:12,410 for example, 283 00:19:12,660 --> 00:19:15,170 uh the anti tumor necrosis factors. 284 00:19:15,180 --> 00:19:15,650 So, 285 00:19:15,750 --> 00:19:19,199 such as uh Infliximab and Adalimumab, 286 00:19:19,209 --> 00:19:23,050 it is well known uh that uh uh those drugs, 287 00:19:23,060 --> 00:19:25,689 first of all are prone to immunization. 288 00:19:25,989 --> 00:19:36,949 Uh Meaning that uh uh the drug itself uh is recognized by the immune system uh and digested by the antigen presenting cells. 289 00:19:36,959 --> 00:19:42,209 If you will uh where you gonna have uh uh an immune uh uh response, 290 00:19:42,380 --> 00:19:56,979 uh mounted a cancer drug to produce uh immunogen that will severely impact its pharmacokinetics where the labels will be inadequate to produce uh the desired uh anti-inflammatory effects. 291 00:19:56,989 --> 00:19:57,150 So, 292 00:19:57,160 --> 00:19:58,890 we are with the risk conductors, 293 00:19:58,900 --> 00:20:01,040 we are combining two things together. 294 00:20:01,189 --> 00:20:07,959 First of all is the genetic test itself which uh predicts the risk of immun immunization. 295 00:20:07,969 --> 00:20:18,010 The name of the test is on HL A uh DQ A 105 ali uh that uh uh promotes the presentation of the, 296 00:20:18,020 --> 00:20:19,130 of the, 297 00:20:19,140 --> 00:20:19,910 of Infliximab, 298 00:20:20,010 --> 00:20:20,750 for example, 299 00:20:20,760 --> 00:20:32,130 to the T cell repertoire in order to uh promote the Ronon expansion and the formation of the anti antibodies together with uh another dimension which is the clearance, 300 00:20:32,140 --> 00:20:33,670 which is as important. 301 00:20:33,949 --> 00:20:36,209 Uh One of the key issue is the, 302 00:20:36,219 --> 00:20:36,770 the, 303 00:20:36,780 --> 00:20:41,239 the monoclonal antibodies and uh such as Infliximab or Adalimumab. 304 00:20:41,329 --> 00:20:42,280 But in fact, 305 00:20:42,290 --> 00:20:45,890 a neon antibodies that those drugs are uh you know, 306 00:20:45,900 --> 00:20:49,010 cleared and consumed uh from the, 307 00:20:49,020 --> 00:20:50,949 from the central compartment if you will, 308 00:20:50,959 --> 00:20:54,520 since we are doing a little bit of uh uh pharmacokinetics here. 309 00:20:54,530 --> 00:20:56,020 And uh uh you know, 310 00:20:56,030 --> 00:21:06,670 if the patient present who is uh a high degree of inflammatory burden is gonna have uh the patient will have a high clearance and that's gonna worsen uh in the, 311 00:21:06,680 --> 00:21:13,939 in the presence again of the HL AD Q A 105 genetic marker that uh associate with uh immunization. 312 00:21:13,949 --> 00:21:16,859 So I but this is a combination of both, 313 00:21:17,199 --> 00:21:19,359 these are the predictive factors of pharmacokinetic, 314 00:21:20,359 --> 00:21:38,209 which we combine together where the patient presenting with a risk of immunization as well as accelerated clearance due to the fact that the patient has high inflammation or due to the fact that they are so intrinsic pharmacokinetic properties that makes that the patient, 315 00:21:38,219 --> 00:21:38,300 you know, 316 00:21:38,310 --> 00:21:39,479 will clear the drug very, 317 00:21:39,489 --> 00:21:40,260 very fast. 318 00:21:40,560 --> 00:21:41,670 For example, 319 00:21:41,680 --> 00:21:46,819 due to the inefficient uh recirculation of the drug itself with the new, 320 00:21:46,869 --> 00:21:46,930 the, 321 00:21:46,939 --> 00:21:50,599 the the in the reticular on the system. 322 00:21:50,920 --> 00:21:51,619 Together, 323 00:21:51,630 --> 00:22:02,109 those patients presenting with uh uh together these uh poor prognostic factor of pharmacokinetic origin will tend to be severely underdose, 324 00:22:02,380 --> 00:22:06,719 will not be responding to the drug uh adequately as and they, 325 00:22:06,729 --> 00:22:10,719 and they probably should in the first place if you are able to address uh you know, 326 00:22:10,729 --> 00:22:12,270 the the the exposure. 327 00:22:12,439 --> 00:22:14,079 So what we do with this test, 328 00:22:14,089 --> 00:22:21,640 we will be able to inform uh the clinic that the patient is at risk of achieving, 329 00:22:21,650 --> 00:22:30,829 of achieving suboptimal pharmacokinetics and therefore being able to adjust the dose uh uh to start with more adequately. 330 00:22:30,839 --> 00:22:38,650 So that the the the proper uh exposure is achieved uh during induction to again to, 331 00:22:38,660 --> 00:22:39,040 to, 332 00:22:39,050 --> 00:22:39,380 to, 333 00:22:39,390 --> 00:22:40,890 to achieve a better outcome. 334 00:22:41,040 --> 00:22:47,270 And I think the pharmacist will have a very important role to play here in terms of absolutely, 335 00:22:47,280 --> 00:22:51,239 that information is priceless in the management of these medications. 336 00:22:51,250 --> 00:22:54,930 So thanks for elaborating on that. 337 00:22:56,010 --> 00:22:59,040 And if I may add in our previous conversation, 338 00:22:59,050 --> 00:23:00,810 uh before the recording of podcast, 339 00:23:00,819 --> 00:23:08,869 we had discussed um you guys' robust platform for collaborating with payers to obtain market access and reimbursements for the test. 340 00:23:09,109 --> 00:23:14,109 But without stealing the Thunder from uh Prometheus market access and reimbursement team, 341 00:23:14,199 --> 00:23:22,619 can you please uh briefly detail how Prometheus has proactively worked with payers to solve the problem. 342 00:23:22,920 --> 00:23:27,349 Um the population health problem by building the evidence payers want, 343 00:23:27,359 --> 00:23:41,170 want to see um about your test before you go to the market and then build the test and then hope the payers will see the value and the result and then that will improve the market access and reimbursement for your um precision medicine test. 344 00:23:42,160 --> 00:23:42,339 Yeah. 345 00:23:42,349 --> 00:23:43,180 So briefly I can, 346 00:23:43,189 --> 00:23:43,579 I'm, 347 00:23:43,589 --> 00:23:46,619 I'm probably not the right person to answer that question. 348 00:23:46,630 --> 00:23:47,369 We have a very, 349 00:23:47,380 --> 00:23:52,400 very efficient market access group uh uh pro meters that does a splendid job. 350 00:23:52,410 --> 00:23:59,780 But uh uh uh what I can tell you that we have an evidence uh uh development plan in place where we, 351 00:23:59,790 --> 00:24:14,000 we are establishing the clinical utility of our testing solution by demonstrating uh the payer value uh with respect of uh patient management and uh uh and the, 352 00:24:14,010 --> 00:24:16,630 and the impact of our technology on the, 353 00:24:16,640 --> 00:24:18,119 on physician behavior. 354 00:24:18,430 --> 00:24:21,319 Uh We have uh uh already uh you know, 355 00:24:21,329 --> 00:24:25,160 commercialized uh two of those tests for which we have initiated, 356 00:24:25,170 --> 00:24:29,040 initiated the Power studies uh that uh uh you know, 357 00:24:29,050 --> 00:24:32,000 already provide uh you know, 358 00:24:32,104 --> 00:24:34,484 differentiated and the value to, 359 00:24:34,494 --> 00:24:35,915 to the payer where we are, 360 00:24:35,925 --> 00:24:36,025 the, 361 00:24:36,035 --> 00:24:46,005 the clinicians are basically using our technology to make treatment decision uh as well as uh some prospective clinicality study which we are initiating, 362 00:24:46,145 --> 00:24:47,555 initiating to. 363 00:24:47,564 --> 00:24:48,574 Um uh again, 364 00:24:48,584 --> 00:24:49,425 demonstrate the, 365 00:24:49,435 --> 00:24:49,915 the, 366 00:24:49,925 --> 00:24:50,244 the, 367 00:24:50,255 --> 00:24:53,594 the payer value you uh uh we can certainly follow up with, 368 00:24:53,604 --> 00:24:58,755 uh you can certainly follow up with our market access group uh uh as appropriate there. 369 00:24:58,765 --> 00:25:00,765 Uh They can fill you with more information. 370 00:25:01,349 --> 00:25:01,589 No, 371 00:25:01,599 --> 00:25:02,520 that totally makes sense. 372 00:25:02,530 --> 00:25:03,310 That totally makes sense. 373 00:25:03,319 --> 00:25:10,890 But um we're excited that you're also farm d So how did you get to this role of outside the box path? 374 00:25:10,900 --> 00:25:11,550 There? 375 00:25:11,640 --> 00:25:17,530 There may be a pharmacist student or pharmacist wanting to switch or transition into a role such as yours, 376 00:25:17,540 --> 00:25:19,609 which is a Chief Scientific Officer. 377 00:25:19,619 --> 00:25:20,609 I want to learn more. 378 00:25:20,619 --> 00:25:23,920 So how would you um can you talk a little bit about that? 379 00:25:24,560 --> 00:25:24,780 Well, 380 00:25:24,790 --> 00:25:26,270 we are clinical laboratories. 381 00:25:26,280 --> 00:25:29,400 So in order to uh uh to be in my role, 382 00:25:29,410 --> 00:25:34,020 you need to have uh uh you need to have expertise in clinical laboratory science. 383 00:25:34,030 --> 00:25:36,140 So for the students is basically, 384 00:25:36,150 --> 00:25:36,300 you know, 385 00:25:36,310 --> 00:25:40,770 to do the family degree and then complete the family degree with uh a doctorate, 386 00:25:40,780 --> 00:25:40,930 you know, 387 00:25:40,939 --> 00:25:44,260 which is uh focus on clinical laboratory science. 388 00:25:44,270 --> 00:25:46,079 So you can achieve uh uh you know, 389 00:25:46,089 --> 00:25:47,640 the all the elements you need to be, 390 00:25:47,650 --> 00:25:48,219 for example, 391 00:25:48,229 --> 00:25:53,189 board certified uh as uh as as medical laboratory director. 392 00:25:53,199 --> 00:25:55,160 So you can uh uh so, 393 00:25:55,170 --> 00:25:55,589 uh yeah, 394 00:25:55,599 --> 00:25:56,030 this is, 395 00:25:56,040 --> 00:25:56,400 this is, 396 00:25:56,410 --> 00:25:57,209 this is uh you know, 397 00:25:57,219 --> 00:25:59,160 a great opportunity I think for pharmacies, 398 00:25:59,170 --> 00:26:10,800 there is an absolute need to uh have the clinical pharmacist provide uh uh drug information to healthcare professional as well as uh assist patient with the monitoring of their disease, 399 00:26:10,810 --> 00:26:15,229 the effectiveness of the therapy and um and uh you know, 400 00:26:15,239 --> 00:26:16,060 monitoring the, 401 00:26:16,069 --> 00:26:20,969 the side effect and the toxicity from uh from those uh those medication. 402 00:26:24,650 --> 00:26:24,959 Well, 403 00:26:24,969 --> 00:26:32,119 the I know our audience is going to have uh additional questions for you. 404 00:26:32,130 --> 00:26:32,540 I mean, 405 00:26:32,989 --> 00:26:35,609 you've provided them with so much great information, 406 00:26:35,619 --> 00:26:44,959 but it's only the beginning of what they could possibly learn um about um the testing that you do for IBD and, 407 00:26:44,969 --> 00:26:46,729 and even your career path. 408 00:26:47,050 --> 00:26:47,530 So, 409 00:26:47,540 --> 00:26:49,300 if you wouldn't mind telling us, 410 00:26:49,310 --> 00:26:51,359 um because we have to wrap up, 411 00:26:51,369 --> 00:26:52,670 unfortunately, 412 00:26:53,150 --> 00:26:55,810 this episode of the podcast, 413 00:26:55,819 --> 00:27:00,250 uh could you tell us how our audience members might be able to contact you directly. 414 00:27:01,260 --> 00:27:01,449 Yeah, 415 00:27:01,459 --> 00:27:07,079 I can be contacted on my uh on my email at TT W at como slab dot com. 416 00:27:07,949 --> 00:27:08,810 All right. 417 00:27:09,069 --> 00:27:09,300 Well, 418 00:27:09,310 --> 00:27:14,290 thank you again so much uh for joining us on this episode. 419 00:27:14,300 --> 00:27:15,290 We really, 420 00:27:15,300 --> 00:27:29,530 really hope that our listeners um ideas of not only what PGX can be but how PGX can be utilized in a comprehensive testing suite. 421 00:27:29,709 --> 00:27:35,670 We really hope that our a our audience will um listen in and learn this information. 422 00:27:36,280 --> 00:27:37,869 Um And to our audience, 423 00:27:37,880 --> 00:27:39,439 thank you for tuning in. 424 00:27:39,449 --> 00:27:42,619 We really hope that you've learned from this episode. 425 00:27:43,130 --> 00:27:46,339 Uh We do a whole lot of PG Xing here on this podcast. 426 00:27:46,349 --> 00:27:48,380 We talk about PGX Science, 427 00:27:48,390 --> 00:27:52,030 clinical application and the business of PGX. 428 00:27:52,260 --> 00:27:54,880 So we'd love to hear about from you. 429 00:27:55,099 --> 00:27:56,479 I love to hear from you. 430 00:27:56,489 --> 00:27:58,439 Um What can we teach you? 431 00:27:58,449 --> 00:28:00,920 What more can we teach you through our podcast? 432 00:28:00,930 --> 00:28:12,349 So please drop us a message on linkedin and let us know and please share this link to this podcast link episode with everyone so they can tune in and listen to the PGX for promises podcast. 433 00:28:12,520 --> 00:28:15,369 Leave us a review on Apple podcast or Spotify. 434 00:28:15,459 --> 00:28:18,130 And you can also visit us on PGX four, 435 00:28:18,140 --> 00:28:22,989 the number four Rx dot com to listen to all our other episodes. 436 00:28:23,000 --> 00:28:23,079 Well, 437 00:28:23,089 --> 00:28:23,790 thank you. 438 00:28:24,199 --> 00:28:28,750 Thanks for your interest in PGX and for spending some time with us. 439 00:28:28,760 --> 00:28:35,670 Please share this podcast and leave us a review on Apple podcasts or Spotify for all of our episodes. 440 00:28:35,680 --> 00:28:39,390 Please visit PGX four Rx dot com. 441 00:28:39,569 --> 00:28:43,380 That's PGX four Rx dot com.  

BUFFALO, NY- October 16, 2023 – A new research paper was published on the cover of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 15, Issue 19, entitled, “BMAL1 modulates senescence programming via AP-1.” Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are coordinately regulated has not been thoroughly studied. In this new study, researchers Sarah K. Jachim, Jian Zhong, Tamas Ordog, Jeong-Heon Lee, Aditya V. Bhagwate, Nagaswaroop Kengunte Nagaraj, Jennifer J. Westendorf, João F. Passos, Aleksey V. Matveyenko, and Nathan K. LeBrasseur from the Mayo Clinic in Rochester, Minnesota, hypothesized that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program. “Here, we demonstrate BMAL1 is significantly upregulated in senescent cells and has altered rhythmicity compared to non-senescent cells.” Through BMAL1-ChIP-seq, they showed that BMAL1 is uniquely localized to genomic motifs associated with AP-1 in senescent cells. Integration of BMAL1-ChIP-seq data with RNA-seq data revealed that BMAL1 presence at AP-1 motifs is associated with active transcription. Finally, the researchers showed that BMAL1 contributes to AP-1 transcriptional control of key features of the senescence program, including altered regulation of cell survival pathways, and confers resistance to drug-induced apoptosis. “Overall, these results highlight a previously unappreciated role of the core circadian clock component BMAL1 on the molecular phenotype of senescent cells.” DOI - https://doi.org/10.18632/aging.205112 Corresponding authors - Nathan K. LeBrasseur - lebrasseur.nathan@mayo.edu Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205112 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, AP-1, circadian clock, cellular senescence, senolytic, transcription regulation About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Ryley Hill, San Diego State University Both natural and anthropogenic hydrologic loads have been associated with stimulating seismicity. However, there are few documented examples that hydrologic loads can trigger large earthquakes. The southern San Andreas Fault (SSAF) in Southern California lies next to the Salton Sea, a successor of ancient Lake Cahuilla that periodically filled and desiccated over the past millennium. Here we use new geologic and paleoseismic data to demonstrate that the past six major earthquakes on the SSAF likely occurred during highstands of Lake Cahuilla. To investigate possible causal relationships, we computed time-dependent Coulomb stress changes produced by lake level fluctuations over the last ~1100 years. Using a fully coupled model of a poroelastic crust overlying a viscoelastic mantle, we find that hydrologic loads increased Coulomb stress on the SSAF by several hundred kilopascals and fault-stressing rates by more than a factor of 2, likely sufficient for triggering. Stress perturbations are dominated by pore pressure changes, but are enhanced by the poroelastic “memory" effect whereby increases in pore pressure due to previous lake high stands do not completely vanish by diffusion and constructively interfere with the undrained response in subsequent high stands. The destabilizing effects of lake inundation are enhanced by a nonvertical fault dip, the presence of a fault damage zone, and lateral pore pressure diffusion. Our model provides physical insights into relations between lake level and time-dependent seismic hazard, and may be applicable to other regions with hydrologic loading from either natural or anthropogenic sources.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.31.551234v1?rss=1 Authors: Kern, S., Nagel, J., Gerchen, M. F., Gürsoy, C., Meyer-Lindenberg, A., Kirsch, P., Dolan, R. J., Gais, S., Feld, G. B. Abstract: Declarative memory retrieval is thought to involve reinstatement of the neuronal activity patterns elicited and encoded during a prior learning episode. Recently, it has been suggested that two mechanisms operate during reinstatement, dependent on task demands: individual memory items can be reactivated simultaneously as a clustered occurrence or, alternatively, replayed sequentially as temporally separate instances. In the current study, participants learned associations between images that were embedded in a directed graph network and retained over a brief 8-minute consoli-dation period. During a subsequent cued recall session, participants retrieved the learned infor-mation while undergoing magnetoencephalographic (MEG) recording. Using a trained stimulus de-coder, we found evidence for clustered reactivation of learned material. Reactivation strength of individual items during clustered reactivation decreased as a function of increasing graph distance, an ordering present solely for successful retrieval but not with retrieval failure. In line with previous research, we found evidence that sequential replay was dependent on retrieval performance and limited to low performers. The results provide further evidence for the existence of different perfor-mance-dependent retrieval mechanisms suggesting graded clustered reactivation as a plausible mechanism to search within abstract cognitive maps. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546615v1?rss=1 Authors: Tang, D.-l., Parrell, B., Beach, S., Niziolek, C. Abstract: When individuals make a movement that produces an unexpected outcome, they learn from the resulting error. This process, essential in both acquiring new motor skills and adapting to changing environments, critically relies on error sensitivity, which governs how much behavioral change results from a given error. Although behavioral and computational evidence suggests error sensitivity can change in response to task demands, neural evidence regarding the flexibility of error sensitivity in the human brain is lacking. Critically, the sensitivity of the nervous system to auditory errors during speech production, a complex and well-practiced motor behavior, has been extensively studied by examining the prediction-driven suppression of auditory cortical activity. Here, we tested whether the nervous system's sensitivity to errors, as measured by this suppression, can be modulated by altering speakers' perceived variability. Our results showed that error sensitivity was increased after exposure to an auditory perturbation that increased participants' perceived variability, consistent with predictions generated from previous behavioral data and state-space modeling. Conversely, we observed no significant changes in error sensitivity when perceived variability was unaltered or artificially reduced. The current study establishes the validity of behaviorally modulating the nervous system's sensitivity to errors. As sensitivity to sensory errors plays a critical role in sensorimotor adaptation, modifying error sensitivity has the potential to enhance motor learning and rehabilitation in speech and, potentially, more broadly across motor domains. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.15.537013v1?rss=1 Authors: O'Leary, J. D., Bruckner, R., Autore, L., Ryan, T. J. Abstract: Memories are stored as ensembles of engram neurons and their successful recall involves the reactivation of these cellular networks. While progress has been made in understanding the biology of engrams, significant gaps remain in connecting these cell ensembles with the process of forgetting. Here, we examine whether forgetting is governed by changes in engram plasticity and suggest that it helps animals prioritize relevant memory representations for adaptive behavior. We utilized a mouse model of object memory and investigated the conditions in which a memory could be preserved, retrieved, or forgotten. The results indicate that engram activity correlated with the rate of forgetting. Direct modulation of engram activity via optogenetic stimulation or inhibition either facilitated or prevented the recall of an object memory. In addition, the modulation of engram activity was able to prevent forgetting itself. Moreover, through pharmacological and behavioral interventions, we successfully prevented or accelerated forgetting of an object memory. Finally, we show that these results can be explained by a computational model in which engrams that are subjectively less relevant for adaptive behavior are more likely to be forgotten. Together, these findings suggest that forgetting is an adaptive form of engram plasticity that involves circuit remodeling, which allows engrams to switch from an accessible state to an inaccessible state. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.07.535979v1?rss=1 Authors: Chowdhury, D., Dhabal, S., Bhatt, M., Maity, D., Chakraborty, S., Priyadarshi, S., Haldar, S. Abstract: Methotrexate is a well-known antineoplastic drug used to prevent cancer aggravation. Despite being a targeted therapeutic approach, its administration comes with the risk of cancer recurrence, plausibly through its proven off-target effect on focal adhesions. Since FA dynamics is dependent on force transmission through its constituent proteins, including talin, methotrexate might affect the mechanical activity of these proteins. Here we have combined single-molecule studies, computational dynamics, cell-based assays, and genomic analysis to unveil the focal adhesion-regulating role of methotrexate central to its effect on talin dynamics and downstream pathways. Interestingly, our single-molecule force spectroscopic study shows that methotrexate modulates the bimodal force distribution of talin in a concentration-dependent manner. Steered molecular dynamics reveal that methotrexate-talin interactions alter talin mechanical stability exposing their vinculin binding sites. Finally, we found that methotrexate-regulated talin-dynamics remodel cancer cell mechanical phenotypes like cell polarity, adhesion, and migration by regulating talin-vinculin association-mediated YAP signaling. These results further correlate with genomic analysis of methotrexate-treated patients, demonstrating its clinical importance. Taken together, these findings disseminate the effects of methotrexate-modulated mechanosensitivity of adhesion proteins on cellular events. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.06.535865v1?rss=1 Authors: Rowies, F. T., Batalha, C. M. P. F., Nakahara, T. S., Malnic, B., de Souza-Pinto, N. C. Abstract: Olfactory dysfunction is considered a biomarker of several pathological conditions, including age-associated neurodegenerations, glioblastoma and COVID-19. Olfactory sensory neurons (OSNs) are specialized neurons that detect odorants and send olfactory information to the brain through the olfactory bulb. To perform their function, they are in direct contact with the environment, where they are exposed to several environmental toxins such as atmospheric levels of O2 and volatile molecules. Nonetheless, very little is known about DNA damage levels and expression of DNA repair pathways in these cells. Here we measured nuclear and mitochondrial DNA damage in olfactory epithelium (OE) and compared with levels detected in olfactory bulb (OB) and temporal cortex (TC), as a non-olfactory related central nervous system region. Surprisingly, DNA damage was lower in OE and OB when compared with TC, both for nuclear and mitochondrial genomes. Accordingly, expression of representative genes for all excision repair pathways was detected in OSNs. Moreover, expression of most evaluated DNA repair genes was lower in mature versus OSN progenitors, suggesting that DNA repair is downregulated during differentiation. Analysis of single cell expression data confirmed that expression of the most differentially expressed DNA repair genes decreased from progenitor to mature OSNs. Finally, in situ hybridization data showed that APE1 mRNA levels are lower in the mature OSNs layer of the olfactory epithelium, closest to the nasal cavity lumen. Altogether, we show here that DNA repair pathways are relevant in protecting OSNs against DNA damage accumulation and that differentiation through the OE is accompanied by changes in the expression levels of DNA repair genes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.31.534952v1?rss=1 Authors: Ghibaudo, V., Juventin, M., Buonviso, N., Peter-Derex, L. Abstract: Coupling of sleep spindles with cortical slow waves and hippocampus sharp-waves ripples is crucial for sleep-related memory consolidation. Recent literature evidenced that nasal respiration modulates neural activity in large-scale brain networks. In the rodent, this respiratory drive strongly varies according to vigilance states. Particularly, during sleep, respiration promotes the coupling between hippocampal sharp-wave ripples and cortical DOWN/UP state transitions. However, no study has examined whether sleep spindles could be respiration-modulated in humans. In this work, we aimed to investigate the influence of breathing on brain oscillations during non-rapid-eye-movement stage 2 sleep (N2) in humans by examining the coupling between sleep spindles and respiration cycle. Full night polysomnography of twenty healthy participants were analysed. Spindles and slow waves were detected during N2 sleep stage. Spindle-related sigma power as well as spindle and slow waves events were analysed according to the respiratory phase. We found a significant coupling between slow and fast spindles with respiration cycle, with enhanced sigma activity and probability of occurrence of spindles during the middle part of the expiration phase. A different coupling was observed between breathing and slow waves that were more distributed around both respiration phase transitions. Our findings suggest that breathing cycle influences the dynamics of brain activity during non-rapid-eye-movement sleep. This may enable sleep spindles to synchronize with other brain rhythms including hippocampus sharp wave ripples and facilitate information transfer between distributed brain networks. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.22.533752v1?rss=1 Authors: Dennis, C., Pouchin, P., Richard, G., Mirouse, V. Abstract: The basement membrane (BM) is an essential structural element of tissues, and its diversification participates in organ morphogenesis. However, the traffic routes associated with BM formation and the mechanistic modulations explaining its diversification are still poorly understood. Drosophila melanogaster follicular epithelium relies on a BM composed of oriented BM fibrils and a more homogenous matrix. Here, we determined the specific molecular identity and cell exit sites of BM protein secretory routes. First, we found that Rab10 and Rab8 define two parallel routes for BM protein secretion. When both routes were abolished, BM production was fully blocked; however, genetic interactions revealed that these two routes competed. Rab10 promoted lateral and planar-polarized secretion, whereas Rab8 promoted basal secretion, leading to the formation of BM fibrils and homogenous BM, respectively. We also found that the dystrophin-associated protein complex (DAPC) associated with Rab10 and both were present in a planar-polarized tubular compartment containing BM proteins. DAPC was essential for fibril formation and sufficient to reorient secretion towards the Rab10 route. Moreover, we identified a dual function for the exocyst complex in this context. First, the Exo70 subunit directly interacted with dystrophin to limit its planar polarization. Second, the exocyst complex was also required for the Rab8 route. Altogether, these results highlight important mechanistic aspects of BM protein secretion and illustrate how BM diversity can emerge from the spatial control of distinct traffic routes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.20.533578v1?rss=1 Authors: Gu, L., Liu, L., Shao, W., Gu, J., Xu, Q., Wang, Y., Yu, Q., Lian, X., Zhang, H. Abstract: Generation of the unconsciousness associated with arousal during the initial stage of anesthesia by midazolam is critical for general anesthesia, however, the exact mechanism remains unknown. Here, firstly, we found that the destruction of noradrenergic neurons in the locus coeruleus (LCNE) could prolong the emergence time of midazolam-induced anesthesia. Secondly, the same results were found by activation of the noradrenergic pathway between the LC and the ventrolateral preoptic nucleus (VLPO) using optogenetics and chemogenetics approaches, respectively. Thirdly, this effect was mediated by alpha 1 and beta adrenergic receptors rather than alpha2 adrenergic receptors in the VLPO. Moreover, the noradrenergic pathway to modulate the arousal between the LC and VLPO was controlled by GABAA receptors in the LC and VLPO in our models. Our data demonstrate that activation of the NEergic pathway between the LC and VLPO can promote arousal to prevent delayed recovery from midazolam-induced anesthesia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.28.530397v1?rss=1 Authors: Verma, A., Asthana, S., Saini, D. K., Ayappa, K. G. Abstract: CXCR4 is a G-protein coupled receptor which mediates signalling for diverse functions such as cell proliferation and migration, hematopoiesis and plays a role in embryogenesis and development. Signal transduction occurs primarily through transmembrane helices that function in the multicomponent lipid environment of the plasma membrane. Elevated levels of plasma membrane oxysterols occur in cardiovascular and metabolic disorders, physiological stress and inflammatory conditions. We use experimental and simulation approaches to study the impact of oxysterol chemistry and composition on CXCL12-mediated CXCR4 signalling. Experiments on HeLa cells show a pronounced decrease in calcium oscillation response for the tail oxidized sterols in comparison with the ring oxidized sterols with 22(R) hydroxycholesterol showing a near complete loss of signalling followed by 27-hydroxycholesterol and 25-hydroxycholesterol. All-atom molecular dynamics simulations reveal that tail oxidized, 27-hydroxycholesterol, displaces cholesterol and ubiquitously binds to several critical signalling residues, as well as the dimer interface. Enhanced 27-hydroxycholesterol binding alters CXCR4 residue conformations, disrupts the toggle switch and induces secondary structure changes at both N and C termini. Our study provides a molecular view of the observed mitigated CXCR4 signalling in the presence of oxysterols revealing that disruption of cholesterol-protein interactions, important for regulating the active state, is a key factor in the loss of CXCR4 signalling. Additionally, a signalling class switching from Gi to Gs as revealed by increased CREB and ERK phosphorylation is observed in the experiments. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.07.527584v1?rss=1 Authors: Qiu, Z., Jiang, J., Becker, S. I., Pegna, A. J. Abstract: In the current EEG study, we used a dot-probe task in conjunction with backward masking to examine the neural activity underlying awareness and spatial processing of fearful faces and the neural processes for subsequent cued spatial targets. We presented face images under different viewing conditions (subliminal and supraliminal) and manipulated the relation between a fearful face in the pair and a subsequent target. Through both mass univariate analysis and multivariate pattern analysis, we found that fearful faces can be processed to an extent where they attract spatial attention only when they are presented supraliminally and when they are task-relevant. The spatial attention capture by fearful faces also modulated the processing of subsequent lateralised targets that were spatially congruent with the fearful face, in both behavioural and neural data. There was no evidence for nonconscious processing of the fearful faces in the current paradigm. We conclude that spatial attentional capture by fearful faces requires visual awareness and it is modulated by top-down task demands. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Ralph trained in mineral surveying, but became a computer analyst. But after a change in profession he entered aviation as a flying instructor, and an airline captain. Thus he has studied and observed climate and weather for 40 years in the real world, as a part of his profession. Slides for this presentation: https://tomn.substack.com/p/ralph-ellis-on-ice-ages “Modulation of ice ages via precession and dust-albedo feedbacks”: https://www.sciencedirect.com/science/article/pii/S1674987116300305 —— https://linktr.ee/tomanelson1 Tom Nelson's Twitter: https://twitter.com/tan123 Substack: https://tomn.substack.com/ About Tom: https://tomnelson.blogspot.com/2022/03/about-me-tom-nelson.html Notes for climate skeptics: https://tomn.substack.com/p/notes-for-climate-skeptics ClimateGate emails: https://tomnelson.blogspot.com/p/climategate_05.html

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.31.526457v1?rss=1 Authors: Funamizu, A., Marbach, F., Zador, A. M. Abstract: The activity of neurons in the auditory cortex is driven by both sounds and non-sensory context. To investigate the neuronal correlates of non-sensory context, we trained head-fixed mice to perform a two-alternative choice auditory task in which either reward or stimulus expectation (prior) was manipulated in blocks. Using two-photon calcium imaging to record populations of single neurons in auditory cortex, we found that both sensory and reward expectation modulated the activity of these neurons. Interestingly, the optimal decoder was stable even in the face of variable sensory representations. Neither the context nor the mouse's choice could be reliably decoded from the recorded auditory activity. Our findings suggest that in spite of modulation of auditory cortical activity by task priors, auditory cortex does not represent sufficient information about these priors to exploit them optimally and that decisions in this task require that rapidly changing sensory information be combined with more slowly varying task information extracted and represented in brain regions other than auditory cortex. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.28.522133v1?rss=1 Authors: Rathod, M., Franz, H., Beyersdorfer, V., Wanuske, M.-T., Fischer, K. L., Stüdle, C., Zimmermann, A., Spindler, V. Abstract: Glycosylation is an essential mediator of cell-cell adhesion and epidermal differentiation. We used CRISPR/Cas9-based gene editing to determine the role of dolichol phosphate mannosyltransferase 1 (DPM1), a key enzyme for N- and O-glycosylation. DPM1 loss resulted in weakening of cell-cell adhesion, impaired localization of the desmosome components desmoplakin and desmoglein 2, and cytoskeletal organization defects in human keratinocytes. In a 3D organotypic human epidermis model, loss of DPM1 resulted in impaired differentiation with abnormally increased cornification, reduced thickness of non-corneal layers, and the formation of intercellular gaps in the epidermis. Using proteomic approaches, SERPINB5 was identified as novel interaction partner of desmoplakin, ameliorating the effects of DPM1 loss on cell-cell adhesion and epidermal differentiation. Further analysis showed that the changes induced by DPM1 and SERPINB5 loss were at least in part dependent on elevated TGF-{beta} signalling. Together, we identify DPM1 through SERPINB5 as a novel regulator of cell-cell adhesion and differentiation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Dive into Magnetohydrodynamic (MHD) simulations of the HD 189733 star-planet system in order to predict radio transit modulations of exoplanets. Learn how MHD simulations can model electromagnetic field interactions between local stars and exoplanet magnetospheres at varying planetary radii, and field intensities to generate synthetic radio images (10MHz-1GHz), EM field strength, viewing phase angles, and local star parameters. Topics include: Alfven Wave Solar Atmosphere Model (AWSOM),ray tracing algorithm,Plasma Physics Absorption coefficient,imaging Modulated waves, spacebased instruments, Scar telescope mission, and future research with radio, EUV, and Xray transits to run algorithms on datasets to classify 1,000 Earth-sized planets within 50ly Soumitra Hazra, Post-Doctoral Research Associate, Lowell Center for Space Science and Technology Exoplanet Radio Transits as a Probe for Exoplanetary Magnetic Fields -- Time-dependent MHD Simulations Soumitra Hazra, et al, 2022, Earth and Planetary Astrophysics, https://doi.org/10.48550/arXiv.2208.06006 --- Support this podcast: https://anchor.fm/frontierspace/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.08.519576v1?rss=1 Authors: Ives, J., Labendzki, P., Perapoch Amado, M., Greenwood, E., Viswanathan, N., Northrop, T., Wass, S. V. Abstract: Previous infant entrainment research has shown neural entrainment to a wide range of stimuli and amplitude modulated frequencies. However, it is unknown if infants neurally entrain more strongly to some frequencies more than others, and to which low amplitude modulated frequency infants show the strongest entrainment. The current study seeks to address this by testing the neural entrainment of N=23 4-6-month-old infants and N=22 control group adult caregivers while they listened to a range of sinusoidally amplitude modulated beep stimuli at rest (no sound), 2, 4, 6, 8, 10 and 12 Hz. Analysis examined differences across power and phase, regions of interest predetermined by previous literature and by segmented time windows. Results showed that the strongest entrainment was at 2Hz for both adult and infant participants; that there was no significant difference in power and phase, entrainment was occipital temporal and slightly left fronto-central in adults and right fronto-central and left occipito-temporal in infants, leading to some regions of interest used in previous studies being significant in infants and all regions of interest being significant in adults. Segmenting by time window did not show any significant increase or decrease in entrainment over time, but longer time windows showed a stronger entrainment response. In conclusion, it is important to choose appropriate stimulation frequencies when investigating entrainment between stimulation frequencies or across ages; whole head recording is recommended to see the full extent of activation; there is no preference on power vs phase analyses; and longer recordings show stronger effects. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.23.517709v1?rss=1 Authors: Ivaldo, C., Passalacqua, M., Furfaro, A. L., d'Abramo, C., Ruiz, S., Chatterjee, P. K., Metz, C. N., Nitti, M., Marambaud, P. Abstract: Classical cadherins, including vascular endothelial (VE)-cadherin, are targeted by matrix metalloproteinases (MMPs) and {gamma}-secretase during adherens junction (AJ) disassembly, a mechanism that might have relevance for endothelial cell (EC) integrity and vascular homeostasis. Here, we show that oxidative stress triggered by H2O2 exposure induced efficient VE-cadherin proteolysis by MMPs and {gamma}-secretase in human umbilical endothelial cells (HUVECs). The cytoplasmic domain of VE-cadherin produced by {gamma}-secretase, VE-Cad/CTF2 - a fragment that has eluded identification so far - could readily be detected after H2O2 treatment. VE-Cad/CTF2, released into the cytosol, was tightly regulated by proteasomal degradation and was sequentially produced from an ADAM10/17-generated C-terminal fragment, VE-Cad/CTF1. Interestingly, BMP9 and BMP10, two circulating ligands critically involved in vascular maintenance, significantly reduced VE-Cad/CTF2 levels during H2O2 challenge, as well as mitigated H2O2- mediated actin cytoskeleton disassembly during VE-cadherin processing. Notably, BMP9/10 pretreatments efficiently reduced apoptosis induced by H2O2, favoring endothelial cell recovery. Thus, oxidative stress is a trigger of MMP- and {gamma}-secretase-mediated endoproteolysis of VE-cadherin and AJ disassembly from the cytoskeleton in ECs, a mechanism that is negatively controlled by the EC quiescence factors, BMP9 and BMP10. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.26.513851v1?rss=1 Authors: Krugliak, A., Draschkow, D., Vo, M. L.-H., Clarke, A. Abstract: We typically encounter objects in a context, for example, a sofa in a living room or a car in the street, and this context influences how we recognize objects. Objects that are congruent with a scene context are recognised faster and more accurately than objects that are incongruent. Furthermore, objects that are incongruent with a scene elicit a stronger negativity of the N300/N400 EEG component compared to objects that are congruent with the scene. However, exactly how context modulates access to semantic object information is unknown. Here, we used a modelling-based approach with EEG to directly test how context influences the processing of semantic object information. Using representational similarity analysis, we first asked whether EEG patterns dissociated objects in congruent or incongruent scenes, finding that representational differences between the conditions emerged towards 300 ms. Next, we tested the relationship between EEG patterns and a semantic model based on property norms, revealing that the processing of semantic information for both conditions started around 150 ms, while after around 275 ms, semantic effects were stronger and lasted longer for objects in incongruent scenes compared to objects in congruent scenes. The timing of these effects overlapped with known N300/N400, suggesting previous congruency effects might be explained by differences in processing semantic object information. This suggests that scene contexts can provide a prior expectation about what kind of objects could appear, which might allow for more efficient semantic processing if the object is congruent with the scene, and extended semantic effects for incongruent objects. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.25.512385v1?rss=1 Authors: Sheppard, P. A. S., Chandramohan, D., Lumsden, A., Vellone, D., Denley, M. C. S., Srivastava, D. P., Choleris, E. Abstract: Background: Social memory is essential to the functioning of a social animal within a group. Estrogens can affect social memory too quickly for classical genomic mechanisms. Previously, 17{beta}-estradiol (E2) rapidly facilitated short-term social memory and increased nascent synapse formation, these synapses being potentiated following neuronal activity. However, what mechanisms underlie and co-ordinate the rapid facilitation of social memory and synaptogenesis are unclear. Here, the necessity of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling for rapid facilitation of short-term social memory and synaptogenesis was tested. Methods: Mice performed a short-term social memory task or were used as task-naive controls. ERK and PI3K pathway inhibitors were infused intra-dorsal hippocampally 5 minutes before E2 infusion. Forty minutes following intrahippocampal E2 or vehicle administration, tissues were collected for quantification of glutamatergic synapse number in the CA1. Results: Dorsal hippocampal E2 rapid facilitation of short-term social memory depended upon ERK and PI3K pathways. E2 increased glutamatergic synapse number (GluA1/bassoon colocalization) in task-performing mice but decreased synapse number in task-naive mice. Critically, ERK signaling was required for synapse formation/elimination in task-performing and task-naive mice, whereas PI3K inhibition blocked synapse formation only in task-performing mice. Conclusions: Whilst ERK and PI3K are both required for E2 facilitation of short-term social memory and synapse formation, only ERK is required for synapse elimination. This demonstrates previously unknown, bidirectional, rapid actions of E2 on brain and behaviour and underscores the importance of estrogen signaling in the brain to social behaviour. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.23.513371v1?rss=1 Authors: Huang, J.-Y., Hess, M., Bajpai, A., Barton, S. J., Li, X., Hobson, L. N., Lu, H.-C. Abstract: Neuronal subnetworks are common features of adult cortical circuits and serve as functional units for information processing and encoding. To determine when neuronal subnetworks are established, we employed in vivo calcium imaging to monitor neuronal activity in the primary somatosensory cortex (S1) of awake mice during early postnatal development. We found several striking developmental trajectories: (1) neuronal activity frequencies and network synchrony were sex-dependent; (2) neuronal subnetworks merged as early as P11; (3) the number of neurons in a subnetwork decreases with increasing age; (4) subnetwork neurons are initially spatially segregated, but become intermingled with other subnetworks neurons with increasing age; (5) neurons within the same subnetwork acquire a more cohesive activity pattern as age increases, and (6) enhancing GABAergic activity at P15 acutely increased female but not male subnetwork coherence. Together, our findings demonstrate that P11-P21 is the critical time for subnetwork assembly and GABAergic inputs strengthen subnetwork coherence. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.17.512498v1?rss=1 Authors: Douchamps, V., di Volo, M., Torcini, A., Battaglia, D., Goutagny, R. Abstract: The hippocampus and the entorhinal cortex display a rich oscillatory activity, believed to support neural information processing in key cognitive functions. In the hippocampal region CA1, a slow gamma rhythm (30-80 Hz) generated in CA3 would support memory retrieval whereas a medium gamma rhythm (60-120 Hz) generated in the entorhinal cortex would support memory encoding. However, descriptions involving discrete gamma sub-bands can only partially account for the haphazard diversity of oscillatory behaviors observed in individual recordings during spatial navigation behavior. Here, we stress that transient gamma oscillatory episodes at any frequency or phase relative to the ongoing theta (4-12 Hz) rhythm can be recorded at any layer within CA1. Eventually, the commonly reported averages are dominated by a minority of very strong power events overshadowing gamma heterogeneity. Nevertheless, we show that such gamma diversity can be naturally explained by a simple mechanistic model, and that behavior-related information (position within a maze) can be decoded from most individual gamma events, despite their low power and erratic-like nature. Our results indicate that behavior specifically shapes ensembles of irregular hippocampal gamma oscillations, in a way which evolves with learning, depends on the hippocampal layer and is hard to reconcile with the hypothesis of rigid, narrowly tuned gamma sub-bands. Beyond randomness, the pervasive gamma diversity may thus reflect complexity at the "fringe-of-synchrony" likely functional but invisible to classic average-based analyses. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.15.512353v1?rss=1 Authors: Lind, S., Wu, Y., Sundqvist, M., Forsman, H., Dahlgren, C. Abstract: Allosterically modulated free fatty acid receptor 2 (FFA2R/GPR43) can be activated without the involvement of any orthosteric FFA2R agonist, by signals generated for example by P2Y2R, the G protein coupled receptor for ATP. An FFA2R specific positive allosteric modulator (PAM; Cmp58) was used to disclose the molecular mechanism by which signals generated by ATP/P2Y2R transactivates FFA2R. The P2Y2R induced signal that transactivates the allosterically modulated FFA2R was generated downstream of the Gq containing G protein that couple to P2Y2R. A receptor induced rise in the cytosolic concentration of ionized calcium ([Ca2+]i) was hypothesized to be the receptor transactivation signal. The Gq dependent transient rise in [Ca2+]i induced by the ATP activated P2Y2Rs was not affected by Cmp58. The hypothesis gained, however, support from the finding that the modulator transferred FFA2R to a Ca2+sensitive state. The rise in [Ca2+]i induced by the Ca2+ specific ionophore ionomycin, activated the allosterically modulated FFA2R. The response induced by ionomycin was rapidly terminated and the FFA2Rs could then no longer be activated by the orthosteric FFA2R agonist propionate or be transactivated by the signal generated by the activated ATP receptor. The desensitized/non-responding state of FFA2R was, however, revoked by an earlier described cross-sensitizing/activating allosteric FFA2R modulator. The receptor transactivation of the allosterically modulated FFA2Rs, represent a unique regulatory receptor cross-talk mechanism by which the activity of a G protein coupled receptor is controlled by a signaling system operating from the cytosolic side of the plasma membrane. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.05.510949v1?rss=1 Authors: Watts, M. E., Oksanen, M., Lejerkrans, S., Mastropasqua, F., Gorospe, M., Tammimies, K. Abstract: Circular RNAs (circRNAs) are emerging as a key component of the complex neural transcriptome implicated in brain development. However, the specific expression patterns and functions of circRNAs in human neuronal differentiation have not been explored. Using total RNA sequencing analysis, we identified expressed circRNAs during the differentiation of human neuroepithelial stem (NES) cells into developing neurons and discovered that many circRNAs originated from host genes with synaptic functions. Interestingly, when assessing population data and rare de novo variants in autism spectrum disorder (ASD) candidate host genes, exons giving rise to circRNAs had a significantly higher frequency of genetic variants. Screening for RNA-binding protein sites identified enrichment of Splicing Factor Proline and Glutamine Rich (SFPQ) motifs in increased circRNAs, several of which we validated as being reduced by SFPQ knockdown and enriched in SFPQ ribonucleoprotein complexes. Our study provides an in-depth characterisation of circRNAs in a human neuronal differentiation model and highlights SFPQ as both a regulator and binding partner of circRNAs elevated during neuronal maturation. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Influence of fine structures on gyrosynchrotron emission of flare loops modulated by sausage modes by Mijie Shi et al. on Thursday 15 September Sausage modes are one leading mechanism for interpreting short period quasi-periodic pulsations (QPPs) of solar flares. Forward modeling their radio emission is crucial for identifying sausage modes observationally and for understanding their connections with QPPs. Using the numerical output from three-dimensional magnetohydrodynamic (MHD) simulations, we forward model the gyrosynchrotron (GS) emission of flare loops modulated by sausage modes and examine the influence of loop fine structures. The temporal evolution of the emission intensity is analyzed for an oblique line of sight crossing the loop center. We find that the low- and high-frequency intensities oscillate in-phase at the period of sausage modes for models with or without fine structures. For low-frequency emissions where the optically thick regime arises, the modulation magnitude of the intensity is dramatically reduced by the fine structures at some viewing angles. On the contrary, for high-frequency emissions where the optically thin regime holds, the effect of fine structures or viewing angle is marginal. Our results show that the periodic intensity variations of sausage modes are not wiped out by the fine structures, and sausage modes remains a promising candidate mechanism for QPPs even when flare loops are fine-structured. arXiv: http://arxiv.org/abs/http://arxiv.org/abs/2209.07176v1

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.31.506084v1?rss=1 Authors: Lugtmeijer, S., Geerligs, L., Tsvetanov, K. A., Mitchell, D. J., Campbell, K. L. Abstract: Working memory is critical to higher-order executive processes and declines throughout the adult lifespan. However, our understanding of the neural mechanisms underlying this decline is limited. Recent work suggests that functional connectivity between frontal control and posterior visual regions may be critical, but examinations of age differences therein have been limited to a small set of brain regions and extreme group designs (i.e., comparing young and older adults). In this study, we build on previous research by using a lifespan cohort and a whole-brain approach to investigate working memory load-modulated functional connectivity in relation to age and performance. The article reports on analysis of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. Participants from a population-based lifespan cohort (N=111, age 23-86) performed a visual short-term memory task during functional magnetic resonance imaging. Visual short-term memory was measured with a delayed recall task for visual motion with three different loads. Whole-brain load-modulated connectivity was estimated using psychophysiological interactions in a hundred regions of interest, sorted into seven networks (Schaefer et al., 2018, Yeo et al., 2011). Results showed that load-modulated functional connectivity was strongest within the dorsal attention network followed by the visual network during encoding and maintenance. With increasing age, load-modulated functional connectivity strength decreased throughout the cortex. Within the dorsal attention network, increased load-modulated connectivity strength was related to better task performance in an age-invariant way. Our results demonstrate the widespread negative impact of age on the modulation of functional connectivity by working memory load. Older adults might already be close to ceiling in terms of their resources at the lowest load and therefore less able to further increase connectivity with increasing task demands. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

References Dr Guerra's synthesis of the relevant literature BioEssays, Volume: 39, Issue: 5, First published: 20 February 2017. Front Cardiovasc Med. 2020; 7: 2. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Bill and Jeff recap their Ep. 40 Youtube video - The Electro-Harmonix Blurst Modulated Filter, video out now.  Also, the guys discuss pedals in general, preferences and all kinds of interesting things related to guitars, pedal boards, bands and fan mail, while hanging out at The SoCal Riff Ranch!

The researchers recruited healthy older participants to two groups according to their history of tea drinking frequency and investigated both functional and structural networks to reveal the role of tea drinking on brain organization. The suppression of hemispheric asymmetry in the structural connectivity network was observed as a result of tea drinking. The authors did not observe any significant effects of tea drinking on the hemispheric asymmetry of the functional connectivity network. Dr. Junhua Li and Dr. Lei Feng said, "Tea has been a popular beverage since antiquity, with records referring to consumption dating back to the dynasty of Shen Nong (approximately 2700 BC) in China." Tea is consumed in diverse ways, with brewed tea and products with a tea ingredient extremely prevalent in Asia, especially in China and Japan. Although individual constituents of tea have been related to the roles of maintaining cognitive abilities and preventing cognitive decline, a study with behavioural and neurophysiological measures showed that there was a degraded effect or no effect when a constituent was administered alone and a significant effect was observed only when constituents were combined. The superior effect of the constituent combination was also demonstrated in a comparative experiment that suggested that tea itself should be administered instead of tea extracts; a review of tea effects on the prevention of Alzheimers disease, found that the neuroprotective role of herbal tea was apparent in eight out of nine studies. It is worth noting that the majority of studies thus far have evaluated tea effects from the perspective of neurocognitive and neuropsychological measures, with direct measurement of brain structure or function less-well represented in the extant literature. These studies focusing on brain regional alterations did not ascertain tea effects on interregional interactions at the level of the entire brain. The Li/Feng Research team concluded, "In summary, our study comprehensively investigated the effects of tea drinking on brain connectivity at both global and regional scales using multi-modal imaging data and provided the first compelling evidence that tea drinking positively contributes to brain structure making network organization more efficient." Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.102023 DOI - https://doi.org/10.18632/aging.102023 Full Text - https://www.aging-us.com/article/102023/text Correspondence to: Junhua Li email: junhua.li@essex.ac.uk and Lei Feng email: pcmfl@nus.edu.sg Keywords: tea drinking, brain efficiency, fMRI, DTI, default mode network, hemispheric asymmetry About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways. Please visit our website at http://www.Aging-US.com or connect with us on: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Aging-US is published by Impact Journals, LLC please visit http://www.ImpactJournals.com or connect with @ImpactJrnls Media Contact 18009220957x105 MEDIA@IMPACTJOURNALS.COM

Welcome to Balance and Moderation… A Wellness podcast, with some personality… Big love is the motto and our message is for everyone, so don't forget to share this with all the beautiful people in your life. Enjoy! Episode 33 is all about circadian rhythm. This is the 24-hour cycle in the physiological processes of human beings. Modulated by sleeping and eating are the daily patterns that affect brain wave activity, hormone production, cell regeneration, and other biological functions in the body. Check out our instagram @theBAMpodcast Send any questions and inquiries you have to balance.moderation@gmail.com Hosts: Sheridan Lee @TheSoulAndScience Rob Young @WellnessRob Show Links Circadian rhythm https://www.sciencedaily.com/terms/circadian_rhythm.htm The link between circadian rhythms and aging: Gene associated with longevity also regulates the body's circadian clock https://www.sciencedaily.com/releases/2013/06/130620132320.htm Disruption Of Circadian Rhythms Affects Both Brain And Body, Mouse Study Finds https://www.sciencedaily.com/releases/2009/10/091026225744.htm Disrupted circadian rhythms linked to later Parkinson's diagnoses https://www.sciencedaily.com/releases/2020/06/200615142802.htm Circadian rhythms help guide waste from brain https://www.sciencedaily.com/releases/2020/09/200902082326.htm Chronic drinking can disrupt circadian rhythms https://www.sciencedaily.com/releases/2010/08/100824161428.htm What is blue light? The effect blue light has on your sleep and more. https://www.health.harvard.edu/staying-healthy/blue-light-has-a-dark-side

Dr. Jasmin Jo interviews Dr. Caroline Chung about her paper: “A prospective phase II randomized trial of proton radiotherapy vs intensity modulated radiotherapy for patients with newly diagnosed GBM” published online in Neuro-Oncology in Feb 2021.

Gauge/Gravity Duality 2013

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.389106v1?rss=1 Authors: Jetta, D., Bahrani Fard, M. R., Sachs, F., Munechika, K., Hua, S. Z. Abstract: Adherent cells utilize local environmental cues to make decisions on their growth and movement. We have previously shown that HEK293 cells grown on the fibronectin stripe patterns were elongated. Here we show that Piezo1 function is involved in cell spreading. Inhibiting the Rho-ROCK pathway also reversibly inhibited cell extension indicating that myosin contractility is involved. Piezo1 expressing HEK cells plated on fibronectin stripes elongated, while a knockout of Piezo1 eliminated elongation. Inhibiting Piezo1 conductance using GsMTx4 or Gd3+ blocked cell spreading, but the cells grew thin tail-like extensions along the patterns. Images of GFP-tagged Piezo1 showed plaques of Piezo1 moving to the extrusion edges, co-localized with focal adhesions. Surprisingly, in non-spreading cells Piezo1 was located primarily on the nuclear envelope. The growth of thin extrusion tails did not occur in Piezo1 knockout cells suggesting that Piezo1 may have functions besides acting as a cation channel. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.11.378646v1?rss=1 Authors: Lee, W. H., Liu, W., Fan, J.-S., Yang, D. Abstract: The viral protease domain (NS3pro) of dengue virus is essential for virus replication and its cofactor NS2B is indispensable for the proteolytic function. Although several NS3pro-NS2B complex structures have been obtained, the dynamic property of the complex remains poorly understood. Using NMR relaxation techniques, here we found that NS3pro-NS2B exists in both closed and open conformations which are in dynamic equilibrium on a sub-millisecond timescale in aqueous solution. Our structural information indicates that the C-terminal region of NS2B is disordered in the open conformation but folded in the closed conformation. Using mutagenesis, we showed that the closed-open conformational equilibrium can be shifted by changing NS2B stability. Moreover, we revealed that the proteolytic activity of NS3pro-NS2B correlates well with the population of the closed conformation. Our results suggest that the closed-open conformational equilibrium can be used by both nature and man to control the replication of dengue virus. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.10.376699v1?rss=1 Authors: Milne, A. E., Zhao, S., Tampakaki, C., Bury, G., Chait, M. Abstract: The brain is highly sensitive to auditory regularities and exploits the predictable order of sounds in many scenarios, from parsing complex auditory scenes to the acquisition of language. To understand the impact of stimulus predictability on perception it is important to determine how the discovery of predictable structure influences processing and attention. Here we use pupillometry to gain insight into the effect of sensory regularity on arousal. Pupillometry is a commonly used measure of salience and processing effort, with more perceptually salient or perceptually demanding stimuli consistently associated with larger pupil diameters. In two experiments we tracked human listeners' pupil dynamics while they listened to sequences of 50ms tone pips of different frequencies. The order of the tone pips was either random, or contained deterministic regularities (experiment 1, n = 18, 11 female) or a probabilistic structure (experiment 2, n = 20, 17 female). The sequences were rapid, preventing conscious tracking of sequence structure thus allowing us to focus on automatic extraction of different types of regularities. We hypothesized that if regularity facilitates processing, a smaller pupil diameter would be seen in response to regular relative to random patterns. Conversely, if regularity is associated with attentional capture (i.e. engages processing resources) the opposite pattern would be expected. In both experiments we observed a smaller sustained (tonic) pupil diameter for regular compared with random sequences, consistent with the former hypothesis and confirming that predictability facilitates sequence processing. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.30.360990v1?rss=1 Authors: Peng, Y., Li, S., Onufriev, A., Landsman, D., Panchenko, A. R. Abstract: Despite histone tails' critical roles in epigenetic regulation, little is known about mechanisms of how histone tails modulate the nucleosomal DNA solvent accessibility and recognition of nucleosomes by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full human nucleosome, totaling 26 microseconds of molecular dynamics simulations. We explore the histone tail binding with the nucleosomal and linker DNA and observe rapid conformational transitions between bound and unbound states allowing us to estimate kinetic and thermodynamic properties of the histone tail-DNA interactions. Different histone types exhibit distinct, although conformationally heterogeneous, binding modes and each histone type occludes specific DNA regions from the solvent. Using a comprehensive set of experimental data on nucleosome structural complexes, we find that majority of the studied nucleosome-binding proteins and histone tails target mutually exclusive regions on nucleosomal or linker DNA around the super-helical locations {+/-}1, {+/-}2, and {+/-}7. This finding is explained within the generalized competitive binding and tail displacement models of partners recruitment to nucleosomes. Finally, we demonstrate the crosstalk between different histone post-translational modifications, where charge-altering modifications and mutations typically suppress tail-DNA interactions and enhance histone tail dynamics. Copy rights belong to original authors. Visit the link for more info

http://i1i.site DADADAP vocal training Dm Bes7 modulated by StijnOnline https://sites.google.com/view/stijn-online/ https://sites.google.com/view/stijnGABELER https://sites.google.com/view/dailystijn https://sites.google.com/view/veganstijn https://api.whatsapp.com/send?phone=31622869860 --- Send in a voice message: https://anchor.fm/stijnonline/message

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.21.349043v1?rss=1 Authors: Michon, F., Krul, E., Sun, J.-J., Kloosterman, F. Abstract: Reward value is known to modulate learning speed in spatial memory tasks, but little is known about its influence on the dynamical changes in hippocampal spatial representations. Here, we monitored the trial-to-trial changes in hippocampal place cell activity during the acquisition of place-reward associations with varying reward size. We show a faster reorganization and stabilization of the hippocampal place map when a goal location is associated with a large reward. The reorganization is driven by both rate changes and the appearance and disappearance of place fields. The occurrence of hippocampal replay activity largely followed the dynamics of changes in spatial representations. Replay patterns became more selectively tuned towards behaviorally relevant experiences over the course of learning. These results suggest that high reward value enhances memory retention via accelerating the formation and stabilization of the hippocampal cognitive map and enhancing its reactivation during learning. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.15.338111v1?rss=1 Authors: Arslanova, I., Wang, K., Haggard, P., Gomi, H. Abstract: Many perceptual studies focus on the brain's capacity to discriminate between stimuli. However, our normal experience of the world also involves integrating multiple stimuli into a single perceptual event. Neural circuit mechanisms such as lateral inhibition are believed to enhance local differences between sensory inputs from nearby regions of the receptor surface. However, this mechanism would seem dysfunctional when sensory inputs need to be combined rather than contrasted. Here, we investigated whether the brain can strategically regulate the strength of suppressive interactions that underlie lateral inhibition between finger representations in human somatosensory processing. To do this, we compared sensory processing between conditions that required either comparing or combining information. We delivered two simultaneous tactile motion trajectories to index and middle fingertips of the right hand. Participants had to either compare the directions of the two stimuli, or to combine them to form their average direction. To reveal preparatory tuning of somatosensory cortex, we used an established event-related potential design to measure the interaction between cortical representations evoked by digital nerve shocks immediately before each tactile stimulus. Consistent with previous studies, we found a clear suppressive interaction between cortical activations when participants were preparing to compare the tactile motion directions. Importantly, this suppressive interaction was significantly reduced when participants had to combine the same stimuli. These findings suggest that the brain can strategically switch between a comparative and a combinative mode of somatosensory processing, according to the perceptual goal, by preparatorily adjusting the strength of a process akin to lateral inhibition. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.13.337857v1?rss=1 Authors: Henderson, M., Cornblath, E. J., Li, H. L., Changolkar, L., Zhang, B., Brown, H. J., Gathagan, R. J., Olufemi, M. F., Bassett, D. S., Trojanowski, J. Q., Lee, V. M. Y. Abstract: Tau pathology is a diagnostic feature of Alzheimer's disease (AD) but is also a prominent feature of Parkinson's disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathology's initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.12.335943v1?rss=1 Authors: Glickman, M., Moran, R., Usher, M. Abstract: Evidence-integration is a normative algorithm for choosing between alternatives with noisy evidence, which has been successful in accounting for a vast amount of behavioral and neural data. However, this mechanism has been challenged as tracking integration boundaries sub-serving choice has proven elusive. Here we first show that the decision boundary can be monitored using a novel, model-free behavioral method, termed Decision-Classification Boundary. This method allowed us to both provide direct support for evidence-integration contributions and to identify a novel integration-bias, whereby incoming evidence is modulated based on its consistency with evidence from preceding time-frames. This consistency bias was supported in three cross-domain experiments, involving decisions with perceptual and numerical evidence, which showed that choice-accuracy and decision confidence are modulated by stimulus consistency. Strikingly, despite its seeming sub-optimality, this bias fosters performance by enhancing robustness to integration noise. We argue this bias constitutes a new form of micro-level, within-trial, confirmation bias and discuss implications to broad aspects of decision making. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.11.335000v1?rss=1 Authors: Rens, G., Orban de Xivry, J.-J., Davare, M., van Polanen, V. Abstract: Transcranial magnetic stimulation (TMS) studies showed that corticospinal excitability (CSE) is modulated during observation of object lifting, an effect termed 'motor resonance'. Specifically, motor resonance is driven by movement features indicating object weight, such as object size or observed movement kinematics. We investigated in 16 humans (8 females) whether motor resonance is also modulated by an object's weight distribution. Participants were asked to lift an inverted T-shaped manipulandum with interchangeable center of mass after first observing an actor lift the same manipulandum. Participants and actor were instructed to minimize object roll and rely on constrained digit positioning during lifting. Constrained positioning was either collinear (i.e. fingertips on the same height) or noncollinear (i.e. fingertip on the heavy side higher than the one on the light side). The center of mass changed unpredictably before the actor's lifts and participants were explained that their weight distribution always matched the one of the actor. Last, TMS was applied during both lift observation and planning of lift actions. Importantly, our results revealed that CSE was similarly modulated during lift observation and planning: when participants observed or planned lifts in which the weight distribution was asymmetrically right-sided, CSE, recorded from the thumb muscles, was significantly increased compared to when the weight distribution was left-sided. Moreover, this increase seemed to be primarily driven by the observed and planned thumb positioning when lifting the right-sided asymmetrical weight distribution. In conclusion, our results suggest that complex intrinsic object properties such as weight distributions can be encoded by an individual's motor system during both observation and planning of lifting actions. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.30.273888v1?rss=1 Authors: Fischer, P., Pogosyan, A., Green, A. L., Aziz, T. Z., Hyam, J., Foltynie, T., Limousin, P., Zrinzo, L., Samuel, M., Keyoumars, A., Da Lio, M., De Cecco, M., Luchetti, A., Brown, P., Tan, H. Abstract: Beta oscillations are readily observed in motor cortex and the basal ganglia, but to which extent they are functionally relevant is unclear. To understand how activity transfer between different nodes of the cortico-basal ganglia network is affected by cortical beta oscillations in different behavioural conditions, we recorded local field potentials and electroencephalography (EEG) activity in a low-force motor control task and during rest in Parkinson's patients undergoing deep brain stimulation (DBS) surgery. The patients received DBS of either the subthalamic nucleus (STN) or the internal globus pallidus (GPi), which allowed us to investigate if STN and GPi broad-band high-frequency activity (HFA; >150 Hz) is co-modulated with the phase of motor cortical beta activity. We found significant modulation patterns in the STN and the GPi, which were inverted while patients performed the task, showing that GPi activity fluctuations likely are crafted by other inputs than the direct excitatory STN afferents. We also found that consistent STN modulation disappeared during rest, showing disengagement in this condition, while GPi modulation was maintained, again evidencing that beta-band activity fluctuations in the GPi can be relatively independent of those in the STN. The difference between HFA modulation patterns in the task and rest recordings suggests a potential functional role of beta phase-locked HFA modulation in controlling sustained contractions. Examination of HFA co-modulation patterns at different sites of the cortico-basal ganglia-thalamo-cortical network under different behavioural conditions may provide a tool with which to define the impact of beta synchronization on network communication. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.10.244558v1?rss=1 Authors: LI, Z., Buck, M. Abstract: Despite large differences in behaviors and living conditions, vertebrate organisms share the great majority of proteins often with subtle differences in amino acid sequence. By comparing a set of substantially homologous proteins between model vertebrate organisms at a sub-proteome level, we discover a pattern of amino acid conservation and a shift in amino acid use, noticeably with an apparent distinction between homeotherms (warm-blooded species) and poikilotherms (cold-blooded species). Importantly, we establish a connection between the thermoadaptation of protein sequences manifest in the evolved proteins and two of their physical features: a change in their proteins dynamics and in their solvation. For poikilotherms such as frog and fish, the lower body temperature is expected to increase the association of proteins due to a decrease in protein dynamics and correspondingly lower entropy penalty on binding. In order to prevent overly-sticky protein association at low temperatures, we find that poikilotherms enhance the solvation of their proteins by favoring polar amino acids on their protein surface. This study unveils a general mechanism behind amino acid choices that constitute part of the thermoadaptation of vertebrate organisms at the molecular level. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.04.237057v1?rss=1 Authors: Jang, A. I., Sharma, R., Drugowitsch, J. Abstract: Traditional accumulation-to-bound decision-making models assume that all choice options are processed simultaneously with equal attention. In real life decisions, however, humans tend to alternate their visual fixation between individual items in order to efficiently gather relevant information (Yang et al., 2016; Hoppe & Rothkopf, 2016; Chukoskie et al., 2013). These fixations also causally affect one's choices, biasing them toward the longer-fixated item (Shimojo et al., 2003; Armel et al., 2008). We derive a normative decision-making model in which fixating a choice item boosts information about that item. In contrast to previous models (Krajbich et al., 2010; Song et al., 2019), we assume that attention enhances the reliability of information rather than its magnitude, consistent with neurophysiological findings (Averbeck et al., 2006; Cohen & Maunsell, 2009). Furthermore, our model actively controls fixation changes to optimize information gathering. We show that the optimal model reproduces fixation patterns and fixation-related choice biases seen in human decision-makers, and provides a Bayesian computational rationale for the fixation bias. This insight led to additional behavioral predictions that we confirmed in human behavioral data. Finally, we explore the consequences of changing the relative allocation of cognitive resources to the attended versus the unattended item, and show that decision performance is benefited by a more balanced spread of cognitive resources. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.26.221747v1?rss=1 Authors: Kang, Y., Wu, J.-X., Chen, L. Abstract: Resting membrane potential determines the excitability of the cell and is essential for the cellular electrical activities. NALCN channel mediates sodium leak currents, which positively tune the resting membrane potential towards depolarization. NALCN channel is involved in many important neurological processes and is implicated in a spectrum of neurodevelopmental diseases. Despite its functional importance, the mechanisms of ion permeation and voltage-modulation for NALCN channel remain elusive. Here, we report the cryo-EM structure of rat NALCN and mouse FAM155A complex to 2.7 [A] resolution. The structure reveals detailed interactions between NALCN and extracellular cysteine-rich domain of FAM155A. The non-canonical architecture of NALCN selectivity filter dictates its sodium selectivity and calcium block. The asymmetric arrangement of two functional voltage-sensors confers the modulation by membrane potential. Moreover, mutations found in human diseases were mapped to the domain-domain interfaces or the pore domain of NALCN, intuitively suggesting their pathological mechanisms. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.07.186452v1?rss=1 Authors: Biau, E., Wang, D., Park, H., Jensen, O., Hanslmayr, S. Abstract: Audiovisual speech perception relies on our expertise to map a speaker's lip movements with speech sounds. This multimodal matching is facilitated by salient syllable features that align lip movements and acoustic envelope signals in the 4 - 8 Hz theta band. The predominance of theta rhythms in speech processing has been firmly established by studies showing that neural oscillations track the acoustic envelope in the primary auditory cortex. Equivalently, theta oscillations in the visual cortex entrain to lip movements and the auditory cortex is recruited during silent speech perception. These findings suggest that neuronal theta oscillations play a functional role in organising information flow across visual and auditory sensory areas. We presented silent speech movies while participants performed a pure tone detection task to test whether entrainment to lip movements enslaves the auditory system and drives behavioural outcomes. We showed that auditory detection varied depending on the ongoing theta phase conveyed by lip movements in the movies. In a complementary experiment presenting the same movies while recording participants' electro-encephalogram (EEG), we found that silent lip movements entrained neural oscillations in the visual and auditory cortices with the visual phase leading the auditory phase. These results support the idea that the visual cortex entrained by lip movements increases the sensitivity of the auditory cortex at relevant time-windows for speech comprehension as a filtering modulator relying on theta phase synchronisation. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.20.162917v1?rss=1 Authors: Bola, L., Yang, H., Caramazza, A., Bi, Y. Abstract: In high-level visual shape areas in the human brain, preference for inanimate objects is observed regardless of stimulation modality (visual/auditory/tactile) and subjects' visual experience (sighted/blind individuals), whereas preference for animate entities seems robust only in the visual modality. Here, we test a hypothesis explaining this effect: visual shape representations can be reliably activated through different sensory modalities only when they systematically map onto action system computations. We studied fMRI activations in congenitally blind and sighted subjects listening to animal, object, and human sounds. We found that face shape areas in blind individuals preferentially respond to human facial expression sounds, with transparent face shape/motor representation mapping, but not to speech or animal sounds. Using face areas' activation, we could distinguish facial expressions from other sounds in both groups. We conclude that auditory stimulation can activate visual shape representation of those stimuli - inanimate or animate - for which shape-action mapping is transparent. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.12.148437v1?rss=1 Authors: Jolivet, R. B., Magistretti, P. J. Abstract: Spike-frequency adaptation is a prominent feature of spiking neurons. Using a Hodgkin-Huxley-type model, we studied adaptation originating from the Na,K-ATPase electrogenic pump and its evolution in presence of a medium-duration calcium-dependent potassium channel. We found that the Na,K-ATPase induces spike-frequency adaptation with a time constant of up to a few seconds and interacts with the calcium-dependent potassium current through the output frequency, yielding a very typical pattern of instantaneous frequencies. Because channels responsible for spike-frequency adaptation can interact with each other, our results suggest that their meaningful time courses and parameters can be difficult to measure experimentally. To circumvent this problem, we developed a simple phenomenological model that captures the interaction between currents and allows the direct evaluation of the underlying biophysical parameters directly from the frequency vs. current curves. Finally, we found that for weak stimulations, the pump induces phasic spiking and linearly converts the stimulus amplitude in a finite number of spikes acting like an inhibitory spike-counter. Our results point to the importance of considering interacting currents involved in spike-frequency adaptation collectively rather than as isolated elements and underscore the importance of sodium as a messenger for long-term signal integration in neurons. Within this context, we propose that the Na,K-ATPase plays an important role and show how to recover relevant biological parameters from adapting channels using simple electrophysiological measurements. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.11.145219v1?rss=1 Authors: Pongpipat, E. E., Kennedy, K. M., Foster, C. M., Boylan, M. A., Rodrigue, K. M. Abstract: Working memory (WM) and its BOLD-related parametric modulation under load decrease with age. Functional connectivity (FC) generally increases with WM load; however, how aging impacts connectivity and whether this is load-dependent, region-dependent, or associated with cognitive performance is unclear. This study examines these questions in 170 healthy adults (Mage = 52.99 +/- 19.18) who completed fMRI scanning during an n-back task (0-, 2-, 3-, and 4- back). FC was estimated utilizing a modified generalized psychophysiological interaction approach with seeds from fronto-parietal (FP) and default mode (DM) regions that modulated to n-back difficulty. FC analyses focused on both connectivity during WM engagement (task vs control) and connectivity in response to increased WM load (linear slope across conditions). Each analysis utilized within- and between-region FC, predicted by age (linear or quadratic), and its associations with in- and out-of-scanner task performance. Engaging in WM either generally (task vs control) or as a function of difficulty strengthened integration within- and between- FP and DM regions. Notably, these task-sensitive functional connections were robust to the effects of age. Stronger negative FC between FP and DM regions was also associated with better WM performance in an age-dependent manner, occurring selectively in middle- and older-adults. These results suggest that FC is critical for engaging in cognitively demanding tasks, and its lack of sensitivity to healthy aging may provide a means to maintain cognition across the adult lifespan. Thus, this study highlights the contribution of maintenance in brain function to support working memory processing with aging. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.05.136531v1?rss=1 Authors: Gann, M. A., King, B. R., Dolfen, N., Veldman, M. P., Chan, K. L., Puts, N. A. J., Edden, R. A. E., Davare, M., Swinnen, S. P., Mantini, D., Robertson, E. M., Albouy, G. Abstract: While it is widely accepted that motor sequence learning (MSL) is supported by a prefrontal-mediated interaction between hippocampal and striatal networks, it remains unknown whether the functional responses of these networks can be modulated in humans with targeted experimental interventions. The present proof-of-concept study employed a comprehensive multimodal neuroimaging approach, including functional magnetic resonance (MR) imaging and MR spectroscopy, to investigate whether individually-tailored theta-burst stimulation of the dorsolateral prefrontal cortex can modulate responses in the hippocampus and striatum during motor learning. Our results indicate that stimulation influenced task-related connectivity patterns within hippocampo-frontal and striatal networks. Stimulation also altered the relationship between the levels of gamma-aminobutyric acid (GABA) in the stimulated prefrontal cortex and learning-related changes in both activity and connectivity in fronto-striato-hippocampal networks. This study provides the first experimental evidence that brain stimulation can alter motor learning-related functional responses in the striatum and hippocampus. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.29.118737v1?rss=1 Authors: Andersson, M., Kjer, H. M., Rafael-Patino, J., Pacureanu, A., Pakkenberg, B., Thiran, J.-P., Ptito, M., Bech, M., Bjorholm Dahl, A., Andersen Dahl, V., Dyrby, T. B. Abstract: Axonal conduction velocity, which ensures efficient function of the brain network, is related to axon diameter. Non-invasive, in vivo axon diameter estimates can be made with diffusion magnetic resonance imaging, but the technique requires 3D validation. Here, high resolution, 3D synchrotron X-ray Nano-Holotomography images of white matter samples from the corpus callosum of a monkey brain reveal that blood vessels, cells and vacuoles affect axonal diameter and trajectory. Within single axons, we find that the variance in diameter and conduction velocity correlates with the mean diameter, contesting the value of precise diameter determination in larger axons. These complex 3D axon morphologies drive previously reported 2D trends in axon diameter and g-ratio. Furthermore, we find that these morphologies bias the estimates of axon diameter with diffusion magnetic resonance imaging and, ultimately, impact the investigation and formulation of the axon structure-function relationship. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.21.109728v1?rss=1 Authors: Lee, S., Parthasarathi, T., Kable, J. W. Abstract: Recent work has shown that the brain's default mode network (DMN) is active when people imagine the future. Here we test whether future imagination can be decomposed into two dissociable psychological processes linked to different subcomponents of the DMN. While measuring brain activity with fMRI as subjects imagine future events, we manipulate the vividness of these events to modulate the demands for scene construction, and we manipulate the valence of these events to modulate the demands for evaluation. We found that one subcomponent of the DMN, the ventral DMN or medial temporal lobe subsystem, responds to the vividness but not the valence of imagined events. In contrast, another subcomponent, the dorsal or core DMN, responds to the valence but not the vividness of imagined events. This separate modifiability of different subcomponents of the DMN by vividness and valence provides strong evidence for a neurocognitive dissociation between (1) the construction of novel, imagined scenes from individual components from memory and (2) the evaluation of these constructed events as desirable or undesirable. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.20.106674v1?rss=1 Authors: Zoubovsky, S. P., Williams, M. T., Hoseus, S., Tumukuntala, S., Riesenberg, A., Schulkin, J., Vorhees, C. V., Campbell, K., Lim, H.-W., Muglia, L. J. Abstract: Prenatal stress (PS) is associated with increased vulnerability to affective disorders. Transplacental glucocorticoid passage and stress-induced maternal environment alterations are recognized as potential routes of transmission that can fundamentally alter neurodevelopment. However, molecular mechanisms underlying aberrant emotional outcomes or the individual contributions intrauterine stress versus maternal environment play in shaping these mechanisms remain unknown. Here, we report anxiogenic behaviors, anhedonia, and female hypothalamic-pituitary-adrenal axis hyperactivity as a consequence of psychosocial PS in mice. Sex-specific placental responses to stress and evidence of fetal amygdala programming precede these abnormalities. In adult offspring, we observe amygdalar transcriptional changes demonstrating sex-specific dysfunction in synaptic transmission and neurotransmitter systems. We find these abnormalities are primarily driven by in-utero stress exposure. Importantly, maternal care changes postnatally reverse anxiety-related behaviors and partially rescue gene alterations associated with neurotransmission. Our data demonstrate the influence maternal environment exerts in shaping offspring emotional development despite deleterious effects of intrauterine stress. Copy rights belong to original authors. Visit the link for more info

The boys are back. Hold on peeps! This a political one, the gents dive into the events of SONA and what the president promised and what he's done! Tune in!

ASMR. Live recordings with real-time modulation. Video at; https://vimeo.com/384974280

Today's episode cover's a question from Dan about how to structure an online course. You'll learn the differences between memberships and modulated courses, when you should use each of them, and, most importantly, you'll hear a story about Dan's personal transformation from someone who "does nothing" into a business owner...

Tommy attempts peace with his future overlords while Pete helps a listener see peace in ghosting the e-anxiety. This week's tune: Hell Yeah by Ride Free - Sponsor: This week's show is brought to you by Audible. Get a free audiobook to spice up your morning tea at AudibleTrial.com/ScentofaPodcast. From there, search for Gateway by Frederick Pohl! Or any book you please! Whatever you pick, you can sleep well knowing that you’re supporting the show … also, you never have to worry about not being heard.

My QSO Today is with John Stanley, K4ERO, a frequent contributor of articles about antenna design and performance to QST, QEX, the ARRL Antenna Book, and the ARRL Handbook.  An MIT graduate, John and his wife Ruth, WB4LUA, spent many years abroad working as engineers for Christian Broadcast stations in India and South America. John shares his ham radio story and his antenna expertise in this QSO Today.

Esse duo traz seu synthpop britânico para o Brasil com 3 apresentações! TOUR: 10/MAI - Teatro Positivo - Curitiba/PR 11/MAI - Espaço das Américas - São Paulo/SP 12/MAI - Vivo Rio - Rio de Janeiro/SP TRACKLIST: Erasure - You Surrond Me Erasure - Be Careful What You Wish For! (Paint A Rumour Remix) Erasure - Ship Of Fools (Extended Mix) Erasure - Sometimes (Extended Mix) Erasure - Love To Hate You (LFO Modulated Filter Remix) Erasure - Breathe (Dance Remix) Erasure - Blue Savannah (Der Deutche Mix) Erasure - Paradise (Black Light Odyssey Remix) Erasure - Stop (12 Remix) Erasure - Oh L'Amour (Extended Remix) Erasure - A Little Respect (Extended Version) ON AIR: Rádio Comunitária CPA FM - 105,9 MHz - Cuiabá/MT Sexta, 22h | Sábado, 22h25 - GMT-4 (Horário da Amazônia) www.radiocpafm.amaisouvida.com.br/ Rádio Boiuna - 87,9 MHz - Boa Vista do Ramos/AM Domingo, 9h - GMT-4 (Horário da Amazônia) www.radios.com.br/aovivo/radio-boiuna-879-fm/26485 Rádio Trans BJ - 87,9 MHz - Bom Jardim de Minas/MG Sábado, 20h - GMT-3 (Horário de Brasília) http://radiotransbj.com Rádio FM Tibau - 104.9 MHz - Tibau/RN Sábado, 19h - GMT-3 (Horário de Brasília) www.fmtibau.com.br Rádio Vespasiano FM - 87,9 MHz - Vespasiano/MG Sábado, 20h - GMT-3 www.vespasianofm.com Rádio Campo FM - 87,5 MHz - Campo do Tenente/PR Domingo, 15h00 - GMT-3 (Horário de Brasília) www.tenenteanafm.com.br Rádio Comunitária Itaquera - 87,5 MHz - São Paulo/SP Sábado, 21h | Domingo, 19h - GMT-3 (Horário de Brasília) http://rcitaquera.com.br/ Rádio Ipanema Comunitária - 87,9 MHz - Porto Alegre/RS Sábado, 21h - GMT-3 (Horário de Brasília) http://www.ipanemacomunitaria.com.br Beat Top Som Domingo, 05h - GMT-3 (Horário de Brasília) http://beattopsom.com/ Rádio Cidade Paraíba Domingo, 18h | Terça, 21h - GMT-3 (Horário de Brasília) http://radiocidadeparaiba.radiostream123.com/ Antena Web (Portugal) Quarta, 01h - GMT+1 (Horário da Europa Ocidental) http://www.antenaweb.info FCM Cidade Sábado, 22h - GMT-3 (Horário de Brasília) http://www.fcmpublicidade.com.br Pop Mix Sábado, 15h | Domingo, 14h - GMT-3 (Horário de Brasília) http://popmixradioweb.com/ Agente Oficial: Marina Navarro Viagens e Turismo https://www.facebook.com/marinanavarroviagenseturismo/ Divulgação: Brazuka Tracklists https://www.facebook.com/BrazukaTracklists/ https://soundcloud.com/brazukatracklists/ https://www.youtube.com/brazukatracklists

The Ubercast EP40Connect with Uberjak'd:linktr.ee/uberjakd1. ID - ID2. The Spook Returns - B3nte. Badjack & KSHMR3. Bang Bang Boom - Krunk & Tommie Sunshine4. Accelerate - Eric Mendoza & Zerocool5. ID - ID6. Party Till We Die - Timmy Trumpet & MakJ7. When the Funk Drops [Uberjakd edit] - Uberjakd & Deorro f. Far East Movement8. Queef - Joel Fletcher & Deorro9. Jetfuel [Uberjakd intro edit] - Uberjakd & Joel Fletcher10. Shake it - Joey Dale & Maddix11. Disco Weapon - MOTi & Maurice West12. Muscular - Ibranvoski & Syzz13. Close [Brooks remix] - IZECOLD14. ILYSM - Autoerotique & Steve Aoki15. I Got my - Bougenvilla16. Blip - D.O.D17. Flute [Uberjakd remix] - New World Sound18. Get Down - Hardwell & W&W19. Pursuit of Love [Jaymac edit] - Kid Cudi Vs Dimitri Vegas and Like mike20. Big Fat Spotless [Uber edit] - Martin Garrix & Jay Hardway21. Certified - Morten22. Caribbean Rave - W&W23. Omnia - Hold me24. Amsterdam - Jay Hardway25. Acid Rain - Will Sparks & Joel fletcher26. 7 Nation Mumbai [Uber edit] - JDG & Samuel james27. Make it right [Ilan Bluestone remix] - Armin28. Modulated lions - Ilan Bluestone29. Mosquito - Neelix30. Colors - Avalon, Tristan & Vini Vici31. FTS (Ridvan edit] - Showtek32. Turn day to night - The Galaxy33. Turn up - EMME x Erotic Cafe34. Invisible Children [Jinco & Francis edit] - Tigerlilly & KSHMR35. Swords [Bad Royale remix] - M.I.A36. Mr Brightside [Two Friends remix] - The killers37. Fix You Up - Uberjakd f. Yton

Progressive Vocal House "A Modulated Escape" #clubkerrynyc #DJset #free #Podcast iTunes http://bit.ly/iTunesKerry RSSFeed: http://clubkerrynyc.libsyn.com/rss Choose Your Device: 30 Ways To Listen: http://on.fb.me/GROD86 (Android, Windows Phone, iOS) Club Kerry NYC iOS App: http://bit.ly/kerryiosapp Club Kerry NYC Android App: http://bit.ly/AndroidKerry Club Kerry NYC Windows App: http://bit.ly/KerryWindows Premium Subscribe for extra episodes! Track List (50:09): 1. Escape (feat. Steph Jones) - Tritonal 2. Runaways (Jay Hardway Remix) - Sam Feldt & Deepend feat. Teemu *DJ FAVE* 3. Modulated Lions (Extended Mix) - Marc Voldt **DJ FAVORITE!***a 4. Broken (Toby Green Remix) - Tritonal (and Jenaux feat Adam Lambert) 5. Close To You (Dim2Play & Techcrasher Remix) - Seida ***Maxi Priest Retro Alert!*** 6. Sink Deep (Nora en Pure Club Remix) - Kyle Watson, Popartlive **DJ Fave** 7. Get Better - Misha Klein feat. Nikita Malinin 8 Breathe - Jonas Aden vs Kings 9. Send Them Off! (Tiesto Remix) - Bastille 10. What Is Love 2016 (Regi & Lester Williams Extended Remix) - Lost Freguencies 11. Trouble - Solano, Landis 12. Never Ever (Original Mix) - JMA, Tonski 13. Pray For Rain (Muzzaik Remix) - MOGUAI 14. Speed Up (Tom Swoon Remix) - Funkerman 15. Move Your Body (Alan Walker Remix) - Sia

Dr Nutting meets with ecancertv at ASCO 2016 to share the results from a multicentre trial which sought to determine if hearing loss associated with parotid cancer radiotherapy could be spared via intensity modulation. He reports that the trial failed to spare hearing loss as hoped, but they will take these results forward to establish safe levels in further trials.

Concept Audio Podcast #22 'Mood Modules 2' Modulated by Melomake Продолжение одноименного выпуска 'Mood Modules'.

David J. Gladstone ScD DABMP

Summary: Allergic diseases have exponentially increased during the last decades. The complexity of its aetiology is due to multifaceted interactions between genetic and environmental factors on the development of the immune system. While advances of technology have identified allergy susceptibility genes, functional assays are needed to better understand the underlying mechanisms. Epidemiological studies have consistently shown that rural/farm environments are protective for the development of allergic diseases, including asthma and atopic sensitization. Importantly, prenatal and early life exposures have been shown to confer the strongest protection effects. The mechanisms of how farming modulates the immune system are still not disentangled in detail but include regulation of innate receptors and Regulatory T cells. In the herewith presented thesis, the following main findings were achieved in the context of genetic and immunological influences on development of allergic disease in two different birth cohort studies: First, 200 neonates were assessed for genetic influence of polymorphisms on neonatal immune responses and development of allergic diseases in childhood. The present study suggested a role for polymorphisms in the Th2-pathway, particularly for STAT6 rs324011, on immune regulation at an early stage of immune maturation, namely significantly lower Treg-associated gene expression and Th1-polarization. Polymorphisms in the Th1-pathway, namely the transcription factors TBX21 and HLX1, were shown to be relevant in shaping early immune responses and mainly Th2 cytokines at birth. Th1 and Th2 genotype-related immune responses at birth were partially associated with development of allergic diseases and/or protection during early life. These children are currently followed until the age of 6 years to further investigate allergic and respiratory disease during age-related immune maturation. Secondly, almost 150 children were investigated at the age of 6 years to assess the role of regulatory T cells in relation to farm exposures and clinical outcomes of allergic diseases. Our data indicated an inverse association of farm exposures and the prevalence of asthma during childhood. Children exposed to hay, stable and farm milk had a lower prevalence of asthma. Regarding underlying immune mechanisms, we have detected that children with contact to hay have increased levels of Treg cells and that farm milk intake earlier during childhood can still be partially reflected on Treg cells levels at age 6 years. Assessing Treg functional mechanisms, changes in cytokine secretion were observed depending on the farming and asthmatic status of the children, however confirmation in a larger number of children is required In summary the present work indicated that Th1 and Th2 polymorphisms were associated with modulated immune responses already at birth and influenced allergic disease development during the first three years of life. Furthermore, farm exposures were associated with a lower prevalence of asthma and associated with modulation of regulatory T cell frequency in German children at age 6 years.

Background: To report an unplanned interim analysis of a prospective, one-armed, single center phase I/II trial (NCT01566123). Methods: Between 2007 and 2013, 27 patients (pts) with primary/recurrent retroperitoneal sarcomas (size > 5 cm, M0, at least marginally resectable) were enrolled. The protocol attempted neoadjuvant IMRT using an integrated boost with doses of 45-50 Gy to PTV and 50-56 Gy to GTV in 25 fractions, followed by surgery and IOERT (10-12 Gy). Primary endpoint was 5-year-LC, secondary endpoints included PFS, OS, resectability, and acute/late toxicity. The majority of patients showed high grade lesions (FNCLCC G1:18%, G2:52%, G3:30%), predominantly liposarcomas (70%). Median tumor size was 15 cm (6-31). Results: Median follow-up was 33 months (5-75). Neoadjuvant IMRT was performed as planned (median dose 50 Gy, 26-55) in all except 2 pts (93%). Gross total resection was feasible in all except one patient. Final margin status was R0 in 6 (22%) and R1 in 20 pts (74%). Contiguous-organ resection was needed in all grossly resected patients. IOERT was performed in 23 pts (85%) with a median dose of 12 Gy (10-20 Gy). We observed 7 local recurrences, transferring into estimated 3- and 5-year-LC rates of 72%. Two were located outside the EBRT area and two were observed after more than 5 years. Locally recurrent situation had a significantly negative impact on local control. Distant failure was found in 8 pts, resulting in 3-and 5-year-DC rates of 63%. Patients with leiomyosarcoma had a significantly increased risk of distant failure. Estimated 3-and 5-year-rates were 40% for PFS and 74% for OS. Severe acute toxicity (grade 3) was present in 4 pts (15%). Severe postoperative complications were found in 9 pts (33%), of whom 2 finally died after multiple re-interventions. Severe late toxicity (grade 3) was scored in 6% of surviving patients after 1 year and none after 2 years. Conclusion: Combination of neoadjuvant IMRT, surgery and IOERT is feasible with acceptable toxicity and yields good results in terms of LC and OS in patients with high-risk retroperitoneal sarcomas. Long term follow-up seems mandatory given the observation of late recurrences. Accrual of patients will be continued with extended follow-up.

Background: To report our experience with increased dose intensity-modulated radiation and concurrent systemic chemotherapy as definitive treatment of locally advanced esophageal cancer. Patients and methods: We analyzed 27 consecutive patients with histologically proven esophageal cancer, who were treated with increased-dose IMRT as part of their definitive therapy. The majority of patients had T3/4 and/or N1 disease (93%). Squamous cell carcinoma was the dominating histology (81%). IMRT was delivered in step-and-shoot technique in all patients using an integrated boost concept. The boost volume was covered with total doses of 56-60 Gy (single dose 2-2.14 Gy), while regional nodal regions received 50.4 Gy (single dose 1.8 Gy) in 28 fractions. Concurrent systemic therapy was scheduled in all patients and administered in 26 (96%). 17 patients received additional adjuvant systemic therapy. Loco-regional control, progression-free and overall survival as well as acute and late toxicities were retrospectively analyzed. In addition, quality of life was prospectively assessed according to the EORTC QLQs (QLQ-OG25, QLQ-H&N35 and QLQ-C30). Results: Radiotherapy was completed as planned in all but one patient (96%), and 21 patients received more than 80% of the planned concurrent systemic therapy. We observed ten locoregional failures, transferring into actuarial 1-, 2- and 3-year-locoregional control rates of 77%, 65% and 48%. Seven patients developed distant metastases, mainly to the lung (71%). The actuarial 1-, 2- and 3-year-disease free survival rates were 58%, 48% and 36%, and overall survival rates were 82%, 61% and 56%. The concept was well tolerated, both in the clinical objective examination and also according to the subjective answers to the QLQ questionnaire. 14 patients (52%) suffered from at least one acute CTC grade 3/4 toxicity, mostly hematological side effects or dysphagia. Severe late toxicities were reported in 6 patients (22%), mostly esophageal strictures and ulcerations. Severe side effects to skin, lung and heart were rare. Conclusion: IMRT with concurrent systemic therapy in the definitive treatment of esophageal cancer using an integrated boost concept with doses up to 60 Gy is feasible and yields good results with acceptable acute and late overall toxicity and low side effects to skin, lung and heart.

Here, I studied the role of two candidate genes i.e. neuropeptide S receptor 1 (Npsr1) and transmembrane protein 132D (Tmem132d), in two psychopathological animal models of anxiety-related behavior because of recent studies showing importance of these candidates in limbic areas and the frontal cortex of panic disorder patients, respectively. The two animal models are rat (r) and mouse (m), high anxiety-related behavior (rHAB/mHAB) and low anxiety-related behavior(rLAB/mLAB). To understand the anxiolytic role of neuropeptide S (NPS), basal Npsr1 mRNA expression was studied in limbic brain regions of HAB vs. LAB rodents, i.e. the paraventricular nucleus of hypothalamus (PVN) and amygdala, because these regions have been implicated in anxiety and fear attenuating responses of NPS and also due to differences in long-term activity based on cytochrome c oxidase activity in mHAB vs. mLAB. There was significantly lower basal Npsr1 mRNA expression in the basolateral amygdala of mHAB and also in the PVN of rHAB compared to corresponding LABs. To study the genetic underpinnings underlying this differential expression, Npsr1 DNA sequencing was carried out, which revealed several polymorphisms including single-nucleotide polymorphisms (SNP), insertions and deletions. By using dual reporter (luciferase) assays, I could show that the SNPs in the whole HAB promoter construct cause a significant decrease in promoter activity, thus confirming our in vivo findings in both rats and mice. Interestingly, however, when the promoter constructs were shortened to 500 bp relative to translational (ATG) start site, there was a two-fold higher HAB promoter activity, which could be attributed to the introduction of a polymorphism with putative binding site for the glucocorticoid receptor (GR) transcription factor. The higher HAB promoter activity was suppressed by dexamethasone (a GR activator), thus suggesting the presence of a polymorphism that favors GR binding. These findings are analogous to the higher HAB specific allele expression in cross-mated F1 offspring, which allows us to study the HAB vs. LAB alleles in the same cellular environment, irrespective of any epigenetic or other environmentally mediated factors that might modulate or interact with cis-acting factors. In addition, there was no difference in Npsr1 mRNA expression in the basolateral amygdala of mHAB and mLAB subjected to environmental enrichment (EE) and unpredictable chronic mild stress (UCMS), respectively. Thus it is a non-plastic gene as it does not respond to environmental challenges faced by the susceptible animal models. Similarly, for Tmem132d, using dual luciferase assays, two SNPs in the mHAB promoter region were shown to cause an increase in its corresponding promoter activity, and there was no difference in DNA methylation in the mHAB vs. mLAB Tmem132d promoter region, which explains the observed higher Tmem132d mRNA expression in the anterior cingulate cortex of mHAB. However, mHABs subjected to EE had higher Tmem132d mRNA expression, while mLAB undergoing UCMS had corresponding lower gene expression. To study the cis-trans interaction, we also subjected cross-mated F1 offspring to EE or UCMS and found that both groups have higher mLAB allelic expression, which could be attributed to differences in DNA methylation. Finally, I could show that there was no difference in DNA methylation in the basal mHAB vs. mLAB Tmem132d promoter and that two SNPs in the mHAB promoter were sufficient to cause a higher corresponding promoter activity, which explains the in vivo findings observed in the anterior cingulate cortex. Furthermore, F1 offspring subjected to EE or UCMS had a significantly lower mHAB-specific allele expression which was negatively correlated with DNA methylation, in the Tmem132d promoter region, thus this suggests cross-talk between genetic and environmentally mediated epigenetic factors. In summary, the data suggests a strong evolutionary conserved role of the NPS system considering the similar findings in rats and mice. However, Npsr1 is a nonplastic gene as it is not amenable to the different environmental manipulations applied to the animals. On the other hand, the plastic gene Tmem132d, is differentially expressed, thus making the animals more susceptible to environmental influences. Here, it could be revealed, that SNPs in the mHAB Tmem132d promoter cause higher promoter activity and that environmental manipulation can modulate the gene’s corresponding expression through DNA methylation.

Gauntlett, J (Imperial College London) Wednesday 18 September 2013, 09:00-09:45

Copic, M (Univerza v Ljubljani) Thursday 21 February 2013, 11:00-12:00

In roleplay and furry art, yiff modulation (YM) conveys information over an orgasm wave by varying its instantaneous orientation. This contrasts with straight modulation, in which the orientation of the orgasm is varied while its attractiveness remains constant.

Tue, 1 Jan 2013 12:00:00 +0100 https://epub.ub.uni-muenchen.de/23106/1/1742-2094-10-34.pdf Myint, Aye-Mu; Bogerts, Bernhard; Schwabedissen, Louise M. Zu; Bielau, Hendrik; Brisch, Ralf; Mawrin, Christian; Sarnyai, Zoltan; Bernstein, Hans-Gert; Guillemin, Gilles J.; Gos, Tomasz

Gauntlett, J (Imperial College London) Tuesday 15 May 2012, 11:30-12:30

Tissue-specific transcripts are likely to be of importance for the corresponding organ. While attempting to define the specific transcriptome of the human lung, we identified the transcript of a yet uncharacterized protein, SFTA2. In silico analyses, biochemical methods, fluorescence imaging and animal challenge experiments were employed to characterize SFTA2. Human SFTA2 is located on Chr. 6p21.33, a disease-susceptibility locus for diffuse panbronchiolitis. RT-PCR verified the abundance of SFTA2-specific transcripts in human and mouse lung. SFTA2 is synthesized as a hydrophilic precursor releasing a 59 amino acid mature peptide after cleavage of an N-terminal secretory signal. SFTA2 has no recognizable homology to other proteins while orthologues are present in all mammals. SFTA2 is a glycosylated protein and specifically expressed in nonciliated bronchiolar epithelium and type II pneumocytes. In accordance with other hydrophilic surfactant proteins, SFTA2 did not colocalize with lamellar bodies but colocalized with golgin97 and clathrin-labelled vesicles, suggesting a classical secretory pathway for its expression and secretion. In the mouse lung, Sfta2 was significantly downregulated after induction of an inflammatory reaction by intratracheal lipopolysaccharides paralleling surfactant proteins B and C but not D. Hyperoxia, however, did not alter SFTA2 mRNA levels. We have characterized SFTA2 and present it as a novel unique secretory peptide highly expressed in the lung.

Betcke, T (University College London) Tuesday 13 December 2011, 09:00-09:30

The measurement of polarization information in optical imaging is made complicated by the fact that traditional optical detectors are polarization-blind and only measure intensity. In order to determine the polarization state of light across the scene, the intensity at each point must be modified in a controllable fashion over a series of measurements so that the distribution of polarization information can be inferred from these measurements. There are two general strategies for accomplishing this. The first method — generally referred to as wavefront division polarimetry — breaks the light into a series of channels, each with its own combination of polarization elements. The light in each of these channels is directed to an independent detector array, and the outputs are combined in order to estimate the polarization state. Wavefront division polarimeters have the advantage of obtaining the full space-time-wavelength resolution of the detectors. However, the disadvantage of such systems is the need for alignment, temporal synchronization and polarimetric aberration compensation across the channels. Additionally, there are practical limits to how many such channels can be put into a single system. The second strategy, and the one considered in this talk, is the class of modulated polarimeter that uses a single detector array to capture intensity information that has been modulated in space, time, wavelength or some combination of the three. Modulated polarimeters have the advantage of inherent spatial, temporal and wavelength alignment, but this comes at the expense of a reduction of the overall system bandwidth, since now a single detector is used to measure multiple channels.

Background: Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor a has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described. Methods: Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects. Results: Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD. Conclusions: These results add a novel link to the immune hypothesis of depression by providing evidence for an upregulation of microglial QUIN in brain regions known to be responsive to infusion of NMDA antagonists such as ketamine. Further work in this area could lead to a greater understanding of the pathophysiology of depressive disorders and pave the way for novel NMDA receptor therapies or immune-modulating strategies.

Lubich, C (Universitaet Tuebingen, DE) Wednesday 15 September 2010, 09:00-10:00

The aim of this work is to develop an experimental method to measure in-plane surface properties on the nanometer scale by torsional resonance mode atomic force microscopy and to understand the underlying system dynamics. The invention of the atomic force microscope (AFM) and the advances in development of new AFM based techniques have significantly enhanced the capability to probe surface properties with nanometer resolution. However, most of these techniques are based on a flexural oscillation of the force sensing cantilever which are sensitive to forces perpendicular to the surface. Therefore, there is a need for highly sensitive measurement methods for the characterization of in-plane properties. To this end, scanning shear force measurements with an AFM provide access to surface properties such as friction, shear stiffness, and other tribological surface properties with nanometer resolution. Dynamic atomic force microscopy utilizes the frequency response of the cantilever-probe assembly to reveal nanomechanical properties of the surface. The frequency response function of a cantilever in torsional motion was investigated by using a numerical model based on the finite element method (FEM). We demonstrated that the vibration of the cantilever in a torsional oscillation mode is highly sensitive to lateral elastic (conservative) and visco-elastic (non-conservative) in-plane material properties, thus, mapping of these properties is possible in the so-called torsional resonance mode AFM (TR-mode). The theoretical results were then validated by implementing a frequency modulation (FM) detection technique to torsion mode AFM. This method allows for measuring both conservative and non-conservative interactions. By monitoring changes of the resonant frequency and the oscillation amplitude, we were able to map elastic properties and dissipation caused by the tip-sample interaction. During approach and retract cycles, we observed a slight negative detuning of the torsional resonance frequency, depending on the tilt angle between the oscillation plane and the surface before contact to the HOPG surface. This angle leads to a mixing of in-plane (horizontal) and out-of-plane (vertical) sample properties. These findings have a significant implication for the imaging process and the adjustment of the microscope and may not be ignored when interpreting frequency shift or energy dissipation measurements. To elucidate the sensitivity of the frequency modulated torsional resonance mode AFM (FM-TR-AFM) for the energy dissipation measurement, different types of samples such as a compliant material (block copolymer), a mineral (chlorite) and a macromolecule (DNA) were investigated. The measurement of energy dissipation on these specimens indicated that the TR-AFM images reveal a clear difference for the domains which have different mechanical properties. Simultaneously a topographic and a chemical contrast are obtained by recording the detuning and the dissipation signal caused by the tip-surface interaction. Using FM-TR-AFM spectroscopically, we investigated frequency shift versus distance curves on the homopolymer polystyrene (PS). Depending on the molecular weight, the frequency detuning curve displayed two distinct regions. Firstly, a rather compliant surface layer was probed; secondly, the less mobile bulk of the polymer was sensed by the oscillatory motion of the tip. The high sensitivity of this technique to mechanical in-plane properties suggests that it can be used to discriminate different chemical properties (e.g. wetting) of the material by simultaneously measuring energy dissipation and surface topography.

Our understanding of human visual perception generally rests on the assumption that conscious visual states represent the interaction of spatial structures in the environment and our nervous system. This assumption is questioned by circumstances where conscious visual states can be triggered by external stimulation which is not primarily spatially defined. This work discusses psychophysical experiments investigating flicker induced subjective experiences of colour and form. Using the presentation of spatially uniform flicker with a precise temporal resolution it is shown that subjective experiences do not only depend on stimulation frequency, but also on stimulation phase. In addition, the occurrence of one subjective experience appears to be associated with the occurrence of others. The phenomenology of subjective colour and form is further explored and the physiological mechanisms underlying subjective colour are investigated using electroencephalography. While these data indicate that conscious visual experience may be evoked directly by particular variations in the flow of spatially unstructured light over time it may be assumed that the systems reponsible are essentially temporal in character and capable of representing a variety of visual forms and colours, coded in different frequencies or at different phases of the same processing rhythm.

Sat, 1 Jan 1994 12:00:00 +0100 http://epub.ub.uni-muenchen.de/3652/ http://epub.ub.uni-muenchen.de/3652/1/3652.pdf Singer-Lahat, Dafna; Lotan, Ilana; Biel, Martin; Flockerzi, Veit; Hofmann, Franz; Dascal, Nathan Singer-Lahat, Dafna; Lotan, Ilana; Biel, Martin; Flockerzi, Veit; Hofmann, Franz und Dascal, Nathan (1994): Cardiac calcium channels expressed in Xenopus oocytes are modulated by dephosphorylation but not by cAMP-dependent phosphorylation. In: Receptors and Channels, Vol. 2: pp. 215-226.

Sat, 1 Jan 1994 12:00:00 +0100 http://epub.ub.uni-muenchen.de/3225/ http://epub.ub.uni-muenchen.de/3225/1/3225.pdf Grothe, Benedikt Grothe, Benedikt (1994): Interaction of excitation and inhibition in processing of pure tone and amplitude-modulated stimuli in the medial superior olive of the mustached bat. In: Journal of Neurophysiology,

1. In bovine adrenal chromaffin cells made permeable either to molecules less than or equal to 3 kDa with alphatoxin or to proteins less than or equal to 150 kDa with streptolysin O, the GTP analogues guanosine 5'-[beta gamma-imido]triphosphate (p[NH]ppG) and guanosine 5'-[gamma-thio]triphosphate (GTP[S]) differently modulated Ca(2+)-stimulated exocytosis. 2. In alphatoxin-permeabilized cells, p[NH]ppG up to 20 microM activated Ca(2+)-stimulated exocytosis. Higher concentrations had little or no effect. At a free Ca2+ concentration of 5 microM, 7 microM-p[NH]ppG stimulated exocytosis 6-fold. Increasing the free Ca2+ concentration reduced the effect of p[NH]ppG. Pretreatment of the cells with pertussis toxin prevented the activation of the Ca(2+)-stimulated exocytosis by p[NH]ppG. 3. In streptolysin O-permeabilized cells, p[NH]ppG did not activate, but rather inhibited Ca(2+)-dependent catecholamine release under all conditions studied. In the soluble cytoplasmic material that escaped during permeabilization with streptolysin O, different G-protein alpha-subunits were detected using an appropriate antibody. Around 15% of the cellular alpha-subunits were detected in the supernatant of permeabilized control cells. p[NH]ppG or GTP[S] stimulated the release of alpha-subunits 2-fold, causing a loss of about 30% of the cellular G-protein alpha-subunits under these conditions. Two of the alpha-subunits in the supernatant belonged to the G(o) type, as revealed by an antibody specific for G(o) alpha. 4. GTP[S], when present alone during stimulation with Ca2+, activated exocytosis in a similar manner to p[NH]ppG. Upon prolonged incubation, GTP[S], in contrast to p[NH]ppG, inhibited Ca(2+)-induced exocytosis from cells permeabilized by either of the pore-forming toxins. This effect was resistant to pertussin toxin. 5. The p[NH]ppG-induced activation of Ca(2+)-stimulated release from alphatoxin-permeabilized chromaffin cells may be attributed to one of the heterotrimeric G-proteins lost during permeabilization with streptolysin O. The inhibitory effect of GTP[S] on exocytosis is apparently not mediated by G-protein alpha-subunits, but by another GTP-dependent process still occurring after permeabilization with streptolysin O.

The present study examined the role of N-methyl-D-aspartic acid (NMDA) receptors in synaptic plasticity in regular-spiking cells of rat frontal cortex. Intracortical stimulation, at levels subthreshold for elicitation of action potentials, evoked a late excitatory postsynaptic potential (EPSP) in layer II III neurons that was sensitive to the selective NMDA antagonist -2-amino-5-phosphonovaleric acid (APV). This late EPSP showed marked short-term frequency-dependent depression, suggesting that it is polysynaptic in origin. Polysynaptic late EPSPs were selectively enhanced following high-frequency stimulation. This sustained increase in synaptic efficacy, or long-term potentiation, was expressed in regular spiking cells and appeared to result from activation of NMDA receptors on excitatory interneurons. These data demonstrate the existence of an NMDA-modulated polysynaptic circuit in the neocortex which displays several types of use-dependent plasticity.

Collicular evoked potentials in Rhinolophus ferrum equinum show very prominent responses to the final frequency modulated part of a acoustic stimulus, simulating the natural echolocation sound.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.22.055038v1?rss=1 Authors: Jiang, X., Ma, X., Geng, Y., Zhao, Z., Zhou, F., Zhao, W., Yao, S., Yang, S., Zhao, Z., Becker, B., Kendrick, K. M. Abstract: The neuropeptide oxytocin is a key modulator of social-emotional behavior and its intranasal administration can influence the functional connectivity of brain networks involved in the control of attention, emotion and reward reported in humans. However, no studies have systematically investigated the effects oxytocin on dynamic or directional aspects of functional connectivity. The present study employed a novel computational framework to investigate these latter aspects in 15 oxytocin-sensitive regions using data from randomized placebo-controlled between-subject resting state functional MRI studies incorporating 200 healthy subjects. Results showed that oxytocin extensively modulated effective connectivity both between and within emotion, reward, salience and social cognition processing networks and their interactions with the default mode network, but had no effect on the frequency of dynamic changes. Top-down control over emotional processing regions such as the amygdala was particularly affected. Oxytocin effects were also sex-dependent, being more extensive in males. Overall, these findings suggest that modulatory effects of oxytocin on both within- and between-network interactions may underlie its functional influence on social-emotional behaviors, although in a sex-dependent manner. Furthermore, they demonstrate a useful approach to determining pharmacological influences on resting state effective connectivity and support oxytocin's potential therapeutic use in psychiatric disorders. Copy rights belong to original authors. Visit the link for more info