Podcasts about allelic

URGENT MESSAGE: Denise has generously organised a 20% discount for the first 60 people to purchase her upcoming 28 Day WholeFood Challenge course beginning in January 2024:Use the code: NatMedPodcast20We're born with a genetic blueprint, including some variations we may have acquired along the way. These variations, called SNPs (short for Single Nucleotide Polymorphisms), influence certain characteristics of our DNA blueprint to change gene expression. What we now know is that diet can have effects on gene expression  leading to powerful effects on our health.And what better clinician to lead us through how to master your genes using food, than Dr Denise Furness.Strap in and have the rewind button handy. This is an information-packed podcast!ReferencesMCM6 - lactoseMCM6 is located upstream from the LCT gene, which produces the enzyme lactase required to digest lactose. MCM6 influences LCT and lactase expression.PMID: 11788828, PMID: 12915462, PMID: 15114531HLA-DQ haplotypes - Gluten Human leukocyte antigen (HLA system) encodes the Major Histocompatibility Complex (MHC). These genes code for antigens (proteins) that help cells recognise self versus non-self. Genetic variations within HLA-DQA1 & HLA-DQB1 are linked to coeliac disease and other autoimmune conditions.PMID: 30763397, PMID: 29244800MTHFR FolateMTHFR converts 5,10-methylenetetrahydrofolate (5,10 methyleneTHF) to 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is needed to convert homocysteine to methionine, therefore MTHFR supports methylation (making SAM) reactions throughout the body.MTHFR 677 T allele and increased risk for lower folate and higher homocysteine levels PMID: 25788000, 24091066, 7647779,  9545395 APO-E Alzheimer's, LipidsAPOE's main phenotypes are caused by the combination of two SNPs that combine to form the genotypes/isoforms of ε2, ε3 and ε4 or E2, E3, E4. The E4 allele is associated with higher LDL levels and cardiovascular and neurological complications. PMID: 25328986, PMID: 11882522SLC30A8 - zinc transporterSpecific to pancreatic islets and mainly expressed in β-cells that transport zinc from the cytoplasm into insulin secretory vesicles. Allelic variants have been associated with glucose and pro-insulin levels and confer susceptibility to insulin resistance and diabetes mellitus (T2DM). PMID: 28218639, 17463249, 30936916.FTO and MC4R - weight and obesityFat mass and obesity-associated gene (FTO)Melanocortin-4-receptor (MC4R) PMID: 31954858, 19079261, 26888713

Dr. Corey Watson is an Associate Professor at the University of Louisville. His work focuses on characterising and cataloguing antibody genetic diversity in human and mouse to better understand disease susceptibility and clinical health outcomes. Dr. William Lees is a researcher at University of London. His work focuses on developing Adaptive Immune Receptor (AIR) reference sets for diverse species and the annotation of experimental sequence data. In this episode we talk about the recent work by the Germline Database Working Group of the AIRR-Community. The accuracy of V and J gene segment assignment improves with the quality of the reference germline set. The accurate assignment is critical for characterization of somatic hypermutation. We discuss the challenges in creating a database to hold all relevant and potentially relevant germline information, especially in the light of increased discovery rate through technological advances and improved analysis pipelines. We also reflect on the complexity in handling personalised germline reference sets. The episode is hosted by Dr. Ulrik Stervbo and Dr. Zhaoqing Ding. Comments are welcome to the inbox of onairr@airr-community.org  or on social media under the tag #onAIRR. Further information can be found here: https://www.antibodysociety.org/the-airr-community/airr-c-podcast.  Website of the AIRR-C Germline Database Working Group https://www.antibodysociety.org/the-airr-community/airr-working-groups/germline_database/  Papers mentioned Collins, Andrew M., Mats Ohlin, Martin Corcoran, James M. Heather, Duncan Ralph, Mansun Law, Jesus Martínez-Barnetche, et al. 2023. “AIRR-C Human IG Reference Sets: Curated Sets of Immunoglobulin Heavy and Light Chain Germline Genes.” BioRxiv. https://doi.org/10.1101/2023.09.01.555348  Rodriguez, Oscar L., Yana Safonova, Catherine A. Silver, Kaitlyn Shields, William S. Gibson, Justin T. Kos, David Tieri, et al. 2023. “Genetic Variation in the Immunoglobulin Heavy Chain Locus Shapes the Human Antibody Repertoire.” Nature Communications 14 (1). https://doi.org/10.1038/s41467-023-40070-x  Lees, William D., Scott Christley, Ayelet Peres, Justin T. Kos, Brian Corrie, Duncan Ralph, Felix Breden, et al. 2023. “AIRR Community Curation and Standardised Representation for Immunoglobulin and T Cell Receptor Germline Sets.” Immunoinformatics (Amsterdam, Netherlands) 10 (100025): 100025. https://doi.org/10.1016/j.immuno.2023.100025  Jackson, Katherine J. L., Justin T. Kos, William Lees, William S. Gibson, Melissa Laird Smith, Ayelet Peres, Gur Yaari, et al. 2022. “A BALB/c IGHV Reference Set, Defined by Haplotype Analysis of Long-Read VDJ-C Sequences From F1 (BALB/c x C57BL/6) Mice.” Frontiers in Immunology 13. https://doi.org/10.3389/fimmu.2022.888555  Ford, Easton E., David Tieri, Oscar L. Rodriguez, Nancy J. Francoeur, Juan Soto, Justin T. Kos, Ayelet Peres, et al. 2023. “FLAIRR-Seq: A Method for Single-Molecule Resolution of near Full-Length Antibody H Chain Repertoires.” The Journal of Immunology 210 (10): 1607–19. https://doi.org/10.4049/jimmunol.2200825  Omer, Aviv, Ayelet Peres, Oscar L. Rodriguez, Corey T. Watson, William Lees, Pazit Polak, Andrew M. Collins, and Gur Yaari. 2022. “T Cell Receptor Beta Germline Variability Is Revealed by Inference from Repertoire Data.” Genome Medicine 14 (1). https://doi.org/10.1186/s13073-021-01008-4  Rodriguez, Oscar L., Catherine A. Silver, Kaitlyn Shields, Melissa L. Smith, and Corey T. Watson. 2022. “Targeted Long-Read Sequencing Facilitates Phased Diploid Assembly and Genotyping of the Human T Cell Receptor Alpha, Delta, and Beta Loci.” Cell Genomics 2 (12): 100228. https://doi.org/10.1016/j.xgen.2022.100228  Tools mentioned TIgGER (Immcantation) https://tigger.readthedocs.io/en/stable  IgDiscover https://github.com/NBISweden/IgDiscover  Partis https://github.com/psathyrella/partis MiXCR https://mixcr.com

References Nature. 2020 Jun; 582(7813): 577–581 Science Immunology 2018.26 Jan Vol 3, Issue 1 --- 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

References Int J Mol Sci. 2020 Jun; 21(11): 4098. --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.28.529432v1?rss=1 Authors: Vartanian, V., Krey, J. F., Chatterjee, P., Jones, S. M., Curtis, A., Ryals, R., Lloyd, R. S., Barr-Gillespie, P. G. Abstract: Strategies to reveal the discovery of the relationships between novel phenotypic behaviors and specific genetic alterations can be achieved via either target-specific, directed mutagenesis or phenotypic selection following random chemical mutagenesis. As an alternative approach, one can exploit deficiencies in DNA repair pathways that are responsible for the maintenance of genetic integrity in response to spontaneously-induced damage. In the genetic background of mice deficient in the DNA glycosylase NEIL1, elevated numbers of spontaneous mutations arise from translesion DNA synthesis past unrepaired, oxidatively-induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting, and circling. Mapping of the mutation that conferred these behaviors revealed the introduction of a stop codon at amino acid 4 of the Ush1g gene; the allele was Ush1gbw, reflecting the backwards-walking phenotype. Ush1gbw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell's kinocilial links. Due to the vestibular dysfunction, however, visual behavior as measured with optokinetic tracking could not be assessed in Ush1gbw/bw mice. Consistent with other Usher type 1 models, however, Ush1gbw/bw mice had no substantial retinal degeneration compared to Ush1gbw/+ controls out to six months. In contrast to previously-described Ush1g alleles, this new allele provides the first knockout model for this gene. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Hare Hollow FarmJessica HareHarehollowfarm.comFacebook - https://www.facebook.com/Hare-Hollow-Farm-113861266980541Morph Market - https://www.morphmarket.com/stores/hare_hollow_farm/Instagram - https://www.instagram.com/hare_hollow_farm/ ASM Royal TailsJana KingFacebook -https://facebook.com/RoyalReptails/Morph Market -https://www.morphmarket.com/stores/asmroyaltails/Instagram - https://www.instagram.com/asmroyaltails/Intro Music - EEKmusic on audio jungleA community-science approach identifies genetic variants associated with three color morphs in ball pythons (Python regius)https://www.biorxiv.org/content/10.1101/2021.05.19.444867v2.full

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.26.267815v1?rss=1 Authors: Fan, J., Wang, X., Xiao, R., Li, M. Abstract: Allelic expression imbalance (AEI), quantified by the relative expression of two alleles of a gene in a diploid organism, can help explain phenotypic variations among individuals. Traditional methods detect AEI using bulk RNA sequencing (RNA-seq) data, a data type that averages out cell-to-cell heterogeneity in gene expression across cell types. Since the patterns of AEI may vary across different cell types, it is desirable to study AEI in a cell-type-specific manner. Although this can be achieved by single-cell RNA sequencing (scRNA-seq), it requires full-length transcript to be sequenced in single cells of a large number of individuals, which are still cost prohibitive to generate. To overcome this limitation and utilize the vast amount of existing disease relevant bulk tissue RNA-seq data, we developed BSCET, which enables the characterization of cell-type-specific AEI in bulk RNA-seq data by integrating cell-type composition information inferred from a small set of scRNA-seq samples, possibly obtained from an external dataset. By modeling covariate effect, BSCET can also detect genes whose cell-type-specific AEI are associated with clinical factors. Through extensive benchmark evaluations, we show that BSCET correctly detected genes with cell-type-specific AEI and differential AEI between healthy and diseased samples using bulk RNA-seq data. BSCET also uncovered cell-type-specific AEIs that were missed in bulk data analysis when the directions of AEI are opposite in different cell types. We further applied BSCET to two pancreatic islet bulk RNA-seq datasets, and detected genes showing cell-type-specific AEI that are related to the progression of type 2 diabetes. Since bulk RNA-seq data are easily accessible, BSCET provided a convenient tool to integrate information from scRNA-seq data to gain insight on AEI with cell type resolution. Results from such analysis will advance our understanding of cell type contributions in human diseases. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.14.250720v1?rss=1 Authors: Zhu, A., Matoba, N., Wilson, E., Tapia, A. L., Li, Y., Ibrahim, J. G., Stein, J. L., Love, M. I. Abstract: Expression quantitative trait loci (eQTL) studies are used to understand the regulatory function of non-coding genome-wide association study (GWAS) risk loci, but colocalization alone does not demonstrate a causal relationship of gene expression affecting a trait. Evidence for mediation, that perturbation of gene expression in a given tissue or developmental context will induce a change in the downstream GWAS trait, can be provided by two-sample Mendelian Randomization (MR). Here, we introduce a new statistical method, MRLocus, for Bayesian estimation of the gene-to-trait effect from eQTL and GWAS summary data for loci displaying allelic heterogeneity, that is, containing multiple LD-independent eQTLs. MRLocus makes use of a colocalization step applied to each eQTL, followed by an MR analysis step across eQTLs. Additionally, our method involves estimation of allelic heterogeneity through a dispersion parameter, indicating variable mediation effects from each individual eQTL on the downstream trait. Our method is evaluated against state-of-the-art methods for estimation of the gene-to-trait mediation effect, using an existing simulation framework. In simulation, MRLocus often has the highest accuracy among competing methods, and in each case provides more accurate estimation of uncertainty as assessed through interval coverage. MRLocus is then applied to five causal candidate genes for mediation of particular GWAS traits, where gene-to-trait effects are concordant with those previously reported. We find that MRLocus' estimation of the causal effect across eQTLs within a locus provides useful information for determining how perturbation of gene expression or individual regulatory elements will affect downstream traits. The MRLocus method is implemented as an R package available at https://mikelove.github.io/mrlocus. Copy rights belong to original authors. Visit the link for more info

Learn about why natural selection favors superstitions; why the way our noses smell is way more complicated than we thought; and where scientists think 'Oumuamua, the first interstellar object, came from. How natural selection favors superstitions by Cameron Duke Foster, K. R., & Kokko, H. (2008). The evolution of superstitious and superstition-like behaviour. Proceedings of the Royal Society B: Biological Sciences, 276(1654), 31–37. https://doi.org/10.1098/rspb.2008.0981  Hájek, A. (2018). Pascal’s Wager (E. N. Zalta (Ed.)). Stanford Encyclopedia of Philosophy; Metaphysics Research Lab, Stanford University. https://plato.stanford.edu/entries/https://plato.stanford.edu/entries/pascal-wager/index.htmlpascal-wager/index.html  Johnson, D. D. P., Blumstein, D. T., Fowler, J. H., & Haselton, M. G. (2013). The evolution of error: error management, cognitive constraints, and adaptive decision-making biases. Trends in Ecology & Evolution, 28(8), 474–481. https://doi.org/10.1016/j.tree.2013.05.014  The way our noses smell is way more complicated than we thought by Cameron Duke Making sense of scents: 3-D videos reveal how the nose detects odor combinations. (2020, April 9). Phys.org. https://phys.org/news/2020-04-scents-d-videos-reveal-nose.html Xu, L., Li, W., Voleti, V., Zou, D.-J., Hillman, E. M. C., & Firestein, S. (2020). Widespread receptor-driven modulation in peripheral olfactory coding. Science, 368(6487). https://doi.org/10.1126/science.aaz5390  Chess, A., Simon, I., Cedar, H., & Axel, R. (1994). Allelic inactivation regulates olfactory receptor gene expression. Cell, 78(5), 823–834. https://doi.org/10.1016/s0092-8674(94)90562-2  Morrison, J. (2014). Human nose can detect 1 trillion odours. Nature. https://doi.org/10.1038/nature.2014.14904 The Scent of a Molecule. (2017, November 17). Science History Institute. https://www.sciencehistory.org/distillations/the-scent-of-a-molecule We might finally know the origin of the first known interstellar object 'Oumuamua by Grant Currin Origin of the first known interstellar object ’Oumuamua. (2020). EurekAlert! https://www.eurekalert.org/pub_releases/2020-04/caos-oot041220.php  ‌In Depth | Oumuamua – NASA Solar System Exploration. (2019, December 19). NASA Solar System Exploration. https://solarsystem.nasa.gov/asteroids-comets-and-meteors/comets/oumuamua/in-depth Davis, N. (2020, April 13). Interstellar object ‘Oumuamua believed to be ‘active asteroid.’ The Guardian; The Guardian. https://www.theguardian.com/science/2020/apr/13/interstellar-object-oumuamua-believed-to-be-active-asteroid  PSRD: Active Asteroids. (2019). Hawaii.edu. http://www.psrd.hawaii.edu/May19/active-asteroids.html  Subscribe to Curiosity Daily to learn something new every day with Cody Gough and Ashley Hamer. You can also listen to our podcast as part of your Alexa Flash Briefing; Amazon smart speakers users, click/tap “enable” here: https://www.amazon.com/Curiosity-com-Curiosity-Daily-from/dp/B07CP17DJY 

Immune reveals an alternative to a protective vaccine, engineered B cells that produce antiviral antibodies. Hosts: Vincent Racaniello, Stephanie Langel, and Cynthia Leifer Subscribe (free): iTunes, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode Engineering B cells to produce antiviral antibodies (Sci Immun) Time stamps by Jolene. Thanks! Letters read on Immune 22 Weekly Science Picks Steph- Breath of fresh air Cindy- Biologist found dead Vincent- Nobel Prizes and Nature’s Surprises by Erling Norrby Music by Steve Neal. Immune logo image by Blausen Medical. Send your immunology questions and comments to immune@microbe.tv

In this episode, we are joined by: Travis Wyman Nick Mutton Justin Julander Warren Booth Benson Morrill We will be discussing various topics like, what does Co-Dom really mean,   The Axanthic gene, Clarify/explain what does "het" mean, Proving out a trait, Allelic complexes, Parthenogenesis and androgenesis,  Environmental versus heritable size and  Sequencing; what is possible and what is realistic. This will be an amazing show with an all-star lineup.

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.                                                 In our feature discussion today, we will be talking about insights from the PROMISE Trial regarding the prognostic value of non-invasive cardiovascular testing in patients with stable chest pain. First, here's your summary of this week's journal.                                                 The first paper reports novel findings on gene smoking interactions in coronary heart disease. Co-corresponding authors Dr. Salahin from the University of Pennsylvania and Dr. Riley from Columbia University and colleagues used data on almost 61,000 coronary heart disease cases and more than 80,000 controls to investigate effect modification by smoking behavior at established coronary heart disease and smoking-related genetic loci.                                                 They found that the cardio-protective effects associated with allelic variation at the A-D-A-M-T-S seven, or ADAMTS7 locus, were attenuated by 60% in patients who smoked tobacco, compared to those who did not smoke. Allelic variation in ADAMTS7 associated with reduced coronary heart disease risk, was associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines.                                                 Furthermore, exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. These human genomic data therefore provide new insights into potential mechanisms of coronary heart disease in cigarette smokers and suggests that inhibition of ADAMTS7 may be a novel potential therapeutic strategy for coronary heart disease that may have particular benefits in individuals who smoke cigarettes. This is discussed in an editorial entitled Holy Smokes, an Interaction, by Dr. Braxton Mitchell.                                                 The next paper provides first evidence that genetic over-expression of CD39 may offer ischemic cerebral protection. CD39 is an ectoenzyme with a PYRase activity, which cleaves ATP and ADP. CD39 is expressed on the surface of myeloid and vascular endothelial cells where it dissipates the high local concentrations of ATP and ADP, which would otherwise serve as potent pro-inflammatory and pro-thrombotic signals.                                                 In the current study from first author Dr. Bick, corresponding author Dr. Pinsky from University of Michigan Medical Center and colleagues, authors used a model of permanent middle cerebral artery occlusion to show that CD39 expression reduced edema, infarct volume, and inflammation with corresponding improvements in neurological outcomes, compared to control mice. Over-expression of CD39 in only the myeloid cells also reduced cerebral infarct volume. Thus, amplification of endogenous CD39 expression, or even administration of exogenous circulating CD39, may be of future interest as a therapeutic target to minimize ischemic injury caused by cerebral ischemia.                                                 The next paper provides pre-clinical data to show that MicroRNA93 may have a therapeutic role in peripheral artery disease. First author Dr. Ganta, corresponding author Dr. Annicks and colleagues from University of Virginia, used MicroRNA-106b-93-25 cluster knockout mice and showed that MicroRNA93 over-expression alone was sufficient to enhance angiogenesis, arteriogenesis, and perfusion in ischemic muscle via increased M2-like macrophages.                                                 MicroRNA93 targeted interferon regulatory factor 9 to inhibit immune response gene 1, and itaconic acid generation in macrophages to induce M2-like macrophage polarization. Furthermore, MicroRNA93 over-expression produced a paracrine effect on macrophages that induced angiogenesis and skeletal muscle recovery under hypoxic conditions in vitro.                                                 Thus, these data demonstrate that MicroRNA93 induces beneficial effects in multiple cells that can enhance perfusion in ischemic limb and thus identifies MicroRNA93 as a putative therapeutic target in clinical peripheral artery disease.                                                 The next study is a large scale genetic analysis that represents the most comprehensive causal assessment of adiposity with cardiometabolic diseases to date. Co-corresponding authors Dr. Cassis and Dale from University College London used 97 snips for BMI, and 49 snips for waist-hip ratio adjusted for BMI, to conduct mendelian randomization analysis in 14 prospective studies supplemented with coronary heart disease data from CADRIoGRAM+C4D, stroke data from METASTROKE, Type II Diabetes data from DIAGRAM and lipids data from GLGC Consortium.                                                 They found that both waist-hip ratio adjusted for BMI, and BMI had causal effects on coronary heart disease and Type II Diabetes, and were associated with higher left ventricular hypertrophy, glycemic traits, interleukin 6 and circulating lipids. However, only waist-hip ratio adjusted for BMI increased the risk of ischemic stroke. Thus, both the amount of adiposity and its distribution play important roles in influencing multiple cardiometabolic traits and the development of cardiometabolic disease.                                                 Furthermore, the findings indicate that body fat distribution has multiple roles in disease that are independent of general adiposity. This suggests that physicians should pay attention to measures of adiposity beyond BMI.                                                 The next study addresses the conundrum that clinical trials show benefit of lowering systolic blood pressure in people aged 80 years and above, but yet, non-randomized epidemiologic studies suggest lower systolic blood pressure is associated with higher mortality. In the current study by Dr. Ravindrarajah and colleagues of King's College London, a population based cohort study was conducted using electronic health records of 144,403 participants aged 80 years and older, registered with family practices in the United Kingdom, and followed for five years.                                                 Mortality rates increased with frailty level, and were highest at a systolic blood pressure of less than 110 millimeters mercury. Furthermore, systolic blood pressure trajectories showed an accelerated decline in the last two years of life, without evidence of intensification of anti-hypertensive therapy.                                                 Thus, a terminal decline of systolic blood pressure in the final two years of life suggests that non-randomized epidemiological associations of systolic blood pressure with higher mortality may be accounted for by reverse causation. That is, participants with lower blood pressure values were closer on average to the end of life. This is discussed in an accompanying editorial by Dr. Naveed Sattar.                                                 Well, that wraps it up for our summaries. Now for our feature discussion.                                                 The evaluation of stable patients presenting with suspected coronary artery disease is by far one of the most common diagnostic evaluation strategies that we need to undertake in cardiovascular medicine. There's a whole host of evidence supporting prognostication based on various non-invasive tests, such as anatomic imaging with coronary computed tomography angiography, but also with stress testing, or functional testing, such as stress nuclear or echocardiography, or exercise electrocardiography.                                                 However, our paper today really sheds light on the comparison of these two strategies. And I'm just delighted to have starts with me. First, the primary author of the paper, from the PROMISE Trial, Dr. Udo Hoffmann, from Massachusetts General Hospital, Harvard Medical School, and the editorialist of a beautiful accompanying editorial, Dr. Leslee Shaw from Emory University School of Medicine, Atlanta, Georgia.                                                 Welcome both. Dr.  Udo Hoffmann:        Hi, Carolyn. Hi, Leslee. Dr. Leslee Shaw:               Hi, Udo, how are you? Dr. Carolyn Lam:               So, Udo, could you start by just sharing what you did in this PROMISE Trial? Dr. Udo Hoffmann:          The Promise Trial is a large comparative effectiveness trial that was done between 2009 and 2012, with follow-up ending 2013, at [inaudible 00:10:13] sites across the U.S. and Canada. And what it did was compare two strategies for testing patients with suspicion of coronary disease, symptomatic patients. These patients were randomized to either receive a functional test first, or an atomic test first, and the idea was to see whether providing the functional information or the anatomic information leads to differences in outcomes of these patients.                                                 As you know, the primary paper showed that the health outcomes of these two strategies were similar and not different. Now in this paper here, we took the slightly different approach and we really wanted to see how the results of the tests as they were seen by the [inside 00:11:02] so it was all based on the sight interpretations of these tests. How the results of these tests actually were associated, or were associated with the health outcomes. And so we directly compared categories of CT results, and categories of functional testing results, and how they are related to outcomes. The good news I think is that sight interpretations in real life do actually have prognostic value for both the anatomic or the CT, and also the functional testing, and so findings as significant disease [inaudible 00:11:36] ischemia have in fact similar prognostic value. And we also saw that on the lower end of the findings, so mildly abnormal findings for example, that the ability to see nonobstructive CAD, perhaps if you're a difference maker and identify from additional patients or group of patients that is at risk for [inaudible 00:12:01]. Dr. Leslee Shaw:               I think that often times we struggle with negative trial results, if I can put PROMISE in that negative trial results. And here we have a paper that I think really applies clinically. I think it's going to have far-reaching clinical implications. I think if you look at the CTA findings, this is a real world practice. I think there's a simplicity to CTA interpretations that really is amplified in the nice ability to risk stratify. Whereas the functional interpretation, as you both know, is complex. It integrates a lot of factors, wall motion, perfusion imaging, ST segment changes, exertional symptoms, all of that, and I think we see a lot of sight variability in that image interpretation on the ischemia-side of the functional testing arm.                                                 But there's and important finding from this paper, which I think we have seen in bits and pieces prior to this report, and that is that on the CTA side, you had about a third of the patients having pure normal coronaries. So you see that very low risk in that population. But what you see on the functional testing arm is that the event rate in patients with normal studies and in patients with a mildly abnormal study, the event rates were identical, which is fascinating.                                                 And importantly, two thirds of the population on the functional testing arm were in those normal and mildly abnormal subgroups, something like that. And that has important implications for what is in that one third on a CTA side with normal findings versus three quarters? Well I think from this randomized trial, I think we can infer that you're going to have some non-obstructive disease in that population, but you're also going to have non-ischemic obstructive disease.                                                 We know from FFR and all of the angiographic literature that not every obstructive lesion is ischemic. And so on the stress testing side, we have a lot of obstructive disease that potentially is missed. And I think this study really clearly illustrates that limitation of stress testing and it reflects sight variability in imaging and the interpretation. It reflects the patient populations and the struggles with doing stress testing, but also just flat out reflects the ischemic cascade, and what we can expect from an obstructive lesion, or a non-obstructive lesion, that may not elicit ischemia.                                                 So to that extent, I think Udo's paper is just, just far-reaching and really clearly one of the most advanced papers that we have seen in such a long time. From really providing an important message for those imagers and for folks doing stress testing in this country. Dr. Carolyn Lam:               should we then always do anatomic testing first before selective stress testing? Dr. Udo Hoffmann:          The choice of testing is very much I think tied to the population of the patient you're talking about. I think when you follow the literature, 30 years ago when all the classic studies out of [experienced centers 00:18:53] such as Cedar Sinai, were published, the ischemia burden was much higher in the tested population. Back then you had probably a third or 40% of patients who in fact had some abnormality or ischemia on stress testing. One of the findings here in this study, and that is true for both tests, is that the prevalence of severe findings, severe abnormalities, whether ischemia or obstructive disease, is what I found testing is pretty similar, so it's both around 12%, but it is relatively infrequent. And I think that has changed.                                                 And you cannot expect, as Leslee pointed out nicely, it is not expected from a stress test to detect non-obstructive disease that has prognostic value, but doesn't necessarily explain these symptoms that the patient is presenting. So we should not forget that these patients do not come for primarily for prognostic assessment, they come because they're symptomatic. And the primary question is do we find an equivalent that could explain the symptoms of the patient? And only once we are convinced that there's no such equivalent that would for example lead us to further assess the patient for potential reverse [inaudible 00:20:19] therapy, then the second question that can be answered is for the prognostic implication of the test. And I think in this relatively low risk population, this prognostic aspect gains more importance irrelative to the diagnostic aspect. Dr. Carolyn Lam:               I think Leslee made it very clear in her editorial as well, not to forget in essence at the extremes of disease, that both tests, both strategies conveyed similar prognostic information, and it was more for the fine grain teasing apart that perhaps we need to consider very, very carefully what your paper is saying. But at the end of the day, it's about treating the patients for their cardiovascular risk management, isn't it? Recognizing that even if you don't have ischemia, if you've got the risk factors, like you nicely showed, that we should be treating them for the risk factors.                                                 Leslee, want to share some of your thoughts there? You covered that so nicely in your editorial. Dr. Leslee Shaw:               Well I think that's one thing we've seen from PROMISE, SCOT-HEART, and many, many other recent trials as of late, over the last three or four years, is that the stress test is an opportunity not only to assess ischemic burden, or that CTA's not only a test to assess the extent and severity of coronary disease as well as plaque, but it's an opportunity to identify clear, preventive strategies for the patients.                                                 And this is really something that I don't think at least historically within the stress testing community, that we have taken upon ourselves in order to say, "Okay, here we have a symptomatic patient. We not only are going to assess ischemia, but we're going to look at what else they need to do in order for us to guide prevention." I think this is a clear reminder that this is a great opportunity for us to have a bit of a paradigm shift on the diagnostic testing, to take that whole picture if you will of the patient, and really to focus in on prevention because that is a great opportunity, as Udo talked about just a few minutes ago, it's a great opportunity for us to set the patient on the correct course.                                                 The guidelines, as both of you know, focus in on having that diagnostic evaluation and to implement guideline directed medical therapy as a front line examination. This is a great opportunity for us to just use that diagnostic evaluation ad the initiation of appropriate care for the patient, and then to look at symptom burden, recurrent symptoms, the need for additional interventions. But that first step is guideline directed medical therapy for the patient. Dr. Udo Hoffmann:          Continuing on Leslee's excellent point, I think the paper I think is hopefully a starting point to think about randomized trial, because we assume some maybe come to the conclusion, okay, if you have non-obstructive disease, you should be treated with [inaudible 00:23:13] and aspirin. But we don't know that. I think this is really a call for randomized trial. PROMISE was the one, and it was a good trial. It looked at the association of strategy with an outcome. I think one trial that is needed is to look what specific therapeutic decisions based on imaging or based on test diagnostic test findings, would be justified and would potentially lead to improved outcomes. And that is true for both the stress testing and the CT side. So I think this paper shows the opportunities, but I don't think we have the randomized data to exactly define what are the management options for each of these details of the information that these test results deliver us. Dr. Carolyn Lam:              

The insulin-like growth factor 2 receptor (IGF2R) is essential for prenatal growth regulation and shows gene dosage effects on fetal weight that can be affected by in-vitro embryo culture. Imprinted maternal expression of murine Igf2r is well documented for all fetal tissues excluding brain, but polymorphic imprinting and biallelic expression were reported for IGF2R in human. These differences have been attributed to evolutionary changes correlated with specific reproductive strategies. However, data from species suitable for testing this hypothesis are lacking. The domestic cow (Bos taurus) carries a single conceptus with a similar gestation length as human. We identified 12 heterozygous concepti informative for imprinting studies among 68 Bos taurus fetuses at Day 80 of gestation (28% term) and found predominantly maternal IGF2R expression in all fetal tissues but brain, which escapes imprinting. Inter-individual variation in allelic expression bias, i.e. expression of the repressed paternal allele relative to the maternal allele, ranged from 4.6-8.9% in heart, 4.3-10.2% in kidney, 6.1-11.2% in liver, 4.6-15.8% in lung and 3.2-12.2% in skeletal muscle. Allelic bias for mesodermal tissues (heart, skeletal muscle) differed significantly (P

Tue, 1 Jan 1991 12:00:00 +0100 http://epub.ub.uni-muenchen.de/3043/ http://epub.ub.uni-muenchen.de/3043/1/3043.pdf Messer, Gerald; Spengler, Ulrich; Jung, Maria C.; Honold, G.; Eisenburg, Josef; Scholz, S.; Albert, E. D.; Pape, Gerd R.; Riethmüller, Gert; Weiß, Elisabeth Messer, Gerald; Spengler, Ulrich; Jung, Maria C.; Honold, G.; Eisenburg, Josef; Scholz, S.; Albert, E. D.; Pape, Gerd R.; Riethmüller, Gert und Weiß, Elisabeth (1991): Allelic variation in the TNF-beta gene does not explain the low TNF-beta response in patients with primary biliary cirrhosis. In: Scandinavian Journal of Immunology, Vol. 34: pp. 735-

Several new HLA-B (B8, B51, Bw62)- and HLA-C (Cw6, Cw7)-specific genes were isolated either as genomic cosmid or cDNA clones to study the diversity of HLA antigens. The allele specificities were identified by sequence analysis in comparison with published HLAB and -C sequences, by transfection experiments, and Southern and northern blot analysis using oligonucleotide probes. Comparison of the classical HLA-A, -B, and -C sequences reveals that allele-specific substitutions seem to be rare events. HLA-B51 codes only for one allelespecific residue: arginine at position 81 located on the cd helix, pointing toward the antigen binding site. HLA-B8 contains an acidic substitution in amino acid position 9 on the first central/3 sheet which might affect antigen binding capacity, perhaps in combination with the rare replacement at position 67 (F) on the Alpha-l helix. HLA-B8 shows greatest homology to HLA-Bw42, -Bw41, -B7, and -Bw60 antigens, all of which lack the conserved restriction sites Pst I at position 180 and Sac I at position 131. Both sites associated with amino acid replacements seem to be genetic markers of an evolutionary split of the HLA-B alleles, which is also observed in the leader sequences. HLA-Cw7 shows 98% sequence identity to the JY328 gene. In general, the HLA-C alleles display lower levels of variability in the highly polymorphic regions of the Alpha 1 and Alpha 2 domains, and have more distinct patterns of locusspecific residues in the transmembrane and cytoplasmic domains. Thus we propose a more recent origin for the HLA-C locus.

Antigen HLA-B27 is a high-risk genetic factor with respect to a group of rheumatoid disorders, especially ankylosing spondylitis. A cDNA library was constructed from an autozygous B-cell line expressing HLA-B27, HLA-Cw1, and the previously cloned HLA-A2 antigen. Clones detected with an HLA probe' were isolated and sorted into homology groups by differential hybridization and restriction maps. Nucleotide sequencing allowed the unambiguous assignment of cDNAs to HL4-A, -B, and -C loci. The HLA-B27 mRNA has the structural features and the codon variability typical of an HLA class I transcript but it specifies two uncommon amino acid replacements: a cysteine in position 67 and a serine in position 131. The latter substitution may have functional consequences, because it occurs in a conserved region and at a position invariably occupied by a species-specific arginine in humans and lysine in mice. The availability of the complete sequence of HLA-B27 and of the partial sequence of HLA-Cw1 allows the recognition of locus-specific sequence markers, particularly, but not exclusively, in the transmembrane and cytoplasmic domains.