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You've heard the saying, “it's the little things that make a difference,” right? In this episode of Spinal Cast you'll discover just how profound those little things can be! Dr. Samuel Chung (Sam) and Noa Grooms hail from Northeastern University where they have been working with C. elegans (roundworms). They uncovered a fascinating phenomenon: by precisely cutting a fiber in a neuron they can observe regrowth and redevelopment and begin to understand how they can influence it. It is this seemingly small breakthrough that holds the potential to transform the way we approach spinal cord injury therapies. With Dr. Chung's expertise in lasers, optics and bioengineering, combined with Noa's deep understanding of genetics, they are driving a revolution in neuroscience that gives testament to the power of interdisciplinary collaboration. We also discuss the vital role of MCPF funding and the “New Investigator Grant.” By supporting new investigators in the field, MCPF is making strategic investments in high-risk, high-reward projects and championing visionary thinkers. The extraordinary achievements of Sam and Noa underscore the immense value of this approach.What might seem like a ripple now is destined to create waves that will change lives for those living with spinal cord injuries. Tune in!Bios for Sam and Noa can be found below. Thanks again to Sam and Noa for being our guests on today's podcast! This production is a collaborative effort of volunteers working to create a quality audio and visual experience around the subject of spinal cord injury. A special shout out of appreciation to Clientek for providing studio space and top-notch recording equipment. Most importantly, thank YOU for being part of the Spinal Cast audience!Interested in watching these episodes?! Check out our YouTube playlist! - https://youtube.com/playlist?list=PL40rLlxGS4VzgAjW8P6Pz1mVWiN0Jou3v If you'd like to learn more about the Morton Cure Paralysis Fund you can visit our website at - https://mcpf.org/Donations are always appreciated - https://mcpf.org/you-can-help/ Samuel Chung, Ph.D.Prof. Chung is an Assistant Professor in the Bioengineering Department at Northeastern University. He leads a multidisciplinary group to study a special form of regeneration that can regrow the mammalian central nervous system. His laboratory leverages highly precise laser surgery and powerful genetic tools in the simple roundworm C. elegans to illuminate the biological mechanisms of regeneration. His laboratory also develops optical tools to clearly see individual brain cells and their regrowth, with the goal of automating his experiments. Together, his technologies and his unique model in the worm enable him to make broad, fundamental discoveries that may ultimately produce a viable therapy for spinal cord injuries. Noa GroomsNoa Grooms is a recently graduated bioengineering PhD student from Samuel Chung's laboratory at Northeastern University. His research explores the genetic mechanisms underlying brain cell regeneration. In his studies, Noa identified cAMP response element binding protein (CREB) as a primary driver of protein expression that promotes regeneration across several neurons in the roundworm C. elegans. His results also demonstrate a strong cell-type dependence on regenerative capacity and contributions from different genes.
As we begin a new year, it's crucial to understand how the Cortisol Awakening Response (CAR), which is closely tied to our sleep patterns and overall well-being, can impact our ability to wake up refreshed and ready to tackle the day. We'll explore the intricate biochemical processes that govern the CAR, the factors that can lead to its dysregulation, and practical strategies to reset cortisol's diurnal rhythm for optimal energy and productivity (so you can go above and beyond with your goals in 2024). Topics: 1. Introduction - Importance of discussing the cortisol awakening response - Connection between cortisol awakening response and sleep regulation - Overview of the cortisol-melatonin diurnal cycle 2. Retinal Ganglion Cells (RGCs) and Light Response - Role of photoreceptor cells in the retina - Specialized cells - Retinal Ganglion Cells (RGCs) - Melanopsin in RGCs and its light sensitivity - Generation of electrical signals in response to light - Transmission to the suprachiasmatic nucleus (SCN) 3. Suprachiasmatic Nucleus (SCN) and Light Signals - Integration of light signals by SCN - SCN's role in assessing day-night cycle - Adjustment of the body's internal clock 4. Intracellular Signaling in SCN - Activation of intracellular signaling pathways - Role of CREB (transcription factor) - Transcription and translation of CRH within SCN neurons - Release of CRH into the bloodstream 5. Adrenocorticotropic Hormone (ACTH) Release - Travel of CRH to the anterior pituitary gland - Binding of CRH to corticotroph cells - Increase in cyclic adenosine monophosphate levels - Stimulation of ACTH synthesis and release 6. Cortisol Production - ACTH reaching the adrenal glands - Stimulation of cortisol production - Importance of cortisol in the context of discussion 7. Dysregulation of Cortisol Awakening Response - Factors leading to high or low Cortisol Awakening Response - Impact on energy levels and waking up - Focus on the case of chronic fatigue 8. Addressing Dysregulated Cortisol Awakening Response - Assumption of no underlying root causes - Strategies for resetting cortisol's diurnal rhythm - Aligning light exposure with natural environment - Increasing morning light exposure - Incorporating physical activity, including high-intensity exercise earlier in the day - Cold therapy as a stimulatory strategy for the morning - Avoiding overstimulation at night (caffeine, intense exercise, loud sounds, alcohol, LIGHT) 9. Supporting Melatonin for Cortisol's Diurnal Rhythm - Importance of melatonin in sleep regulation - Consuming foods rich in melatonin or precursors - Exploring endoluten, a pineal peptide bioregulator Thanks for tuning in! Book An Intro Coaching Call with Chloe Porter Get Chloe's Book Today! "75 Gut-Healing Strategies & Biohacks" If you liked this episode, please leave a rating and review or share it to your stories over on Instagram. If you tag @synthesisofwellness, Chloe would love to personally thank you for listening! Follow Chloe on Instagram @synthesisofwellness Follow Chloe on TikTok @chloe_c_porter Visit synthesisofwellness.com to purchase products, subscribe to our mailing list, and more! Or visit linktr.ee/synthesisofwellness to see all of Chloe's links, schedule a BioPhotonic Scanner consult with Chloe, or support the show! Thanks again for tuning in! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support
HEALTH NEWS · Intermittent fasting improves Alzheimer's pathology · Melatonin and its derivatives found to enhance long-term object recognition memory · Heat therapy boosts mitochondrial function in muscles · Too young for arthritis? 15% of global population over age 30 have condition · Decreased acetyl-L-carnitine levels associated with depression · Floatation Therapy for Specific Health Concerns Intermittent fasting improves Alzheimer's pathology University of California San Diego School of Medicine, August 21, 2023 One of the hallmarks of Alzheimer's disease is disruption to the body's circadian rhythm, the internal biological clock that regulates many of our physiological processes. Nearly 80% of people with Alzheimer's experience these issues, including difficulty sleeping and worsening cognitive function at night. However, there are no existing treatments for Alzheimer's that target this aspect of the disease. A new study from researchers at University of California San Diego School of Medicine has shown in mice that it is possible to correct the circadian disruptions seen in Alzheimer's disease with time-restricted feeding, a type of intermittent fasting focused on limiting the daily eating window without limiting the amount of food consumed. In the study, published in Cell Metabolism, mice that were fed on a time-restricted schedule showed improvements in memory and reduced accumulation of amyloid proteins in the brain. The authors say the findings will likely result in a human clinical trial. “Circadian disruptions in Alzheimer's are the leading cause of nursing home placement,” said Desplats. “Anything we can do to help patients restore their circadian rhythm will make a huge difference in how we manage Alzheimer's in the clinic and how caregivers help patients manage the disease at home.” Compared to control mice who were provided food at all hours, mice fed on the time-restricted schedule had better memory, were less hyperactive at night, followed a more regular sleep schedule and experienced fewer disruptions during sleep. The test mice also performed better on cognitive assessments than control mice, demonstrating that the time-restricted feeding schedule was able to help mitigate the behavioral symptoms of Alzheimer's disease. The researchers also observed improvements in the mice on a molecular level. In mice fed on a restricted schedule, the researchers found that multiple genes associated with Alzheimer's and neuroinflammation were expressed differently. They also found that the feeding schedule helped reduce the amount of amyloid protein that accumulated in the brain. Amyloid deposits are one of the most well-known features of Alzheimer's disease. Melatonin and its derivatives found to enhance long-term object recognition memory Sophia University (Japan), August 21, 2023 Multiple studies have demonstrated the memory-enhancing effects of melatonin and its derivatives in animal models. It is also known that the formation of both short- and long-term memories require the phosphorylation of certain memory-related proteins. However, the molecular mechanisms underlying melatonin-induced memory enhancement have remained elusive. Now, medical researchers from Sophia University, Japan, have made important findings that contribute significantly to the elucidation of the underlying mechanisms in a recent article that was published NeuroReport on June 7, 2023. The research team, which included Dr. Masahiro Sano (currently affiliated with Tohoku University) and Dr. Hikaru Iwashita (currently affiliated with Kansai Medical University), examined the effects of three compounds on memory formation; these compounds were melatonin, a hormone secreted by the pineal gland located in the brain; N1-acetyl-5-methoxyquinuramine (AMK), melatonin's biological metabolite; and ramelteon, a drug that binds and activates the melatonin receptor. Initial experiments conducted on male mice clearly showed that the administration of melatonin, ramelteon, or AMK at a dose of 1 mg/kg facilitated the formation of long-term memory. The researchers did not investigate the effects of the three compounds on female mice to avoid any likely data variability resulting from the reproductive cycles occurring in female mammals. Prof. Chiba concludes, "Our findings suggest that melatonin is involved in promoting the formation of long-term object recognition memory by modulating the phosphorylation levels of memory-related proteins such as ERK, CaMKIIs, and CREB in both receptor-mediated and nonreceptor-mediated signaling pathways." Heat therapy boosts mitochondrial function in muscles Brigham Young University, July 31, 2023 A new study finds that long-term heat therapy may increase mitochondrial function in the muscles. The discovery could lead to new treatments for people with chronic illness or disease. Mitochondria, the "energy centers" of the cells, are essential for maintaining good health. Exercise has been shown to create new mitochondria and improve function of existing mitochondria. However, some people with chronic illnesses are not able to exercise long enough--previous research suggests close to two hours daily--to reap the benefits. Rodent studies have suggested that heat exposure may also induce the production of more mitochondria. Researchers from Brigham Young University in Utah studied 20 adult volunteers who had not participated in regular exercise in the three months prior to the study. The research team applied two hours of shortwave diathermy--a type of heat therapy generated by electrical pulses--to the thigh muscles of one leg of each person every day. The researchers based the six-day trial of heat on the minimum amount of exercise needed to measure changes in muscle, or about two hours each day. They designed the treatment to mimic the effects of muscle heating that occurs during exercise. Mitochondrial function increased by an average of 28 percent in the heated legs after the heat treatment. The concentration of several mitochondrial proteins also increased in the heated legs, which suggests that "in addition to improving function, [repeated exposure to heat] increased mitochondrial content in human skeletal muscle," the research team wrote. "Our data provide evidence to support further research into the mechanisms of heat-induced mitochondrial adaptations," the researchers explained. People who are not able to exercise for long periods of time due to their health may benefit from [heat] treatments. Too young for arthritis? 15% of global population over age 30 have condition Institute for Health Metrics and Evaluation (US), August 21, 2023 Arthritis is just a problem for the elderly, right? Not so fast. A recent study finds that osteoarthritis affects 15 percent of individuals over the age of 30 worldwide. Contributing factors include obesity, as well as an aging and growing global population. Remarkably, excess weight is responsible for 20 percent of these cases. Moreover, for those over 70, osteoarthritis ranks as the seventh leading cause of years people live with a disability. Experts forecast that by 2050, one billion people will be afflicted by this condition. Women tend to be more susceptible than men. The most commonly impacted areas include the hands, hips, knees, and other joints like the shoulders and elbows. By 2050, estimates predict a 78.6-percent increase in hip pain cases, 75 percent in the knee, 50 percent in the hand, and a staggering 95.1-percent increase in other areas. This research, led by the Institute for Health Metrics and Evaluation (IHME) in Seattle, assessed three decades of osteoarthritis data from over 200 countries. In 1990, the global count was 256 million individuals with osteoarthritis. By 2020, this number skyrocketed to 595 million, marking a 132-percent increase from 1990. The dramatic rise can be attributed to three primary causes: aging, population growth, and the obesity epidemic. The team's findings underscored the mounting influence of obesity over time as its rates have soared. They estimate that effectively addressing obesity could reduce the osteoarthritis burden by one-fifth. Decreased acetyl-L-carnitine levels associated with depression Stanford University, July 30 2023 An article that appeared in the Proceedings of the National Academy of Sciences reported a link between low levels of acetyl-L-carnitine and a greater risk of depression. Acting on the findings of animal research conducted by lead author Carla Nasca, PhD, the researchers recruited men and women between the ages of 20 and 70 years who had been admitted to Weill Cornell Medicine or Mount Sinai School of Medicine for treatment of acute depression. Clinical assessments were conducted upon enrollment and blood samples were analyzed for levels of acetyl-L-carnitine. In comparison with levels measured in blood samples provided by 45 demographically matched healthy men and women, acetyl-L-carnitine blood levels in depressed subjects were substantially lower. Acetyl-L-carnitine levels were lowest among depressed patients who had severe symptoms, a history of treatment resistance, or early onset disease. Having a history of childhood abuse was also associated with low acetyl-L-carnitine levels. "We've identified an important new biomarker of major depression disorder,” Dr Rasgon stated. “We didn't test whether supplementing with that substance could actually improve patients' symptoms. What's the appropriate dose, frequency, duration? This is the first step toward developing that knowledge, which will require large-scale, carefully controlled clinical trials." Floatation Therapy for Specific Health Concerns Medical University of South Carolina, August 6, 2023 We conducted a search of multiple databases using the following search terms: float, floatation therapy, floatation REST, isolation tank, stress, relaxation response, magnesium sulfate, transdermal magnesium, cortisol, pain, depression, anxiety, sleep, and addiction. The reviewed studies revealed benefits of floating, specifically regarding participants experiencing muscular pain, depression, anxiety, stress, and sleep disorders. Long-term benefits appear variable. Traditionally, isolation tanks are enclosed to inhibit light and sound as much as possible and reduce all incoming stimuli. The float experience minimizes sensory signals including visual, auditory, olfactory, thermal, tactile, and gravitational. The studies discussed were conducted with the combination of water and Epsom salt. The salt-saturated water in most commercial centers is cleaned with a filtration system that runs between each session, in addition to manual skimming and treatment with ultraviolet light, hydrogen peroxide, and ozone. Generally, a float session lasts for 60 minutes, although it can be shorter or longer. The benefits of magnesium sulfate (MgSO4), better known as Epsom salt, are well known. The World Health Organization (WHO) lists it as an essential medication. A proposed mechanism of action of the aforementioned benefits of floatation therapy lies in the transdermal absorption of MgSO4. Given the selectivity of the stratum corneum layer of the skin and the ionic nature of elemental magnesium, it appears that specific lipophilic carriers are required for MgSO4 to cross the dermal layer into the circulation. Among the benefits the analysis of studies suggest include: Pain: Kjellgren and colleagues found a significant improvement with floatation therapy in those who experienced the most intense muscle pain (P=0.004), but there was no benefit found in participants who experienced lower levels of pain. There were 37 participants in this study, all of whom had chronic muscular pain of the neck and back regions. Individuals floated 9 times during a 3-week period. Of the 32 participants in this study, 22% became pain-free, 56% had improvement of pain, 19% experienced no increase or decrease of pain, and 3% experienced worsening of pain. Depression and Anxiety: At the Laureate Institute for Brain Research in Tulsa, Oklahoma, researchers have extensively studied floatation therapy, particularly in the areas of depression and generalized anxiety disorder (GAD). One study involving 50 participants at LIBR examined the anxiolytic and antidepressant effects of floating. Results showed a significant reduction in anxiety among participants, regardless of gender. All changes were significant. Anxiety and stress-related disorders in this study included post-traumatic stress disorder, generalized anxiety disorder, panic disorder, agoraphobia, and social anxiety disorder. In addition to reduced anxiety, there was a significant improvement in mood characterized by “serenity, relaxation, happiness, positive affect, overall well-being, energy levels, and feeling refreshed, content and peaceful.” Stress: Research generally finds floatation therapy to be beneficial for stress reduction. The relaxation response (which is associated with the parasympathetic nervous system) occurs when floating, lowering blood pressure and lowering cortisol levels in some studies. Sleep: People have used floatation therapy to aid with sleep. Since magnesium is a common supplement used to aid with sleep, this is a logical area of float research interest. In a study looking at 19 athletes and floating, participants not only had improved athletic performance recovery, but also experienced significant improvements in having “deeper sleep, fewer awakenings during the night, and a sense of renewed energy upon awakening in the morning.”
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.22.550175v1?rss=1 Authors: Trewin, A. J., Weeks, K. L., Wadley, G. D., Lamon, S. Abstract: Cardiomyocyte calcium homeostasis is a tightly regulated process. The mitochondrial calcium uniporter (MCU) complex can buffer elevated cytosolic Ca2+ levels and consists of pore-forming proteins including MCU, and various regulatory proteins such as mitochondrial calcium uptake proteins 1 and 2 (MICU1/2). The stoichiometry of these proteins influences the sensitivity to Ca2+ and activity of the complex. However, the factors that regulate their gene expression remain incompletely understood. Long non-coding RNAs (lncRNAs) regulate gene expression through various mechanisms, and we recently found that the lncRNA Tug1 increased the expression of Mcu and associated genes. To further explore this, we performed antisense LNA knockdown of Tug1 (Tug1 KD) in H9c2 rat cardiomyocytes. Tug1 KD increased MCU protein expression, yet pyruvate dehydrogenase dephosphorylation, which is indicative of mitochondrial Ca2+ uptake was not enhanced. However, RNA-seq revealed that Tug1 KD increased Mcu along with differential expression of greater than 1000 genes including many related to Ca2+ regulation pathways in the heart. To understand the effect of this on Ca2+ signalling, we measured phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and its downstream target cAMP Response Element-Binding protein (CREB), a transcription factor known to drive Mcu gene expression. In response a Ca2+ stimulus, the increase in CaMKII and CREB phosphorylation was attenuated by Tug1 KD. Inhibition of CaMKII, but not CREB, partially prevented the Tug1 KD-mediated increase in Mcu. Together, these data suggest that Tug1 modulates MCU expression via a mechanism involving CaMKII and regulates cardiomyocyte Ca2+ signalling which could have important implications for cardiac function. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Roy L Hales/ Cortes Currents - The Friends of Cortes Island (FOCI) have not found any European Green Crabs in Manson's lagoon and so far there've been no sightings north of Nanaimo. “We haven't found any, that's really good news, but we've been very pleased to partner with DFO. Hopefully, if we ever find them, we'll be able to track them out and stop them from harming the valuable habitat here.” 34 explained Helen Hall, executive director of FOCI. “We got contacted by the Department of Fisheries and Ocean last year. They wanted to come onto the island as part of a project they're doing with a lot of communities up and down the coast, to try and find out whether green crabs are spreading in this area. We set traps in Manson's Lagoon twice last year, and very luckily we didn't find any.” “This year DFO came back and said this is a project they want to keep doing. They bring all the traps over, we trapped last month and we didn't find any.” “It's a brilliant learning exercise for our summer student, 58 Manuel Perdisa and we have two volunteers, Penny and Claude, who have helped us on other projects.” “This week the three of them went out with Patty Menning from DFO. They're setting two types of traps, a large prawn trap and smaller minnow traps. 12 traps were set in Manson's Lagoon on one day and the next day we go back . They get the traps out of the water, empty them into a plastic container which has water in them. We found lots and lots of graceful crabs. We're actually measuring those crabs as a recording exercise, but we also found some other interesting species, then we release everything back into the lagoon. We keep all those records and the data's going back to DFO.. “We haven't found any, that's really good news, but we've been very pleased to partner with DFO. Hopefully, if we ever find them, we'll be able to track them out and stop them from harming the valuable habitat here. According to Renny Talbot, Aquatic Invasive Species Coordinator for Fisheries and Oceans Canada (DFO), there have not been any sightings north of Nanaimo in the Salish Sea area. CC: Where are you looking for European Green Crabs in my broadcast area? Renny Talbot: “We're looking on Cortes Island and Quadra Island, as well as the Fanny Bay area and Comox. We've set up with local stewardship groups and with our First Nations partners, early detection monitoring programs in those locations.” CC: Who is your partner on Quadra? Renny Talbot: “We have a representative, Patty Menning, who's working with the We Wai Kai First Nation.” CC: What about Campbell River? Renny Talbot: “We don't have a site in Campbell River right now. We have done opportunistic trapping in that location, but we didn't have a really good site to set up long term monitoring.” “Our early detection monitoring program: it's once a month and it runs from from April to to October. They do a 24 hour soak. We're looking for European Green Crab, but it's also creating a baseline of those intertidal crab, fish and things like that we're catching. So that if if there is an invasion, we can really understand the ecological impact that's occurring.” “We are lucky that there's some quasi barriers, with the Juan de Fuca as well as with the Johnson Strait, which have limited the the entry of European green Creb larva into the Salish Sea.” “The larvae need greater than 10 degrees Celsius to survive.”
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.20.545648v1?rss=1 Authors: Jiang, A., Lehnert, K., You, L., Hawkins, V., Reid, S. J., Handley, R. R., Jacobsen, J. C., Patassini, S., Rudiger, S. R., McLaughlan, C. J., Kelly, J. M., Verma, P. J., Bawden, C. S., Gusella, J. F., MacDonald, M. E., Waldvogel, H. J., Faull, R. L. M., Snell, R. G. Abstract: Background Huntington's disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in a triad of behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. OVT73 captures an early prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. Methods To better understand the disease initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild type controls. Results We have identified transcriptional upregulation from genes encoding N-methyl-D-aspartate (NMDA), -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in OVT73 medium spiny neurons, the cell type preferentially lost early in the disease. This observation supports the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade initiating process. Moreover, the downstream consequences of excitotoxicity including a downregulation of transcription of components for the oxidative phosphorylation complexes was also observed. We also found that pathways that have been proposed to act to reduce excitotoxicity including the activity of the CREB family of transcription factors (CREB1, ATF2, ATF4 and ATF7) were transcriptionally downregulated. Conclusions To our knowledge, the OVT73 model is the very first large mammalian HD model that exhibits transcriptomic signatures of an excitotoxic process that occurs in the absence of cell loss. Our results indicate that glutamate excitotoxicity is a disease initiating process. Addressing this biochemical defect early may prevent any cell loss and avoid the more complex secondary consequential challenges due to cell death. 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/2023.04.18.537291v1?rss=1 Authors: Sahu, B. S., Mukherjee, M., Mukherjee, C., Ghosh, V., Jain, A., sadhukhan, s., Dagar, s. Abstract: Dense core vesicles (DCVs) and synaptic vesicles (SVs) are specialised secretory vesicles (SSVs) in neurons/neuroendocrine cells harbouring cargo whose abnormal release is associated with pathophysiology. Endoplasmic Reticulum (ER) stress and inter-organellar communication are also associated with disease biology. In pursuit of investigating the cell physiological consequences arising from the crosstalk of a stressed ER and DCVs, ER stress was modelled in PC12 neuroendocrine cells using Thapsigargin (Tg). DCV exocytosis was severely compromised in ER-stressed PC12 cells, reversed by Docosahexaenoic acid (DHA). Experiments with Tunicamycin(Tm), an independent ER stressor, yielded similar results. Concurrently, ER stress caused impaired DCV exocytosis also in INS-1 cells. Molecular analysis revealed blunted SNAP25 expression, potentially attributed to augmented levels of ATF4 (a well-known CREB inhibitor) and its transcriptional regulator CREB (also known to regulate key granulogenic players Chromogranin A, Secretogranin II). Our studies revealed severe defects in DCV exocytosis in ER-stressed cells for the first time, mediated by reduced levels of key 'exocytotic' and 'granulogenic' switches regulated via the CREB/ATF4/eIF2 axis. 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/2023.04.10.536242v1?rss=1 Authors: Bonheur, M., Swartz, K. J., Metcalf, M. G., Zhukovskaya, A., Mehta, A., Connors, K. E., Barasch, J. G., Wen, X., Jamieson, A. R., Martin, K. C., Axel, R., Hattori, D. Abstract: Neural activity is modulated over different timescales encompassing sub-seconds to days reflecting changes in external environment, internal state, and behavior. Using Drosophila as a model, we have developed a rapid and bidirectional reporter that provides a robust cellular readout of recent neural activity. This reporter utilizes nuclear vs cytoplasmic distribution of CREB-regulated transcriptional coactivator, CRTC. Subcellular distribution of GFP-tagged CRTC (CRTC::GFP) bidirectionally changes on the order of minutes and reflects both increases and decreases in neural activity. We establish an automated machine-learning-based routine for efficient quantification of reporter signal. Using this reporter, we demonstrate acute mating-evoked activation of peptidergic neurons. We further investigate the functional role of the master courtship regulator gene, fruitless, and show that fruitless is necessary to ensure activation of male arousal neurons by female cues. Together, our results establish CRTC::GFP as a bidirectional reporter of recent neural activity suitable for examining neural correlates in behavioral contexts. 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/2023.03.20.533566v1?rss=1 Authors: Sun, W., Liu, Z., Jiang, X., Chen, M. B., Dong, H., Liu, J., Sudhof, T. C., Quake, S. R. Abstract: Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala (BLA) is a center of salience networks that underlie emotional experience and thus plays a key role in long-term fear memory formation. Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide signaling, mitogen-activated protein kinase (MAPK), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), ubiquitination pathways, and synaptic connectivity in long-term memory. We also discovered that a neuronal sub-population, defined by increased Penk expression and decreased Tac expression, constitutes the most prominent component of the BLA's memory engram. These transcriptional changes were observed both with single-cell RNAseq and with single-molecule spatial transcriptomics in intact slices, thereby providing a rich spatial map of a memory engram. The spatial data enabled us to show that this neuronal subpopulation further interacts with spatially related astrocytes that are essential for memory consolidation, indicating that neurons require interactions with astrocytes to encode long term memory. 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/2023.02.22.529281v1?rss=1 Authors: Merritt, D. M., Udachina, A., Freidel, N., Almeida, S. M. T., Lau, Y. M. A., van der Kooy, D. Abstract: Memories are often categorized into types, reflecting their behavioural, anatomical and molecular diversity: these classifications both aid understanding of the differences among varieties of memory and help delineate the unifying cross-species principles underlying them. In the nematode worm Caenorhabditis elegans, we find that an associative memory of the pairing of the normally attractive odorant benzaldehyde and starvation depends on de novo transcription and translation, is independent of CREB, and is produced by massed training: a pattern which does not correspond to any of the well-characterized molecular categories of invertebrate memory. Further, as has been shown for many memories in vertebrates, but not previously in nematodes, we find that formation of this memory continues after removal of the stimuli initially causing it, and that it is labile to disruption through protein synthesis inhibition following training, but that inhibition of proteasomal activity does not extend the duration of the memory. Previous findings have implicated insulin pathway signalling as a key component of this benzaldehyde/starvation memory, however we find that the transcriptional activity required for the memory is likely to be independent of the transcription factors that function at the terminus of this pathway. These findings better characterize this model associative memory in relation to other invertebrate memory types and identify ways in which it both shares their traits and differs from them. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
References Neural Plasticity. 2019; 2019: 1648736. Molecular Pharmacology May 2017, 91 (5) 451-463. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.20.521175v1?rss=1 Authors: Monteiro Gomes, G., Bar, J., Karpova, A., Kreutz, M. Abstract: Jacob is a synapto-nuclear messenger protein that encodes and transduces the origin of synaptic and extrasynaptic NMDA receptor signals to the nucleus. The protein assembles a signalosome that differs in case of synaptic or extrasynaptic NMDAR activation. Following nuclear import Jacob docks these signalosomes to the transcription factor CREB. We have recently shown that amyloid-beta and extrasynaptic NMDAR activation triggers the translocation of a Jacob signalosome that results in inactivation of the transcription factor CREB, a phenomenon termed Jacob-induced CREB shut-off (JaCS). JaCS contributes to early Alzheimer's disease pathology and a gene knockout of nsmf, the gene encoding Jacob, protects against amyloid pathology. Given that extrasynaptic activity is also involved in acute excitotoxicity, like in stroke, we asked whether nsmf gene knockout will also protect against acute insults, like oxygen and glucose deprivation and excitotoxic NMDA stimulation. Here we show that organotypic hippocampal slices from wild-type and nsmf-/- mice display similar degrees of degeneration when exposed to either oxygen glucose deprivation or 50 uM NMDA incubation. This lack of neuroprotection indicates that JaCS is mainly relevant in conditions of low level chronic extrasynaptic NMDAR activation that results in cellular degeneration induced by alterations in gene transcription. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Thomas C. Südhof, M.D., Stanford University, discusses facets of the fundamental cell biology of ApoE and APP analyzed in stem cell-derived human neurons. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 38405]
Dr. Ya-Jen Chiu from the Department of Life Science at National Taiwan Normal University in Taipei, discusses a research paper she co-authored that was published by Aging (Aging-US) in Volume 14, Issue 18, entitled, “Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity.” DOI - https://doi.org/10.18632/aging.204306 Corresponding authors - Chiung-Mei Chen - cmchen@cgmh.org.tw, Ying-Chieh Sun - sun@ntnu.edu.tw, Guey-Jen Lee-Chen - t43019@ntnu.edu.tw Video - https://www.youtube.com/watch?v=1rT96K9VeZw Transcript - https://aging-us.net/2022/11/01/behind-the-study-novel-trkb-agonists-activate-trkb-and-downstream-erk-and-akt-signaling/ Abstract Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer's disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood-brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204306 Keywords - aging, Alzheimer's disease, TRKB agonists, Aβ, neuroprotection, therapeutics 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/agingus LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.21.513252v1?rss=1 Authors: Yang, Q., Perfitt, T. L., Quay, J., Hu, L., Colbran, R. J. Abstract: Clustering of neuronal L-type voltage-gated Ca2+ channels (LTCC) in the plasma membrane is increasingly implicated in creating highly localized Ca2+ signaling nanodomains. For example, LTCC activation can increase phosphorylation of the nuclear CREB transcription factor by increasing Ca2+ concentrations within a nanodomain close to the channel, without requiring bulk Ca2+ increases in the cytosol or nucleus. However, the molecular basis for LTCC clustering is poorly understood. The postsynaptic scaffolding protein Shank3 specifically associates with one of the major neuronal LTCCs, the CaV1.3 calcium channel, and is required for optimal LTCC-dependent excitation-transcription coupling. Here, we co-expressed CaV1.3 1 subunits with two distinct epitope-tags with or without Shank3 in HEK cells. Co-immunoprecipitation studies using the cell lysates revealed that Shank3 can assemble multiple CaV1.3 1 subunits in a complex under basal conditions. Moreover, CaV1.3 LTCC complex formation was facilitated by CaV{beta} subunits ({beta}3 and {beta}2a), which also interact with Shank3. Shank3 interactions with CaV1.3 LTCCs and multimeric CaV1.3 LTCC complex assembly were disrupted following addition of Ca2+ and calmodulin (Ca2+/CaM) to cell lysates, perhaps simulating conditions within an activated CaV1.3 LTCC nanodomain. In intact HEK293T cells, co-expression of Shank3 enhanced the intensity of membrane-localized CaV1.3 LTCC clusters under basal conditions, but not after Ca2+ channel activation. Live cell imaging studies also revealed that Ca2+ influx through LTCCs disassociated Shank3 from CaV1.3 LTCCs clusters and reduced the CaV1.3 cluster intensity. Deletion of the PDZ domain from Shank3 prevented both binding to CaV1.3 and the changes in multimeric CaV1.3 LTCC complex assembly in vitro and in HEK293 cells. Finally, we found that shRNA knock-down of Shank3 expression in cultured rat primary hippocampal neurons reduced the intensity of surface-localized CaV1.3 LTCC clusters in dendrites. Taken together, our findings reveal a novel molecular mechanism contributing to neuronal LTCC clustering under basal conditions. 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/2022.10.21.512997v1?rss=1 Authors: Sgammeglia, N., Kaldun, J., Widmer, Y., Fritsch, C., Bruggmann, R., Sprecher, S. G. Abstract: The formation of long-term memories requires changes in the transcriptional program and de novo protein synthesis. One of the critical regulators for long-term memory (LTM) formation and maintenance is the transcription factor CREB. Genetic studies have dissected the requirement of CREB activity within memory circuits, however less is known about the genetic mechanisms acting downstream of CREB and how they may contribute defining LTM phases. To better understand the downstream mechanisms, we here used a targeted DamID approach (TaDa). We generated a CREB-Dam fusion protein using the fruit fly Drosophila melanogaster as model. Expressing CREB-Dam in the mushroom bodies (MBs), a brain center implicated in olfactory memory formation, we identified genes that are differentially expressed between paired and unpaired appetitive training paradigm. Of those genes we selected candidates for an RNAi screen in which we identified genes causing increased or decreased LTM. 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/2022.10.18.512685v1?rss=1 Authors: Chen, L., Liu, Z., Zhao, Z., Pan, W., Hu, T., Wei, X., Nie, J., Ge, F., Ding, J., Fan, Y., Kim, H. Y., Guan, X. Abstract: Adolescent cocaine exposure (ACE) increases the risk of suffering psychiatric disorders including anxiety in later life, which is a big public health concern with limited treating options. Consistent with our previous study, we found that ACE mice exhibited obvious anxiety-like behaviors in their adulthood, which was efficiently suppressed by electro-acupuncture (EA) at acupoints of Baihui (GV 20) and Yintang (GV 29) with stimulus of a mixed frequency of 2/100 Hz for 28 withdrawal days. In the claustrum (CL) of ACE mice, more CaMKII-positive neurons (CaMKIICL) were activated, accompanied with increased expression of dopamine receptor 1 (D1R) on them (D1RCaMKII) and phosphorylated-EKR (p-ERK), p-CREB, and BDNF protein levels. Local blockade of CL D1R by SCH23390 or specific knockdown of CL D1RCaMKII by virus suppressed both anxiety-like behaviors and CaMKIICL activity in ACE mice of adulthood, indicating the critical role of CL D1RCaMKII in ACE-enhanced anxiety. Importantly, EA treatment suppressed CaMKIICL activity and D1RCaMKII staining, along with attenuated levels of p-CREB and BDNF in CL of ACE mice. Collectively, our study for the first time identified a novel molecular mechanism of CL D1RCaMKII and CaMKIICL activity in the process of ACE-increased anxiety in adulthood. Further, by targeting CL D1RCaMKII, EA at acupoints of GV 20 and GV 29 serves as preventative strategy to adolescent drugs exposure-induced anxiety in the later life. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Fala Doutores, tudo bem? No episódio EXTRA de hoje , preparativo para o episódio 100, convidei o Rafael Mendes.
Hello to season 5 episode 2 and The Psychotic Break listeners! In this episode, Madey and Kimi attempt shorter episodes and address the neurological disorder of Alzheimer's. Here are the articles Madey mentioned:CREB helps with Alzheimer'shttps://pubmed.ncbi.nlm.nih.gov/21476939/Ultraprocessed foods lead to inflamed brain:https://amp.cnn.com/cnn/2022/08/01/health/ultraprocessed-food-dementia-study-wellness/index.htmlOur website: https://the-psychotic-break.vercel.appOur Insta: @thepsychoticbreak.pod
On this episode we talk to CREB® Chief Economist Ann-Marie Lurie about the 2022 CREB® Forecast and how Calgary's real estate market is shaping up in the year to come.
On this episode of CREB®Cast, Jason Yule, CREB®'s Director of Communication Services sits down with HomeSpace Society's Emily Campbell to discuss HomeSpace's latest project, Sierra Place and how the CREB® REALTOR® Community Foundation Legacy Grant is helping to make it a reality.
Devin Crebs, supervisor, Therapy Services, UPMC Muncy, on back to school backpack information. We'll discuss the best backpacks, how heavy is too heavy, and when would kids need physical and/or occupational therapy, what is proper posture, and other safety/health back to school information/advice
Devin Crebs, supervisor, Therapy Services, UPMC Muncy, on back to school backpack information. We'll discuss the best backpacks, how heavy is too heavy, and when would kids need physical and/or occupational therapy, what is proper posture, and other safety/health back to school information/advice
Lion’s mane mushroom helps reduce depression and anxiety Tohoku University (Japan), March 21, 2021 Several studies have shown the potential of lion’s mane mushroom to help address several health problems including those that are related to brain function. Lion’s mane mushroom (Hericium erinaceus), also known as hedgehog mushroom, is a mushroom native to North America, Asia and Europe. Its fruiting bodies are said to contain polysaccharides that are beneficial to the human body. This mushroom has a long history of medical uses, especially in Traditional Chinese Medicine (TCM) where it was used to help support brain health. In recent years, its value in supporting cognitive health has been supported by a number of studies. The mushroom helps Reduce depression and anxiety In a study published in the journal Biomedical Research, the mushroom was tested on female participants in order to tests its effects on mental health. After taking lion’s mane mushroom cookies for four weeks, the participants reported reduced depression and anxiety. According to the researchers, this was due to two chemical constituents isolated from lion’s mane’s fruiting body called hericenones and erinacines. These two chemicals stimulate nerve growth factor (NGF) biosynthesis. NGF takes part in a number of activities in the body that are essential in maintaining and organizing neurons. By stimulating NGF biosynthesis, lion’s mane is able to help improve mental health. Meanwhile, in a study on mice, researchers from Tohoku University in Japan discovered that lion’s mane mushroom may be used to prevent cognitive dysfunction. The Japanese researchers administered 10 micrograms of amyloid-beta peptide to the mice on days seven and 14 in their 23-day experimental period. Also, the mice subjects were fed with food containing lion’s mane mushroom over the course of the experimental period. To measure the results of their study, the team used Y-maze and the novel object recognition tests on the subjects. They discovered that the mushroom prevented the negative effects of amyloid-beta peptide on the spatial short-term and visual recognition memory of the mice. The study suggests that the mushroom might reverse even the effects of amyloid-beta peptide – a protein believed to cause Alzheimer’s disease. Lion’s mane for cognitive impairment Moreover, in another study conducted by Japanese scientists, lion’s mane mushroom showed potential in improving symptoms of mild cognitive impairment. This is the stage between aging-related cognitive decline and the development of dementia. Its symptoms include problems with memory, language, thinking or judgment. The team took 30 patients with mild cognitive impairment and gave them 250mg tablets with 96 percent lion’s mane extract to be taken in four pieces for three times a day for 16 weeks. During weeks eight, 12 and 16, the patients underwent observation wherein they showed improvement in their cognitive function as displayed by the increase of their scores on the cognitive function scale. Moreover, the researchers conducted laboratory tests on the patients and saw that the intake of lion’s mane did not result in any side effect. In addition, the patients’ scores in the cognitive function scale decreased by the time their intake of lion’s mane mushroom tablets stopped. Quercetin-3-o-glucuronide alleviates cognitive deficit in mouse model of Alzheimer disease Hua-zhong University of Science & Technology (China), March 22, 2021 According to news reporting from Wuhan, People’s Republic of China, research stated, “Scope Alzheimer’s disease (AD) is characterized by amyloid-beta (A beta) related imbalance, Tau-hyperphosphorylation, and neuroinflammation, in which A beta and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD.” The news correspondents obtained a quote from the research from the Huazhong University of Science and Technology, “As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome. AD mice model built through intracerebroventricular injection of A beta(1-42) and AD cell model developed through the SH-SY5Y cell line and A beta(1-42) are used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain insulin signaling pathway, and high-throughput pyrosequencing of 16S rRNA are assessed. Data show that Q3G attenuates neuroinflammation and brain IR in A beta(1-42)-injected mice and relieves apoptosis in A beta(1-42)-treated SH-SY5Y cells by interrupting the downstream insulin signaling. Q3G ameliorates A beta accumulation and Tau phosphorylation, restores CREB and BDNF levels in the hippocampus , and reverses A beta(1-42)-induced cognitive impairment. Besides, Q3G restores A beta(1-42)-induced reduction of short-chain fatty acids (SCFAs) and gut microbiota dysbiosis.” According to the news reporters, the research concluded: “Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve A beta(1-42)-induced cognitive dysfunction.” This research has been peer-reviewed. Research shows possible link between number of fast-food outlets and heart attacks Hunter Medical Research Institute & University of Newcastle (UK), March 17, 2021 Researchers from the Hunter Medical Research Institute (HMRI), the University of Newcastle and Hunter New England Health (HNE Health) have found that for each new fast-food outlet the number of heart attacks per 100,000 people went up by four. Published in the latest edition of the Internal Medicine Journal the study aimed to determine whether the number of fast-foodoutlets in an area could be considered an environmental risk factor for Myocardial Infarction (heart attack). The team led by Dr. Tarunpreet Saluja from the University of Newcastle, compared all cases of Myocardial Infarction within the Hunter-New England Health District with the Fast-Food Outlet Density (FFD) of each Local Government Area within the district. "Heart attack is one of the leading causes of death worldwide" said Dr. Saluja, "However, recent data suggests that an increasing number of heart attacks cannot be explained by known risk factors." "There is a well-established link between fast food consumption and cardiovascular diseases such as heart attack. This highlights the need to explore the role of food availability in the probability of having a heart attack." The team found that FFD was positively correlated with an increase of myocardial infarction, even after accounting for other factors such as age, obesity, hyperlipidaemia (high cholesterol), hypertension (high blood pressure), smoking status, diabetes, and socioeconomic status. Study co-author and cardiologist at John Hunter Hospital, Professor Andrew Boyle said that while it has been known for some time that consuming fast food was bad for the heart no one had determined whether the number of stores was itself a predicting factor. "Until now there has been very little data on the link between fast-food outlet density and heart attacks, so these results should provide an important consideration for future public‐health policy and community development," said Professor Boyle. Study co-author and Associate Director of HMRI's Data Science Group, Dr. Christopher Oldmeadow, said that developing a new metric to calculate fast-food outlet density was key to the study and there was scope to expand the data to look at more outlets in the future. "For this study, we focused on the 10 most popular fast-food outlets in Australia and used census data to determine the density per 100,000 people in each local government area," Dr. Oldmeadow said. "This worked for the majority of the LGAs, but there is scope to investigate the relationship between smaller, locally operated fast‐food outlets and heart attacks." Vitamin B6 may help calm cytokine storms in COVID-19 University of Hiroshima (Japan), March 14, 2021 Vitamin B6 may help calm cytokine storms and unclog blood clots linked to novel coronavirus (COVID-19) lethality, according to a new study published in the journal Frontiers in Nutrition. In the paper, researchers from Hiroshima University pointed out growing evidence showing that vitamin B6 exerts a protective effect against chronic illnesses such as cardiovascular diseases and diabetes by suppressing inflammation, inflammasomes, oxidative stress, and carbonyl stress. Coronaviruses and influenza are among the viruses that can cause lethal lung injuries and death from acute respiratory distress syndrome worldwide. Viral infections evoke a “cytokine storm,” leading to lung capillary endothelial cell inflammation, neutrophil infiltration, and increased oxidative stress, the researchers said. The researchers said thrombosis or blood clotting and cytokine storm or hyper-inflammation might be closely linked to the graveness of COVID-19. Cytokine storms happen when the immune system dangerously goes into overdrive and starts attacking even the healthy cells. Meanwhile, blood clots linked to COVID-19 can block capillaries, damaging vital organs like the heart, lungs, liver, and kidneys, according to the study. Vitamin B6 is a known anti-thrombosis and anti-inflammation nutrient. Deficiency in this vitamin is also associated with lower immune function and higher susceptibility to viral infections. Studies have so far explored the benefits of vitamins D and C and minerals like zinc and magnesium in fortifying immune response against COVID-19. Research on vitamin B6 has been limited, the researchers said. The researchers said they hope the paper will show vitamin B6's potential in lowering the odds of patients becoming seriously ill with the coronavirus, and prompt further research. "It is of great interest to examine if vitamin B6 exerts protection against novel types of virus infection and pneumonia which will be encountered in the future,” said Thanutchaporn Kumrungsee, PhD, lead author of the paper, in a statement. “At present, there is few information regarding the protective role of nutrients against pneumonia and lung diseases.” Vitamin B6 has a close relationship with the immune system, she said. Its levels always drop in people under chronic inflammation such as obesity, diabetes, and heart diseases. “We can see from the news that obese and diabetic people are at high risk for COVID-19, said Kumrungsee. “Thus, our attempt in this paper is to shed light on the possible involvement of vitamin B6 in decreasing the severity of COVID-19. Green space or light at night: How we can improve health University of Adelaide (Australia), March 18, 2021 There is a growing body of evidence that exposure to green space is good for our health but a new study from the University of Adelaide has found that this may equally be due to how much light we are exposed to at night. Spending time in green space can improve depressive symptoms, obesity, and sleep problems, and reduce the risk of breast and prostate cancer. Conversely, exposure to light at night, particularly urban light pollution, increases the risk of breast and prostate cancer, and can worsen depression, obesity and sleep problems. Researchers identified a negative correlation between green space diversity and outdoor artificial light at night for Australian major cities—in other words, the greener your environment, the less the light pollution, and vice versa. This makes intuitive sense, because the more developed an area is, the fewer trees there will be and the more lights there will be. Published in Environmental Research, the study questions whether the health benefits of green space exposure may in part be a result of avoiding light at night. "There seems to be a pattern here—yet, amazingly, no one has put these two things together—until now,"' said lead author Dr. Jessica Stanhope from the University of Adelaide's School of Allied Health Science and Practice. "It is possible that these factors have been confounding each other in epidemiological studies of the associations between residential green spaces and improved health, and urban outdoor artificial light at night exposure and poor health. "We have shown that green space is inversely associated with outdoor artificial light at night, making it unclear whether health outcomes result from the green space, the light at night, or possibly in an interaction of the two." Researchers recommend that epidemiological studies focus on resolving this problem as a priority, so that recommendations can be made for interventions that would improve the public health. For example, to improve population health, is it more important to plant green space in urban areas to give people in cities better green space exposure, or is it better to invest that effort in reducing urban light pollution, or both? "Some great studies have been done on the association between green space and health, which is a rapidly growing research area; and there are also very neat epidemiological studies of the adverse health effects of exposure to light at night," said Dr. Stanhope. "It is now really important that future studies include both factors so that we can better understand their association—only then can we make better public health recommendations about planning health-giving sustainable urban landscapes." Supplements may protect those with low vitamin D levels from severe COVID-19 Albert Einstein College of Medicine, March 20, 2021 Patients with low vitamin D levels who are hospitalized for COVID-19 may have a lower risk of dying or requiring mechanical ventilation if they receive vitamin D supplementation of at least 1,000 units weekly, according to a study presented virtually at ENDO 2021, the Endocrine Society's annual meeting. "Given how common vitamin D deficiency is in the world and the United States, we believe that this research is highly relevant right now," said co-author Sweta Chekuri, M.D., of Montefiore Health System and Albert Einstein College of Medicine in the Bronx, New York. Research has shown that vitamin D supplementation can prevent inflammation in other respiratory diseases, but there have been limited studies examining the role of vitamin D supplementation in COVID-19. The purpose of the study was to determine whether being supplemented with vitamin D before being admitted to the hospital with COVID-19 resulted in less severe COVID-19 disease in patients with a low vitamin D level. The researchers studied 124 adult patients with low vitamin D that was measured up to 90 days before their admission for COVID-19. They compared the patients who were supplemented with at least 1,000 units of vitamin D weekly to those who had not received vitamin D supplements in terms of whether they were mechanically ventilated or died during admission. They found that patients who were supplemented were less likely to be mechanically ventilated or to die following admission, though the finding wasn't statistically significant (37.5 percent of patients who were not supplemented vs. 33.3 percent of those who were) They also found that more than half of those who should have been supplemented were not. "Though we weren't able to show a definitive link to severe COVID-19, it is clear that patients with low vitamin D should receive supplementation not only for bone health, but also for stronger protection against severe COVID-19," said co-author Corinne Levitus, D.O., of Montefiore Health System and Albert Einstein College of Medicine. "We hope this research will encourage clinicians to discuss adding this supplement with their patients who have low vitamin D, as this may reduce the odds of people developing severe COVID-19." A study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism last fall found over 80 percent of 200 COVID-19 patients in a hospital in Spain had vitamin D deficiency. Study finds changes in gut microbiome connected to Alzheimer-like behavior Oregon Health & Science University, March 19, 2021 New research in mice published in the journal Scientific Reports strengthens the growing scientific consensus regarding the role of the gut microbiome in neurodegenerative disorders including Alzheimer’s disease. The study, led by researchers at Oregon Health & Science University, found a correlation between the composition of the gut microbiome and the behavioral and cognitive performance of mice carrying genes associated with Alzheimer’s. The mice carried the human amyloid precursor protein gene with dominant Alzheimer’s mutations generated by scientists in Japan. The study further suggests a relationship between microbes in the digestive tract and the expression of genes that trigger Alzheimer-like symptoms in mice. “You know the expression, ‘You are what you eat?’” said senior author Jacob Raber, Ph.D., professor of behavioral neuroscience in the OHSU School of Medicine. “This may be part of that. While all mice were fed the same diet, the gut microbiome is affected in a genotype-dependent fashion and this in turn might affect your brain.” The findings are the first to demonstrate a direct connection between the gut microbiome and cognitive and behavioral changes in an Alzheimer’s disease animal model, and they are consistent with a recently published observational study in people newly diagnosed with Alzheimer’s. In fact, a U.S. clinical trial for the treatment of mild to moderate Alzheimer’s disease is currently underway involving a compound that targets microbes in the gut. The research published breaks new ground. In addition to the cognitive and behavioral changes that were measured, the study is the first to demonstrate a relationship between changes in the gut microbiome and epigenetic changes in neural tissue in the hippocampus, an area of the brain affected in Alzheimer’s. This type of research is not possible in people. The microbiome is a complex assemblage of microorganisms such as bacteria that play a critical role in a wide range of functions in the body. In this case, researchers wanted to see if the gut microbiome affected cognitive and behavioral measures in specially bred mice at 6 months of age. So they compared wild-type mice with those genetically engineered to carry the human amyloid precursor protein gene with dominant Alzheimer’s mutations. They found changes in the gut microbiome - measured in fecal pellets - corresponded with epigenetic regulation of the apolipoprotein E and Tomm40 genes, both associated with Alzheimer’s. They found a clear correlation, but they still can’t say whether one causes the other. “Microbes may elicit an impact on behavioral and cognitive measures relevant to Alzheimer’s disease via epigenetic changes in the hippocampus,” Raber said. “Or, alternatively, it might be that the epigenetic changes in the hippocampus affect changes in the gut microbiome.” The next phase of research will determine whether it’s possible to reduce Alzheimer’s-like symptoms in genetically predisposed mice by altering their diet. “The exciting part of this is that you can manipulate the gut microbiome,” Raber said. “We can use probiotics and see what the effect is.”
On this episode of CREB®Cast, CREB®’s chief economist, Ann-Marie Lurie, updates us on the current housing market conditions and dives into projections for the upcoming year.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.05.370221v1?rss=1 Authors: Cherix, A., Poitry-Yamate, C., Lanz, B., Zanoletti, O., Grosse, J., Sandi, C., Gruetter, R., Cardinaux, J.-R. Abstract: Mood disorders (MD) are a major burden on society as their biology remains poorly understood, challenging both diagnosis and therapy. Among many observed biological dysfunctions, homeostatic dysregulation, such as metabolic syndrome (MeS), shows considerable comorbidity with MD. Recently, CREB-regulated transcription coactivator 1 (CRTC1), a regulator of brain metabolism, was proposed as a promising factor to understand this relationship. Searching for imaging biomarkers and associating them with pathophysiological mechanisms using preclinical models, can provide significant insight into these complex psychiatric diseases and help the development of personalized healthcare. Here, we used neuroimaging technologies to show that deletion of Crtc1 in mice leads to an imaging fingerprint of hippocampal metabolic impairment related to depressive-like behavior. By identifying the underlying molecular/physiological origin, we could assign an energy-boosting mood-stabilizing treatment, ebselen, which rescued behavior and neuroimaging markers. Finally, our results point towards the GABAergic system as a potential therapeutic target for behavioral dysfunctions related to metabolic disorders. This study provides new insights on Crtc1's and MeS's relationship to MD and establishes depression-related markers with clinical potential. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.20.347146v1?rss=1 Authors: Shrestha, J., Santerre, M., Allen, C. N., Arjona, S. P., Mukerjee, R., Park, J., Bagashev, A., Wang, Y., Kaul, M., Chin, J., Sawaya, B. E. Abstract: HIV-associated neurocognitive disorders (HAND) remains an unsolved problem in the clinical management of HIV-1 carriers, because existing anti-retroviral therapy while suppressing viral replication, do not prevent neurocognitive impairment (e.g. spatial memory loss). HIV-1 gp120 protein has been proposed to contribute to HAND because it is shed by infected cells and the use of antibodies revealed its presence in cerebrospinal fluid (CSF) even in the combinatory antiretroviral therapy (cART) era. The cyclic AMP response element-binding protein (CREB) has long been known to be a star player in memory. CREB exerts its effect partially through regulating the genes for peroxisome proliferator-activated receptor gamma coactivator (PGC)-1a and brain-derived neurotrophic factor (BDNF). CREB, PGC-1a, and BDNF levels are low in the brains of patients with neurodegenerative diseases and a dearth of either protein is associated with cognitive decline. We have obtained data showing that gp120 contributes to neurodegeneration by altering CREB phosphorylation on serine residue 133 thus disrupting mitochondrial movement and synaptic plasticity leading to spatial memory loss. Inhibition of CREB function was also associated with a decrease of ATP levels and lower mitochondrial DNA copy numbers. Our data was validated in vitro (primary mouse neurons and neuronal cell line, SH-SY5Y) and in vivo (gp120-tg mice and mice injected with gp120). The negative effect of gp120 was alleviated in cells and animals in the presence of Rolipram. Hence, we conclude that HIV-1 gp120 protein contributes to spatial memory impairment via inhibition of CREB protein activity. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.28.316349v1?rss=1 Authors: Yasen, M., Jiang, L., Sharofova, M., Xin, X., Nuraliev, Y., Ye, J., Aisa, H. A. Abstract: The herbal medicine of Kursi Wufarikun Ziyabit contains two herbs (Geranium collinum Steph.ex Willd and Hypericum Scabrum Lnn) in the formula of ethnomedicine. It is usually used in the treatment of diabetes mellitus with a significant therapeutic efficacy. However, the molecular mechanism remains unknown for the action of medicine. In this study, we investigated the mechanism with a focus on an extract (GC30) of the medicine in the regulation of energy metabolism in hepatocytes. GC30 was prepared from a crude extract of the medicine through elution of an AB-8 macro porous resin column loaded with the medicine in 30% ethanol. GC30 exhibited an activity in the inhibition of triglyceride (TG) accumulation in the mouse hepatocytes through a suppression of SREBP1c activity. FGF21 (fibroblast growth factor 21) expression was induced by GC30 in a dosage-dependent manner at concentrations of 25 - 100 g/ml. The induction was observed in mRNA and protein of FGF21, which were peaked at 2 hours and lasted for 8 hours in the response to GC30 (100 g/ml). The transcription of FGF21 gene was induced by GC30 for an increase in the FGF21 gene promoter activity. AMPK and PKA activities were induced by GC30 with an elevation in their phosphorylation status, which were associated with a reduction in ATP abundance and an increase in CREB phosphorylation in cells treated with GC30. Oxygen consumption of mitochondria was inhibited in the hepatocytes by GC30. These activities of GC30 were similar to those of diabetes medicines including metformin and berberine. The data suggest that GC30 inhibited ATP production in mitochondria to activate AMPK and PKA in the hepatocytes to induce FGF21 expression. This study suggests a novel activity of the herbal medicine in the regulation of glucose and lipid metabolism in the hepatocytes. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.24.312264v1?rss=1 Authors: Sanders, T. H. Abstract: Epigenetic modulation of neural circuits facilitates learning and memory. Here, we examined specific inhibition of histone deacetylase 2 (HDAC2) expression in rats receiving a single intracerebroventricular injection of HDAC2-targeted anti-sense oligonucleotides (ASOs) one month prior to cognitive testing. The HDAC2 ASO-injected rats displayed increased novelty preference, decreased cortical and hippocampal HDAC2 mRNA and protein, and upregulated gene expression that persisted 1-month post-injection. Cortical RNA-seq revealed strongly increased transcription of a subset of cyclic adenosine monophosphate (cAMP)-response element binding (CREB) genes known to influence synaptic plasticity, along with dopamine (DRD1, DRD2) and adenosine (ADORA2A) G-protein-coupled receptors (GPCRs). Our analysis identified evidence of a positive-feedback loop that amplified expression of CREB-regulated Gs GPCRs and genes in cAMP/Gs/Gi signaling pathways. Additionally, we found differential expression of enzymes that shift neurotransmitter biosynthesis away from norepinephrine and toward dopamine and acetylcholine (DBH, CHAT). We also observed increased expression of genes important for neurotransmitter packaging (SV2C, VMAT) and release (SYT9). The data indicate that persistent inhibition of HDAC2 expression enables long-lived enhancement of aspects of cognition through increased cortical transcription of a subset of CREB-regulated genes amplified by a positive-feedback mechanism that increases synaptic plasticity and shifts neurotransmitter balance toward increased dopaminergic and cholinergic signaling. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.22.308403v1?rss=1 Authors: Wimmer, M., Cui, R., Blackwell, J., Abel, T. Abstract: The molecular and intracellular signaling processes that control sleep and wake states remain largely unknown. A consistent observation is that the cyclic-AMP response element binding protein (CREB), an activity-dependent transcription factor, is differentially activated during sleep and wakefulness. CREB is phosphorylated by the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway as well as other kinases, and phosphorylated CREB (pCREB) promotes transcription of target genes. Genetic studies in flies and mice suggest that CREB signaling influences sleep/wake states by promoting and stabilizing wakefulness. However, it remains unclear where in the brain CREB is required to drive wakefulness. In rats, CREB phosphorylation increases in the cerebral cortex during wakefulness and decreases during sleep, but it is not known if this change is functionally relevant to the maintenance of wakefulness. Here, we used the cre/lox system to conditionally delete CREB in the forebrain and in the locus coereleus (LC), two regions known to be important for the production of arousal and wakefulness. We used polysomnography to measure sleep/wake levels and sleep architecture in conditional CREB mutant mice and control littermates. We found that forebrain-specific deletion of CREB decreased wakefulness and increased non-rapid eye movement (NREM) sleep. Mice lacking CREB in the forebrain were unable sustain normal periods of wakefulness. On the other hand, deletion of CREB from LC neurons did not change sleep/wake levels or sleep/wake architecture. Taken together, these results suggest that CREB is required in neurons within the forebrain but not in the LC to promote and stabilize wakefulness. Copy rights belong to original authors. Visit the link for more info
A novel tumor type with EWSR-CREB fusions blending features of Angiomatoid FH and Mesothelioma; a discussion with the author Pedram Argani.Study by Argani et al, EWSR1/FUS–CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities. Modern Pathology, 2020. https://www.nature.com/articles/s41379-020-0646-5 See acast.com/privacy for privacy and opt-out information.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.22.262923v1?rss=1 Authors: Bronfman, F. C., Moya-Alvarado, G. Abstract: Brain-Derived Neurotrophic Factor (BDNF) is broadly expressed in many circuits of the central nervous system (CNS). It binds TrkB and p75 to trigger different signaling pathways, including ERK1/2 and PI3K-mTOR, to induce dendritic growth and synaptic plasticity. When binding to BDNF, TrkB and p75 are endocytosed to signaling endosomes to continue signaling inside the cell. Whether BDNF/TrkB-p75 signaling endosomes in axons are regulating long-distance signaling in cell bodies to modify neuronal morphology is unknown. Here, we studied the functional role of BDNF signaling endosomes in long-distance regulation of dendritic growth using compartmentalized cultures of rat and mouse cortical neurons derived from p75exonIII knock-out or TrkBF616A knock-in mice. By applying BDNF to distal axons, we showed the capacity of axonal BDNF to increase dendritic arborization in cell bodies. This process depended on TrkB activity, but not p75 expression. In axons, BDNF/TrkB co-localized with Rab5 endosomes and increased active Rab5. Also, dynein was required for BDNF long-distance signaling, consistent with sorting and transport of signaling endosomes. Using neurons derived from TrkBF616A knock-in mice and the 1NM-PP1 inhibitor, we were able to demonstrate that TrkB receptors activated in the axons by BDNF, were required in the neuronal cell body to increase TrkB activity and phosphorylation of CREB. Also, we were able to visualize endosomes containing activated TrkB. PI3K activity was not required in the axons for dynein dependent BDNF responses. However, dendritic arborization induced by axonal BDNF signaling required both nuclear CREB and PI3K activation in cell bodies. Consistently, axonal BDNF increased protein translation in cell bodies and CREB and PI3K and mTOR activity were required for this process. Altogether, these results show that BDNF/TrkB signaling endosomes generated in axons allows long-distance control of dendritic growth coordinating both transcription and protein translation. Our results suggest a role of BDNF-TrkB signaling endosomes wiring circuits in the CNS. Copy rights belong to original authors. Visit the link for more info
CREB®'s Chief Economist Ann-Marie Lurie updates us on the 2020 housing market and discusses COVID-19's impact so far this year.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.05.238139v1?rss=1 Authors: Borodinsky, L. N., Hamilton, A. M. Abstract: Inducing regeneration in injured spinal cord represents one of modern medicine greatest challenges. Research from a variety of model organisms indicates that Hedgehog (Hh) signaling may be a useful target to drive regeneration. However, the mechanisms of Hedgehog signaling-mediated tissue regeneration remain unclear. Here we examined Hh signaling during post-amputation tail regeneration in Xenopus laevis larvae. We found that while Smoothened (Smo) activity is essential for proper spinal cord and skeletal muscle regeneration, transcriptional activity of the canonical Hh effector Gli is repressed immediately following amputation, and inhibition of Gli1/2 expression or transcriptional activity has minimal effects on regeneration. In contrast, we demonstrate that protein kinase A (PKA) is necessary for regeneration of both muscle and spinal cord, in concert with and independent of Smo respectively, and that its downstream effector CREB is activated in spinal cord following amputation. Our findings indicate that non-canonical mechanisms of Hh signaling are necessary for spinal cord and muscle regeneration. Copy rights belong to original authors. Visit the link for more info
Join us as we sit down and talk shop with some of this year's outstanding REALTORS®:Rob Campbell, 2019 REALTOR® of the Year – T.W.H. (Bill) Saunders Memorial Award recipientRick Campos, Honourary Life Member Award recipientStan Matlashewski, Honourary Life Member Award recipientTom Westcott, 2019 CREB® Volunteer of the Year – Marilyn Jones Memorial Award & Honourary Life Member Award recipient
The Gary Null Show is here to inform you on the best news in health, healing, the environment. Antioxidant-rich powders from blueberry, persimmon waste could be good for gut microbiota Polytechnic University of Valencia (Italy), July 24, 2020 Feeding the world's growing population in a sustainable way is no easy task. That's why scientists are exploring options for transforming fruit and vegetable byproducts -- such as peels or pulp discarded during processing -- into nutritious food ingredients and supplements. Now, researchers reporting in ACS' Journal of Agricultural and Food Chemistry have shown that blueberry and persimmon waste can be made into antioxidant-rich powders that might have beneficial effects on gut microbiota. In recent years, fruit and vegetable powders have become popular as a way to add beneficial compounds, such as polyphenols and carotenoids (two types of antioxidants), to the diet, either by consuming the powders directly or as an ingredient in food products. However, in many cases these healthful compounds are present at similar or even higher levels in byproducts compared to those in other parts of the fruit or vegetable. Noelia Betoret, María José Gosalbes and colleagues wanted to obtain powders from persimmon and blueberry wastes, and then study how digestion could affect the release of antioxidants and other bioactive compounds. They also wanted to determine the effects of the digested powders on gut bacterial growth. The researchers obtained powders from persimmon peels and flower parts, and from the solids left behind after making blueberry juice. The type of powder, drying method, fiber content and type of fiber determined the release of antioxidants during a simulated digestion. For example, freeze-drying preserved more anthocyanins, but these were more easily degraded during digestion than those in air-dried samples. Then, the team added the powders to a fecal slurry and conducted a mock colonic fermentation, sequencing the bacteria present before and after fermentation. Incubation with the fruit powders resulted in an increase in several types of beneficial bacteria, and some bacteria grew better with one powder compared to the other. These findings indicate that persimmon and blueberry waste powders could be included in food formulations to boost the content of carotenoids and anthocyanins, which could have a positive impact on human health, the researchers say. Plant-based diets shown to lower blood pressure even with limited meat and dairy Consuming a plant-based diet can lower blood pressure even if small amounts of meat and dairy are consumed too, according to new research University of Warwick (UK), July 27, 2020 Consuming a plant-based diet can lower blood pressure even if small amounts of meat and dairy are consumed too, according to new research from the University of Warwick. Published online by a team from Warwick Medical School in the Journal of Hypertension today (25 July), they argue that any effort to increase plant-based foods in your diet and limit animal products is likely to benefit your blood pressure and reduce your risk of heart attacks, strokes and cardiovascular disease. They conducted a systematic review of previous research from controlled clinical trials to compare seven plant-based diets, several of which included animal products in small amounts, to a standardised control diet and the impact that these had on individuals' blood pressure. Plant-based diets support high consumption of fruits, vegetables, whole grains, legumes, nuts and seeds, limiting the consumption of most or all animal products (mainly meat and diary). (See Notes to Editors for further details) High blood pressure is the leading risk factor globally for heart attacks, strokes and other cardiovascular diseases. A reduction in blood pressure has important health benefits both for individuals and for populations. Unhealthy diets are responsible for more deaths and disabilities globally than tobacco use, high alcohol intake, drug use and unsafe sex put together. An increased consumption of whole grains, vegetables, nuts and seeds, and fruit, as achieved in plant-based diets, could avert up to 1.7, 1.8, 2.5 and 4.9 million deaths globally respectively every year according to previous research. Vegetarian and vegan diets with complete absence of animal products are already known to lower blood pressure compared to omnivorous diets. Their feasibility and sustainability are, however, limited. Until now, it has not been known whether a complete absence of animal products is necessary in plant-based dietary patterns to achieve a significant beneficial effect on blood pressure. Lead author Joshua Gibbs, a student in the University of Warwick School of Life Sciences, said: "We reviewed 41 studies involving 8,416 participants, in which the effects of seven different plant-based diets (including DASH, Mediterranean, Vegetarian, Vegan, Nordic, high fibre and high fruit and vegetables) on blood pressure were studied in controlled clinical trials. A systematic review and meta-analysis of these studies showed that most of these diets lowered blood pressure. The DASH diet had the largest effect reducing blood pressure by 5.53/3.79 mmHg compared to a control diet, and by 8.74/6.05 mmHg when compared to a 'usual' diet. "A blood pressure reduction of the scale caused by a higher consumption of plant-based diets, even with limited animal products would result in a 14% reduction in strokes, a 9% reduction in heart attacks and a 7% reduction in overall mortality. "This is a significant finding as it highlights that complete eradication of animal products is not necessary to produce reductions and improvements in blood pressure. Essentially, any shift towards a plant-based diet is a good one." Senior author Professor Francesco Cappuccio of Warwick Medical School said: "The adoption of plant-based dietary patterns would also play a role in global food sustainability and security. They would contribute to a reduction in land use due to human activities, to global water conservation and to a significant reduction in global greenhouse gas emission. "The study shows the efficacy of a plant-based diet on blood pressure. However, the translation of this knowledge into real benefits to people, i.e. its effectiveness, depends on a variety of factors related to both individual choices and to governments' policy decisions. For example, for an individual, the ability to adopt a plant-based diet would be influenced by socio-economic factors (costs, availability, access), perceived benefits and difficulties, resistance to change, age, health status, low adherence due to palatability and acceptance. "To overcome these barriers, we ought to formulate strategies to influence beliefs about plant-based diets, plant food availability and costs, multisectoral actions to foster policy changes focusing on environmental sustainability of food production, science gathering and health consequences." Health and happiness depend on each other Georgetown University, July 22, 2020 Good health and a happy outlook on life may seem like equally worthy yet independent goals. A growing body of research, however, bolsters the case that a happy outlook can have a very real impact on your physical well-being. New research published in the journal Psychological Science shows that both online and in-person psychological interventions -- tactics specifically designed to boost subjective well-being -- have positive effects on self-reported physical health. The online and in-person interventions were equally effective. "Though prior studies have shown that happier people tend to have better cardiovascular health and immune-system responses than their less happy counterparts," said Kostadin Kushlev, a professor in Georgetown University's Department of Psychology and one of the authors of the paper, "our research is one of the first randomized controlled trials to suggest that increasing the psychological well-being even of generally healthy adults can have benefits to their physical health." Intervention for Healthy Outcomes Over the course of six months, Kushlev and his colleagues at the University of Virginia and the University of British Columbia examined how improving the subjective well-being of people who were not hospitalized or otherwise undergoing medical treatment affected their physical health. A group of 155 adults between the ages of 25 and 75 were randomly assigned either to a wait-list control condition or a 12-week positive psychological intervention that addressed three different sources of happiness: the "Core Self," the "Experiential Self," and the "Social Self." The first 3 weeks of the program focused on the Core Self, helping individuals identify their personal values, strengths, and goals. The next 5 weeks focused on the Experiential Self, covering emotion regulation and mindfulness. This phase also gave participants tools to identify maladaptive patterns of thinking. The final 4 weeks of the program addressed the Social Self, teaching techniques to cultivate gratitude, foster positive social interactions, and engage more with their community. The program, called Enduring Happiness and Continued Self-Enhancement (ENHANCE), consisted of weekly modules either led by a trained clinician or completed individually using a customized online platform. None of the modules focused on promoting physical health or health behaviors, such as sleep, exercise, or diet. Each module featured an hour-long lesson with information and exercises; a weekly writing assignment, such as journaling; and an active behavioral component, such as guided meditation. "All of the activities were evidence-based tools to increase subjective well-being," Kushlev noted. When the program concluded, the participants were given individual evaluations and recommendations of which modules would be most effective at improving their happiness in the long term. Three months after the conclusion of the trial, researchers followed up with the participants to evaluate their well-being and health. A Happy Future Participants who received the intervention reported increasing levels of subjective well-being over the course of the 12-week program. They also reported fewer sick days than control participants throughout the program and 3 months after it ended. The online mode of administering the program was shown to be as effective as the in-person mode led by trained facilitators. "These results speak to the potential of such interventions to be scaled in ways that reach more people in environments such as college campuses to help increase happiness and promote better mental health among students," Kushlev said. Rely on gut feeling? New research identifies how second brain in gut communicates Finders University (Australia), July 24, 2020 You're faced with a big decision so your second brain provides what's normally referred to as 'gut instinct', but how did this sensation reach you before it was too late? The Enteric Nervous System (ENS) is an extensive network of neurons and transmitters wrapped in and around the human gut with the prime function of managing digestion, but researchers at Flinders University are delving into the complexity of this brain like system to uncover it's secret capabilities. In a new study published in the eNeuro journal, Professor Nick Spencer's laboratory has identified a particular type of neuron in the gut wall that communicates signals to other neurons outside the gut, near the spinal cord and up to the brain. "There is significant interest in how the gut communicates with the brain as a major unresolved issue because of growing evidence that many diseases may first start in the gut and then travel to the brain, an example of which is Parkinson's Disease," says Professor Spencer. "The new study has uncovered how viscerofugal neurons provide a pathway so our gut can "sense" what is going on inside the gut wall, then relay this sensory information more dynamically than was previously assumed to other organs, like the spinal cord and brain which influence our decisions, mood and general wellbeing." The results reveal why the ENS might play an increasingly important part on human health, and could shed light on potential new treatments for conditions like Parkinson's disease. This study represents a big step towards understanding ENS functions and the complexity of the gut and brain connection through the neurons that allow communication in the body. Professor Spencer says there is increasing interest in understanding how the nervous system in the gut (ENS) communicates with the brain, to give us all those sensations we know of. "What is particularly exciting about the gut, is that it is unlike all other internal organs (e.g. heart, liver, bladder) because the gut has its own nervous system, which can function independently of the brain or spinal cord. Understanding how the gut communicates and controls other organs in the body can lead to important breakthroughs for disease treatment and this is an important step in the right direction." The role of functional foods in treating chronic diseases Wuhan Sports University (China), July 24, 2020 In this study, researchers at Wuhan Sports University in China summarized several widely investigated bioactive components used as functional foods and their role in autophagy. Their review was published in the journal Food Science and Human Wellness. Functional foods, which could be either natural or processed foods that contain bioactive compounds, can provide health-promoting effects beyond basic nutrition. These foods also offer the benefit of preventing or treating chronic diseases. The bioactive components in functional foods often have pleiotropic effects, such as antioxidant, anti-inflammatory, hypolipidemic (cholesterol-lowering), blood sugar-regulating, cytoprotective and neuroprotective functions. Autophagy is a highly conserved cellular process used by the body to eliminate aberrant components in eukaryotic cells. It also plays an essential role in promoting health and preventing or treating several chronic diseases. When cells are in a stressful condition, autophagy accelerates the clearance of damaged or toxic cellular protein aggregates or dysfunctional cell organelles to maintain homeostasis. In this review, the researchers focused on several bioactive components of functional foods, such as resveratrol, epigallocatechin-3-gallate, curcumin and trehalose, and their regulatory functions in autophagy. They believe this review could serve as a reference or provide novel ideas for the development of functional foods capable of modulating autophagy for the treatment of chronic diseases. Combination of vitamin E and Lactobacillius plantarum reverses mercuric chloride-induced neurotoxicity King Saud University, July 23, 2020 According to news originating from Riyadh, Saudi Arabia, by NewsRx editors, the research stated, “Mercury is the third most hazardous heavy metal and its toxicity causes a severe health risk through unfavorable detrimental pathological and biochemical effects. Mercury is widely found in many ecological and certain occupational settings.” Our news editors obtained a quote from the research from King Saud University: “The aim of this study is to elucidate the neuroprotective role of vitamin E (VE) and Lactobacillus plantarum (LTB) either alone or in combination against a toxic sublethal dose of Mercuric chloride (MC). First group served as a normal control group; rats from the second group were intoxicated with (5 mg/kg MC once daily); the third group was treated with VE; the fourth group was treated with LTB; and the fifth group was treated with VE and LTB. All treatments were given daily along with MC for fourteen days. The results of the current study confirmed that MC prompted an elevation in serum TNF-a, IL-6 and brain lipid peroxides, protein expression of mitogen-activated protein kinase (MAPK) and mRNA expression of Bax and caspase-3 level as well as DNA degradation. However, Brain-derived neurotrophic factor (BDNF) and cAMP response element-binding (CREB) protein expressions, GSH level and SOD activity were down-regulated. The intake of LTB and/or VE along with MC intoxication significantly mitigated the alteration in all the previous parameters. Moreover, histopathological analysis of brain sections confirmed that MC-induced brain injury and LTB or VE alone or together were capable of ameliorating brain artitechture.” According to the news editors, the research concluded: “The combination of LTB and VE was an effective therapy in the management of MC-induced neuroioxicity and this combination can be considered a useful therapeutic candidate against brain injury induced by MC. BDNF, MAPK and CREB protein expressions are implicated in MC -induced brain injury and its treatment.” Plant-based diets high in carbs improve type 1 diabetes, according to new case studies Physicians Committee for Responsible Medicine, July 24, 2020 Plant-based diets rich in whole carbohydrates can improve insulin sensitivity and other health markers in individuals with type 1 diabetes, according to two case studies published by researchers from the Physicians Committee for Responsible Medicine in the Journal of Diabetes & Metabolism. Both case studies followed individuals with type 1 diabetes who adopted plant-based diets rich in whole carbohydrates--including fruits, vegetables, whole grains, and legumes. The patients' health care teams tracked their blood sugar control, heart disease risk factors, and other health measurements before and after the diet change. One case study followed a female patient who was diagnosed with type 1 diabetes in 2018. At the time, her A1c was 8.7%. She initially adopted a low-carbohydrate (less than 30 grams of carbohydrate per day), high-fat diet that was high in meat and dairy. Her blood sugar stabilized, but she required more insulin per gram of carbohydrate consumed. Her total cholesterol also increased from 175 to 221 mg/dL. In January 2019, she switched to a plant-based diet, eliminating dairy products, eggs, and meat. The patient was able to decrease her insulin dosage, maintain her A1c level at 5.4%, and drop her cholesterol level to 158 mg/dL. "This study challenges the misconception that carbs are the enemy when it comes to diabetes," says study author Hana Kahleova, MD, PhD, director of clinical research at the Physicians Committee. "The patient in this case study experienced the opposite: Adding more healthful carbohydrates to her diet stabilized her glycemic control, reduced her insulin needs, and boosted her overall health." The other individual--a 42-year-old man who had been diagnosed with type 1 diabetes at age 25--eliminated animal products from his diet and switched to a whole food, plant-based diet. He increased his consumption of carbohydrates from 150 grams to 400-450 grams per day. After adopting a carbohydrate-rich plant-based diet, he lost weight, required less insulin, and reduced his A1c--a measure of blood sugar levels over a 3-month period--from 6.2% to a range between 5.5-5.8%. The authors note that a previous small study supported the case studies' results, finding that a high-carbohydrate, high-fiber diet improved glycemic control in 10 people with type 1 diabetes. As a next step, the authors suggest that randomized clinical trials are needed to verify the case studies' findings, assess their generalizability, and quantify the effectiveness of plant-based diets in the management of type 1 diabetes. Previous studies have found that low-fat, plant-based diets can be beneficial for those with type 2 diabetes. Research has also shown that those eating a plant-based diet have approximately half the risk of developing type 2 diabetes, compared with non-vegetarians. "Decades of research has proven that a plant-based diet can be beneficial for those with type 2 diabetes. Now, these groundbreaking case studies are offering hope that the same may be true for those with type 1 diabetes," adds Dr. Kahleova. Raised iron levels linked to reduced life expectancy Imperial College London, July 24, 2020 Having too much iron in the body puts your long term health at risk but it could also take years off your life. These are the findings of a study using large scale genetic data to assess the impacts across a population of having naturally raised levels of iron, in terms of years of life expectancy. According to the researchers, the findings—which help to cut through the noise caused by confounding factors such as age, sex or diet—add to the increasingly complex picture of iron's role in our health and highlight the risks of having raised levels of iron. Dr. Dipender Gill, from Imperial's School of Public Health and who supervised the study, said: "We have known for a long time that having too much or too little iron in your system can have serious impacts on your health, and that effectively modifying iron levels can help many people with underlying conditions. Our findings build on previous work to clarify that picture further, showing that people who have genetic predisposition to slightly raised levels of iron in the body have reduced life expectancy on average. While we did not look directly at the impact of taking supplements, our results suggest that there is a need to better understand the health implications of people boosting their iron levels with supplements when they don't need to." Double-edged sword Iron is used by the body to make red blood cells, which carry oxygen. Most people without underlying health conditions should be able to get enough iron from their diet. But disrupting the balance can lead to a host of health implications: too little iron is associated with fatigue and impaired immune system, while too much can cause liver failure, and in high enough doses can even be fatal. A number of studies suggest small changes in iron levels can have protective and detrimental effects for different diseases, such as heart disease, stroke and infections. But the net effect of varying iron levels on life expectancy remains unclear. In the latest study, published this month in the journal Clinical Nutrition, Dr. Gill and Mr. Iyas Daghlas from Harvard Medical School used a statistical technique called Mendelian randomization to try to explore the effect of increasing levels of iron on health—using people's genetic variation as an indicator of their iron levels. The researchers trawled genetic data from almost 49,000 people to find genetic variants linked to iron levels. They focused on three points in the genome where a single "letter" difference in the DNA—called a single nucleotide polymorphism (SNP)—can slightly increase or reduce a person's iron level. When these same SNPs were then screened in a larger dataset combing lifespan data for more than one million people, they found that the genetic markers for higher iron levels on average associated with reduced life expectancy. The analysis revealed that for every one point of standard deviation increase in genetically predicted serum iron above baseline, people had an estimated 0.7 fewer years of lifespan. Furthermore, the findings were unlikely to be biased by lifestyle factors. A body of work The work builds on a number of previous studies by Dr. Gill, which have used genetic data to investigate the role of iron in hundreds of diseases. A 2017 study revealed the link between high iron levels and lower risk of heart disease. Further studies from 2019 showed naturally higher iron levels were associated with a lower risk of high cholesterol levels, reducing the risk of arteries becoming furred with a build-up of fatty substances, but also carried with it a higher risk of blood clots and skin infections. Taken together, the studies build a complex picture of iron status in health. The authors stress that the genetic markers themselves do not indicate reduced life expectancy or risk in the wider context, but are a tool to study how iron levels relate to health without the influence of a number of complex confounding factors such as diet, economic background, or smoking status. They add that the findings should not currently be applied clinically, at the individual level. Dr. Gill explained: "It's important to put these findings in context. Our analysis is indirect and uses genetic data as a proxy for raised iron levels. But the clinical implications warrant further investigation and could be important for long-term health at the population level." Mr Iyas Daghlas, from Harvard Medical School, said: "These findings should not yet be extrapolated to clinical practice, but they further support the idea that people without an iron deficiency are unlikely to benefit from supplementation, and that it may actually do them harm. We emphasize that these results should not be applied to patient populations with a compelling reason for iron supplementation, such as patients with symptomatic iron deficiency anemia, or in patients with heart failure." Seven reasons to eat more watermelon Life Extension, July 22, 2020 There's a reason why summer is the season for watermelon. Not only does this favorite fruit reach its peak flavors during the warmer months, watermelon is also even more nutrient-rich this time of year. From being a great source of raw lycopene to its hydrating nature, here are seven reasons to eat more watermelon. Lycopene is the pigment that gives red and pink fruits, such as tomatoes, watermelons and pink grapefruit, their characteristic color. Lycopene has been linked to health benefits ranging from heart health to protection against sunburns and certain types of cancers. 1. Watermelon is a top source of lycopene. Tomatoes get the glory when it comes to lycopene, but watermelon actually has more ? about 40 percent more, on average. Our bodies also absorb lycopene from watermelon more easily. Unlike tomatoes, which need to be cooked in order to maximize lycopene absorption, we can effectively absorb and reap the benefits of lycopene from raw watermelon. 2. It's hydrating.No surprise here. (It is called watermelon, after all!) But you may find it interesting that watermelon is 92 percent water, so by enjoying it, you really are eating your way toward better hydration. 3. It may improve blood pressure; is a top source of citrulline, which can help to improve blood flow and blood pressure 4. Because it's so sweet, watermelon has a reputation for being high in sugar, but most fruits arenaturally high in sugar, but they're also rich in nutrients. However, compared to sweet potatoes, watermelon has only one-fourth of the carbs and only half the sugar. 5. All of the goodness of watermelon (lycopene, beta carotene, vitamin C, vitamin A, fiber and overall antioxidants) gets better with age. The redder the fruit's flesh, the higher the nutrient concentration. 6. Most of us eat the red flesh and leave the rinds, but the rinds are entirely edible (just remove the outer peel), and are as nutritious as the flesh itself. The rinds can be sliced and added to your favorite stir-fry recipe, juiced or pureed for chilled soups. 7. It can be prepared in countless creative ways.Simply slice it and eat it plain, or with a sprinkle of salt. Or go with the classic pairing of watermelon: fresh mint and feta (or goat cheese, for a lower-sodium option). Make watermelon salsa, using watermelon in place of some (or all) of the tomatoes in your favorite salsa recipe. Grill it. Juice it. Puree it, rind and all, for soups and mocktails. The options are endless! Molly Kimball, RD, CSSD, registered dietitian with Ochsner Health System, manages the nutrition department of Ochsner Fitness Center and is founder of the Ochsner Eat Fit nonprofit restaurant initiative.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.02.184754v1?rss=1 Authors: Jiang, S. Z., Sweat, S., Dahlke, S., Loane, K., Drossel, G., Xu, W., Tejeda, H. A., Gerfen, C. R., Eiden, L. E. Abstract: Elucidation of the underlying mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor expressing neurons leading to acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK to Egr-1/Zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons (MSNs) of nucleus accumbens slices; and in mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the nucleus accumbens (NAc) in adult mice, using AAV-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-MSNs and cocaine-induced behaviors including locomotor sensitization and conditioned place preference (CPP). Abrogation of NCS-Rapgef2 gene expression in medium prefrontal cortex and basolateral amygdala, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase IIalpha promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1-receptor expressing neurons in the NAc, but not in corticolimbic areas, contributes to cocaine-induced locomotor sensitization and CPP. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling. Copy rights belong to original authors. Visit the link for more info
Corinne Lyall is the broker and owner of Royal LePage Benchmark, and has worked in some capacity in the real estate industry for over 30 years. She is the 2015 Past President of CREB® (Calgary Real Estate Board), was on the Royal LePage Canada's National Advisory Council, and is the current Chair of Pillar9 (the Alberta One MLS Board). Corinne was also President of CREB®'s Charitable Foundation in and helped create partnerships to build the 60-unit Crestwood Affordable Housing project. Other non-real estate boards she has been involved in are Doors Open YYC, WEDO (Women's Entrepreneurship Day), and is currently on the EO (Entrepreneurship Organization) Calgary Chapter board. Corinne is passionate about being involved in the real estate industry, and loves having the opportunity to have leadership roles in organizations where she can influence better relationships and collaboration for positive change and outcomes.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.08.130815v1?rss=1 Authors: Chatterjee, S., Angelakos, C. C., Bahl, E., Hawk, J. D., Gaine, M. E., Poplawski, S. G., Schneider-Anthony, A., Yadav, M., Porcari, G. S., Cassel, J.-C., Giese, K. P., Michaelson, J. J., Lyons, L. C., Boutillier, A.-L., Abel, T. Abstract: CREB-dependent transcription necessary for long-term memory is driven by interactions with CREB-binding protein (CBP), a multi-domain protein that binds numerous transcription factors. Identifying specific domain functions for multi-action proteins is essential to understand processes necessary for healthy living including cognitive function and a robust circadian clock. We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. We found that CBPKIX/KIX mice were impaired in long-term, but not short-term spatial memory in the Morris water maze. Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we discovered dysregulation of CREB and CLOCK target genes and downregulation of circadian genes in CBPKIX/KIX mice. With our finding that the CBP KIX domain was important for transcription of circadian genes, we profiled circadian activity in CBPKIX/KIX mice. CBPKIX/KIX mice exhibited delayed activity peaks after light offset and longer free-running periods in constant dark, although phase resetting to light was comparable to wildtype. These studies provide insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.092338v1?rss=1 Authors: Conte, G., Parras, A., Alves, M., Olla, I., de Diego-Garcia, L., Beamer, E., Alalqam, R., Ocampo, A., Mendez, R., Lucas, J. J., Engel, T. Abstract: Objective: Pharmacoresistance and the lack of disease-modifying actions of current anti-seizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential anti-epileptogenic drugs but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intraamygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug-resistant temporal lobe epilepsy (TLE). Methods: Status epilepticus was induced via intraamygdala microinjection of kainic acid in C57BL/6 mice and gene expression analysed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE. Results: Intraamygdala kainic acid injection in mice triggered extensive dysregulation of gene expression which was ~3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples of patients with TLE revealed a particular high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signalling to be highly conserved across different models of epilepsy and patients. CREB was predicted as one of the main up-stream transcription factors regulating gene expression during acute and chronic phases and inhibition of CREB reduced seizure severity in the intraamygdala kainic acid model. Significance: Our findings suggest the intraamygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rationale target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy. Copy rights belong to original authors. Visit the link for more info
What is learning and memory? Is amnesia really a loss of stored memories or something more? In this interview, we will discuss where memory goes and if there is a way to retrieve them after trauma. Recent studies have shown that spatial memories are encoded as sparse populations of cells that are activated during learning and are necessary for the retrieval of specific memories. We refer to these cells as "memory engram cells" and the focus of Tomás J Ryan and his team is to understand how engram cells are able to store specific memories as information. Here is a quick summary/breakdown of the video above. The old storage theory of amnesia is WRONG. The problem is the ability to retrieve the memory. Short term memory lasts a few hours. It is very disruptable (long term is not). Long term memory lasts your entire lifetime. It requires transcription and translation of many different genes. We have many different genes that regulate memory. They are different for short term and long term - playing roles at different stages. Most popular was CREB (turns on other genes). Engrams cells are structures in the brain where memories are stored. R They used optigenetics to prove engram cells were important for memory. Engram cells only account for 4-6% of the brain cells in the hippocampus (of mice). V Consolidation idea - a short term memory (unstable) forms into a long term memory (stable), thus stabilizing the engram. Optogenetics - let's us express photoactivatable opsins in whatever region of the brain we want. The brain is electrically active. They put certain opsins into brain cells and then stimulate them with light. These opsins can conduct ions - putting positively charged cations from the external environment of the cell into the neuron. This depolarizes the cell, which results in an action potential (creating neuronal activity). What they did at MIT was integrate optogenetics and memory engram cells. They tested parts of the brain using a transgenetics - they took immediate/early genes (genes that show activity as a function of neuronal spike) and used opsins to only activate those genes. Amnesia and Memory Learning is the enhancement of synaptic connections. Memory is a stable thing in the brain and can last for your entire life. Learning and recall are not "things", they are activities. Learning = process of making a memory. Recall = process of retrieving a memory. So the problem is not memory itself. Amnesic engram cells have a loss of synaptic strength. Increasing the synaptic strength helps get the memory (which is commonly seen in Alzheimer's (AD), Huntington's (HD)). If you increase the synaptic potentiation (increasing the dendritic spine density), esp. of the amnesic engram cells, you can get natural access to those memories. Neurotrophic factors (BDNF, NGF, CNTF, GDNF) do this, but are not localized nor memory specific. Learning something new (about something you are amnesic about) will train your brain to those particular engram cells. Once you activate the engram cells (with optogenetics), you can restore access to old information and add new information on those amnesic memories. Without dealing with the cause, you probably won't be able to really restore memories (in diseases like AD, HD, etc.) In late stages of neurodegeneration, you may actually lose memories. Actions to take for prevention Stay mentally active Engage in physical exercise Actions to take for amnesia (acute memory loss) Do everything to remind yourself of those experiences Retrain on the "forgotten" pieces We briefly discussed gene expression and histone acetylation to enhance memory. https://mybiohack.com/blog/tomas-j-ryan-debunking-amnesia-and-stabilizing-engram-cells
On this month's episode of CREB®Cast Ann-Marie Lurie, CREB®’s chief economist, gives us the inside scoop on the Calgary housing market for the coming year.
In this episode, we met with Alan Tennant, hearing firsthand about his journey to become CREB President & CEO, and his perspective on the state of the Real Estate industry.
On this month’s episode of CREB®Cast we’re talking about community investment with Jason Yule, CREB®’s Manager of Communications & Community Investment, and Sharon Bercuson, Chair of CREB®’s REALTOR® Community Foundation.
Ann Marie Lurie is the Chief Economist at the Calgary Real Estate Board and she joins the podcast to talk about the state of the Calgary market, where things are heading from here, and what some of the biggest misconceptions are that people outside of Calgary have about this great city. Click for show notes Andrew la Fleur / Sales Representative 416-371-2333 / andrew@truecondos.com http://www.truecondos.com http://www.twitter.com/andrewlafleur http://www.facebook.com/truecondos https://truecondos.com/new-condos-toronto
Calgary Living - Real Estate & Life Style with host Bryon Howard
5:23 On Professionalism7:00 How Sarah came to Calgary via Vancouver and Canada's North11:35 The cyclical nature of real estate14:28 Sarah's early start in real estate ... coming from Robert Kiyosaki's Rich Dad, Poor Dad.18:04 On Work ... and Calgary bust cycles.21:39 Being of ServiceHow can people reach out how can they contact you?https://www.instagram.com/adventuresintealestatehttps://sarahjohnston.ca///If you have questions, or if you know somebody that needs to be on this podcast, please reach out to me, Bryon Howard.Bryon@TheHoward team.net. Or you can simply pick up the phone give me a call or shoot me a text on my cell phone at 403-589-0004. I look forward to hearing your questions or suggestions on who needs to be on Calgary Living: Real Estate and Lifestyle.Thanks again for tuning in.
On this month’s episode of CREB®Cast we’re talking about new developments with Grant Murray - Senior Vice President, Sales at Concord Pacific Developments Inc.
Calgary Living - Real Estate & Life Style with host Bryon Howard
Some show highlights:5:00 - Purchasing a home is more than just an investment decision.13:47 - Added factor of "Stress Test" ... with little employment groth.16:07 - Struggling with too much supply in market.16:26 - Migration is mostly from International.17:15- Sales are nothing to what they used to be.17:20 - Growth/Increase in prices, is in the lower end.19:00 - I want to be a buyer when there is too much supply.19:15 - Purchasing. How long do you intend to live in Calgary. How long do you plan to be in this market?22:00 - Will there be another Boom in Calgary?23:50 - Condo's - 14% below.24:45 - We are not coming out of this soon.26:00 - What stats should you be considering as a buyer or seller?
On this month’s episode of CREB®Cast we’re talking all about safety and how REALTORS® can keep themselves safe during showings.
In this podcast, S. Thomas Carmichael, MD, PhD, discusses the roles of CREB, CCR5, and tonic GABA signaling in memory formation during stroke recovery, as well as other advances in regenerative medicine from the upcoming ANA 2019 annual meeting. More at: www.consultant360.com/neurology.
Check out this month’s episode of CREB®Cast with Shane Griffin. On this episode we’re talking to Alberta One Realty Listings Services CEO Shane Griffin about the new MLS® system that’s in the works for Alberta.
On this episode of CREB®Cast we’re talking to local Calgary and area REALTOR® Nettie Hendricks about how to thrive in real estate no matter what the market is like.
On this episode we’re talking to CREB®’s chief economist Ann-Marie Lurie about how the market in doing and what we can expect in the months ahead.
This week's episode is not for little kids' ears! But it is one for husbands, wives, moms, dads, and teenagers. And is definitely a discussion topic for you and your pre-teens. It's a good reminder to also mention that this is not a topic solely for those in the foster/adoptive community. There are many children that come from hard places that have had egregious sins committed against them, but in the realm of pornography and masturbation - this is a topic that affects everyone. Even if you don't believe me. One scary and true thing that was said in this episode is that your children may not be looking for porn - but porn is looking for them! This is a multi billion dollar industry that wants to find new addicts. We have Robert Watson as our special guest this week. He is a pastor at Sun Valley Community Church, and he delivered an awesome sermon on this topic last year. You can find it here, but he shares all the main points on the podcast today. This is not just a typical sermon. This is a science lesson and soul lesson wrapped in one. Some bullet points on what we discussed: - In the realm of sex and porn, people don't want to talk about this because the topic is taboo and filled with GUILT and SHAME. We want people to escape from that realm and walk in the light, where there is Freedom and Peace. - Pornography and masturbation are addictions and appetites that need to be filled the more that they are practiced. When you go to the store on an empty stomach - you will make less healthy food choices in the long run, and you will sample anything and everything along the way. Similarly with sex, you may be longing for intimacy or relationship, but you fill yourself with garbage and actual ruin your ability to enjoy true intimacy and relationship by engaging in porn and self-pleasuring. - Young women! Think about what you post online. Why are you always in a bikini? Why do you always need to show your boobs?? WHAT DO YOU WANT? Just some attention? For people to tell you that you are pretty? Hot? Think about WHAT you want (attention? relationship? intimacy?) and think about HOW you want to get it. Brain chemistry and some weird terms (but great rapper names): - There is a protein that your brain creates called DeltaFosB. "[ΔFosB is] almost like a molecular switch. ... Once it's flipped on, it stays on for a while and doesn't go away easily. This phenomenon is observed in response to chronic administration of virtually any drug of abuse. It is also observed after high levels of consumption of natural rewards (exercise, sucrose, high fat diet, sex)." Read the full article here. - Crebb. "CREB is like the brakes on a runaway reward center; it slows the pleasure response. [22]With CREB onboard, porn that once excited a person stops having the same effect. [23] Scientists believe that CREB is partly why consumers have to keep increasing their porn intake to get aroused. [24] That numbed-out state is called “tolerance,” and it’s part of any kind of addiction." Read this full article here. What this means is people need to keep upping the ante on what they are watching and doing and how frequently they are doing those addictive things. - This is not a podcast episode to tell men that they are terrible. Women are also addicted to porn, as well as romance novels! You can read this article about how this happened to a well known Romance Book author, Francine Rivers. - This is why sin is progressive, when we decide to hide and keep it a secret from those we love, it just keeps getting worse. But there is help for everyone in all situations, once we choose to get help! Now what? - The Adam and Eve Effect: This is when you love the one you are with. You don't compare them to anyone else - because back in the day - there was no one to compare Eve to. She was Adam's one and only. And same with Eve. - Robert mentioned this TedTalk by Gary Wilson, who talks about how men who have come out of their porn addiction have been able to learn French, and picked up new, incredible hobbies, very quickly once their brains got freed up from all the porn they were consuming. - There is lots of help out there. You just have to be willing to find it AND use it. We want to make the finding part easy for you: - Covenant Eyes: For internet accountability and filtering. - XXXChurch : To help men and women break free from porn addiction - Celebrate Recovery: Find one near you! This is a Christ-centered 12 step recovery program, and it's amazing. - Disney Circle : to help you filter what people in your house are watching, and even when and how long they are able to watch them. We have this and it's a great tool! - TALK. As in, talk about this with people you love and trust. There is hope and freedom for everyone. The (Good) Words of the Day "Flee from sexual immorality. All other sins a person commits are outside the body, but whoever sins sexually, sins against their own body." -1 Corinthians 6:18 “You have heard that it was said, ‘You shall not commit adultery.’ But I tell you that anyone who looks at a woman lustfully has already committed adultery with her in his heart. If your right eye causes you to stumble, gouge it out and throw it away. It is better for you to lose one part of your body than for your whole body to be thrown into hell. And if your right hand causes you to stumble, cut it off and throw it away. It is better for you to lose one part of your body than for your whole body to go into hell." -Matthew 5:27-30 These verses do not condemn or condone bad behavior. They are wise counsel to RUN AWAY, to be extreme, in escaping the strong grip of the sexual temptation and sin that is out there! We hope that this week's episode has shed some light on a very powerful topic that is ruining families and society. Please feel free to share this with anyone you think might need to hear this today. If you want to connect on Social Media, you can find us at: Robert Watson on Facebook Jihae Watson on Facebook Fostering Voices on Instagram Jihae Watson on Instagram AND we would LOVE it if you would leave us a review on iTunes! This helps others to find our podcast so we can share these voices from the foster care and adoption community!
Hark, dear listeners! Our heroes’ Monday is coming to a close, which means it’s time for…*Thunderclap* **Scary Violin Sting** HAPPY HOUR!!! As our heroes descend into the BoneZone without the aid of their friend Maxwell - who has tummy trouble after too many lunch wines (but really Brandon is getting married! Congrats, dude!) - they are beset by rowdy friends, a stern bartender, and a gathering crowd of fans and foes of Agnes and Hobe’s band, Satanic Panic. Will they eat the bar…or will the bar eat them? In This Episode Maxwell “buries some treasure” Stuart gets (castle) freaky Agnes assembles her band And Brube reveals an in-Creb-ible secret
CREB-regulated transcription coactivator 3 (CRTC3) is found in adipocytes, where it may promote obesity through disruption of catecholamine signaling. We wished to assess whether CRTC3 is a soluble protein secreted by adipose tissue, explore whether CRTC3 is detectable and quantifiable in the circulation, and ascertain whether CRTC3 serum concentrations are related to metabolic markers in children.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 18/19
Asthma is characterized by chronic airway inflammation; mucus hypersecretion and episodes of airway obstruction. It is the most common chronic disease in children and its incidence and prevalence have been markedly increasing over the last few decades. While the pathophysiology has been intensively studied, the underlying causes for asthma development remain largely unknown. Hence there is an unmet, clinical need to identify novel, so far non-characterized pathways, relevant for this disease, to establish new therapies or preventive approaches. We used miRNAs to do so as they are critical regulators of key molecules within signalling pathways. Our group previously identified a pulmonary increase of miR-17 and -144 in ovalbumin-induced allergic airway inflammation in mice and they were shown to target the transcription factor cAMP-responsive element binding protein 1 (Creb1). In this work, we found and validated additional binding sites for the two miRNAs and the newly included miR-21 in the 3’UTR of Creb1 co-activators CRTC1, -2 and -3. Creb1 and the three Crtcs were further shown to be down-regulated in two models of murine experimental asthma (ovalbumin and house dust mite). We postulated that a joint down-regulation of Creb plus its co-activators by the miRNAs might have detrimental, additive effects on the expression of target genes. In this respect, we identified the putative Creb1 target gene Sec14-like 3 (Sec14l3) which was down-regulated in both models for murine experimental asthma and its loss seemed to be associated with goblet cell metaplasia. Furthermore, we found that IL-13 treatment of primary normal human epithelial (NHBE) cells led to a decrease of CREB1/CRTCs and SEC14L3, while the latter correlated with forkheadbox protein J1 (FOXJ1), a marker for ciliated cells. miR-17, -144 and -21 were actively secreted into exosomes by the primary NHBE cells upon IL-13 stimuli, which could be uptaken by a bronchial epithelial cell line and a T cell line . We could also detect miRNA-containing exosomes in nasal washes from children with allergic asthma and broncho-alveolar lavage fluid of mice with OVA-induced allergic airway inflammation. In nasal epithelial cells of children with allergic asthma, the three miRNAs were highly increased compared to healthy controls, while SEC14l3 expression was reduced. In conclusion, this work identified a novel molecular axis (miRNA-Creb/Crtc/Sec14l3) relevant for murine and paediatric asthma and gives first hints that miR-17, -144 and -21 in exosomes might be able to perpetuate the asthmatic response between different cell types.
Sit back and listen to our podcast !!!!Will baby blood hit the anti-aging market? Is the young blood transfusion the new omega 3 / golgi berries for the prevention of cognitive decline? Stanford and Harvard scientists claim so. A new wave of interest was drawn from an old, yet neglected medieval medical technique, where two circulatory systems, one old and one young, were connected in order to refresh the old brain and facilitate its healing and rejuvenating mechanisms. The method, now fancily called heterochronic parabiosis, has recently been brought back to scientific focus for one simple reason: it looks like its working.source: http://tinyurl.com/qcr9bwyThe neurological decline and associated cognitive deterioration experienced during healthy ageing as well as neurodegeneration is one of the biggest mysteries in neuroscience. It seems like we cannot point out a single, culpable black sheep from the several factors that accounts for the progressive decline in the end of life. Rather, it is more likely that there is a cascade of "little things going wrong" that leads to the decline in overall performance. This is exactly why counteracting or slowing down this progress is not an easy task. It is not surprising that a method offering an all-purpose "cure" against old age will rob the bank, especially if it can have headlines such as Vampire therapy of ageing, and put Fifty shades of grey ads in the corner.2014 was the year of young blood. I mean, apart from the season finale of True Blood, Katsimpardi and colleagues (2014) stitched an old and a young mouse together to connected their circulatory systems. This was not only beneficial for the vascularisation of the old brain compared to the young one but also upregulated the neurogenesis in one of the areas of the brain known for its role in the memory formation, the hippocampus. Pretty fascinating stuff, because it implies that we can now fight ageing in two ways: 1) better circulation in the brain (hence more food and oxygen to the neurons, and less probability of a stroke) and 2) more neurons in the area that is most likely to be the correlated with the contextual memory (decline). However, there is a rather big jump between the experimental evidence and literature review of possible candidate mechanisms to put behind all these effects. The authors finally pulled out the chocolate sprinkle (see the podcast) of growth factors called GDF11 to test on their parabionts. However, GDF11 is, according to my knowledge, too big a protein to cross the blood brain barrier (its concentration was not measured, it was only administered in the brain as a separate experiment). This does not mean that it cant account for a lot of circulatory beneficial effects, but I cant necessarily see the direct connection with the neurogenesis. The authors themselves highlight overall effects saying This suggests that neural stem cells exposed to young systemic factors increase their ability to proliferate and differentiate into neurons.(highlighting by me if you cant tell form the shade of purple immediately :P)Hhmmm...anyway... Are these newborn neurons functional parts of the network; can we correlate their operation with physiological and behavioural improvement? Stanford suggested that we can. This paper is an old-school, all rounder evaluation of the vampire approach, so much so that they are not even stitching the bellies together, just transfusing the serum of young mouse to older ones. Clever move, not just because it helps the PR part (stitching together old people with babies, not my dream advert for rejuvenation therapy), but it also makes the implementation easier. They also started by looking for the 'it' factor of rejuvenation by performing a genome-wide microarray analysis of the old and young hippocampi in the parabiont mice. They found a rather good chocolate sprinkle called Creb (cyclic AMP response element–binding protein), that is known for regulating game-changer proteins such as C-Fos (indirect correlate of neural activity), and to be essential for the sustenance of the good old LTP (see later). Now thats a start, but what else changed? If we compare levels of neuroscientific interest to a computer (dare I compare it to the brain itself), they found differences on all levels. If we take the hardware, they showed greater number of dendritic spines in the heterochronic parabionts in the dentate gyrus of the hippocampi, but not in another part (CA1). Sadly, the press was shouting Alzheimer, but in this neurodegenerative disorder, dentate gyrus stays intact for relatively long time. Does not immediately shout Alzheimer to me. Difference of all levels (1. experimental groups, 2. anatomical remodelling: more spines (hardware), 3. change the physiological correlate of synaptic plasticity, more sustained LTP in the control group (software) )source: http://tinyurl.com/qxhdm35Anyway, the authors then addressed if there is anything upgraded in the software. They found that long term potentiation, the gold standard electrophysiological measure of long term memory function was maintained for the entire recording period in the old members of the old-young pairs compared to the aged members of the old-old pairs (controls). We all know how slicework in neuroscience is the bread and butter of describing causality, but we know nothing about what happened in vivo from all this. Lastly, the IT wants to know what happens if we give a new task to this computer, so the behaviour of the heterochromic parabionts vs controls was tested in many, hippocampus-related contextual memory tasks. This tasks are basically the rodent version of the where did I park my car last night kind of lifehacks. Surprise, surprise, rejuvenated old fellow mice did better than re-not-juvenated peers. Now one last thought about this ... where is the evidence that it is a cure for Alzheimers??Taken together, what can modern neuroscience say about the fountain of youth compared to the good old times? Not more than that we can actually prove the effect of young blood. Converging evidence supports the method is somewhat, somehow working. Exactly how my grandma argues for superstition and folk wisdom. It is still a good guess, we might as well give it a go, even without knowing the chocolate sprinkle factor of it. Even if we have no idea how to implement a huge amount of young blood transfusions on a longer term.
Thursday, February 20, 2014 Paul Colombo (Tulane) discusses the dynamic interactions between memory systems, and data that indicate that subjects use different strategies that leverage different memory systems to accomplish the same task. He also discusses his CREB viral vector model system for manipulating interactions between memory systems. Duration: 33 minutes Discussants:(in alphabetical order) Brian Derrick (Prof, UTSA) Carlos Paladini (Assoc Prof, UTSA Salma Quraishi (Asst Prof, UTSA) Todd Troyer (Assoc Prof, UTSA Charles Wilson (Professor, UTSA) acknowledgement: JM Tepper for original music.
We’ve got our first ever guest host, Ian Mahar at OYM this week, talking neurogenesis in the hippocampus, antidepressants and the use of animal models of behaviour. Our tenth episode also has us talking about the pressure of huge conferences, the use of article-level metrics to evaluate a paper’s impact and a strange medical disorder.
Objective: Ursodeoxycholic acid (UDCA) exerts anticholestatic effects in part by protein kinase C (PKC)-dependent mechanisms. Its taurine conjugate, TUDCA, is a cPKCa agonist. We tested whether protein kinase A (PKA) might contribute to the anticholestatic action of TUDCA via cooperative cPKCa-/PKA-dependent mechanisms in taurolithocholic acid (TLCA)-induced cholestasis. Methods: In perfused rat liver, bile flow was determined gravimetrically, organic anion secretion spectrophotometrically, lactate dehydrogenase (LDH) release enzymatically, cAMP response-element binding protein (CREB) phosphorylation by immunoblotting, and cAMP by immunoassay. PKC/PKA inhibitors were tested radiochemically. In vitro phosphorylation of the conjugate export pump, Mrp2/Abcc2, was studied in rat hepatocytes and human Hep-G2 hepatoma cells. Results: In livers treated with TLCA (10 mmol/l)+TUDCA (25 mmol/l), combined inhibition of cPKC by the cPKCselective inhibitor Go¨6976 (100 nmol/l) or the nonselective PKC inhibitor staurosporine (10 nmol/l) and of PKA by H89 (100 nmol/l) reduced bile flow by 36% (p,0.05) and 48% (p,0.01), and secretion of the Mrp2/ Abcc2 substrate, 2,4-dinitrophenyl-S-glutathione, by 31% (p,0.05) and 41% (p,0.01), respectively; bile flow was unaffected in control livers or livers treated with TUDCA only or TLCA+taurocholic acid. Inhibition of cPKC or PKA alone did not affect the anticholestatic action of TUDCA. Hepatic cAMP levels and CREB phosphorylation as readout of PKA activity were unaffected by the bile acids tested, suggesting a permissive effect of PKA for the anticholestatic action of TUDCA. Rat and human hepatocellular Mrp2 were phosphorylated by phorbol ester pretreatment and recombinant cPKCa, nPKCe, and PKA, respectively, in a staurosporine-sensitive manner. Conclusion: UDCA conjugates exert their anticholestatic action in bile acid-induced cholestasis in part via cooperative post-translational cPKCa-/PKA-dependent mechanisms. Hepatocellular Mrp2 may be one target of bile acid-induced kinase activation.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 02/06
Many transcription factors integrate a variety of cellular stimuli to produce a transcriptional response. There is increasing evidence that the timing and kinetics of activation are crucial in determining specificity and strength of gene expression, however so far only few tools are available to address these questions in live cells and these have severe drawbacks, like very low signal strength, complicated handling, irreversibility and lack of good targeting properties.The Ca 2+- and cyclic adenosine monophosphat responsive element-binding protein (CREB) and the related ATF-1 and CREM are stimulus inducible transcription factors that link certain forms of cellular activity to changes in gene expression and are involved in differentiation, cancer, survival and neuronal plasticity. Using fluorescence resonance energy transfer (FRET) we here develop genetically encoded indicators that enable imaging activation of CREB family transcription factors due to phosphorylation of the critical serine 133 and subsequent recruitment of a coactivator in single live cells. The indicator for CREB activation due to phosphorylation (ICAP) consitsts of the kinase inducible domain (KID) of CREB fused together with the KIX of CREB binding protein (CBP) via a flexible linker, sandwiched between a cyan and a yellow variant of the green fluorescent protein. The specificity and reliability of ICAP as a measure for CREB activation was demonstrated first in the cuvette and then in the nucleus and mitochondria of HeLa cells. After that, we analyzed the properties of ICAP in primary hippocampal neurons, where we characterize different signaling pathways with distinct kinetics that lead to CREB activation. Furthermore, combining the imaging of CREB activation with calcium imaging we see a summation of CREB activation in neurons that can be achieved by appropriately timed depolarizing stimuli and occurs even when individual stimulations are separated by hours. Finally, sensors for the activation of ATF-1, CREM and the recruitment of P300, were introduced and preliminarily characterized. On the whole, these array of biosensors complement the toolbox for the investigation of the activation of the CREB family of transcription factors in living cells and organisms.
Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 02/19
This work investigates for the first time the expression and the role of Sonic hedgehog signaling pathway in adult pituitary and in pituitary tumors. Shh is a signaling protein, important in regulating patterning and proliferation in the embryo and the adult. It has a crucial role in pituitary development and Shh deficient mice do not even have a rudimentary Rathke's pouch (the development structure that gives rise to anterior pituitary). This study reveals the presence of an active Shh pathway in the post-developmental pituitary gland, with major impacts on hormone secretion and cell proliferation. After embryonic development, Shh continues to be expressed in the normal adult pituitary, being mainly co-localized in corticotrophs. These cells express also the receptor Ptc2 and the Shh induced transcription factor Gli1, being so Shh-producing and Shh-responsive cells. Shh acts in an autocrine way inside corticotrophs, inducing a major stimulation of ACTH secretion in the normal rat pituitary and in the AtT-20 cell line. The Shh induced ACTH secretion effect is synergistic with CRH. Shh stimulation increases CRH-R1 levels, up-regulating so the response of corticotrophs to CRH. At the same time, Gli1 is not only activated by Shh, but also by CRH and PKA. Gli1 itself activates POMC-transcription and acts in parallel upstream to CREB and AP-1. A major increase in Shh protein levels is seen as a result of CRH stimulation. All these results put in evidence a multiple cross-talk between these two important pathways acting at different levels to insure the final ACTH stimulation. Other types of hormone-secreting adenohypophysial cells possess one of Shh receptors (Ptc1 or Ptc2) and the transcription factor Gli1, so they have an active Shh pathway. Shh produced in the corticotrophs is a signaling protein, so it diffuses and acts also in distance. Shh increases GH secretion from the rat pituitary somatotrophs and from the GH3 cell line, while the effect on Prolactin is not statistically significant. The Sonic hedgehog pathway is downregulated in pituitary adenomas. Screening of 55 pituitary tumors reveals that they have a significantly reduced expression of Shh and Gli1. Although Shh in the normal pituitary is secreted by corticotroph cells, all the Cushing tumors screened had no Shh expression at all. Cell culture experiments performed in the AtT-20 corticotroph cell line in vitro show that Shh reduces cell proliferation by 50% and this effect is partially reducible by Cyclopamine. So Shh maintains the low proliferative capacity of corticotrophs in the normal pituitary gland and its loss may be one of the factors leading to tumor progression. It is concluded that Shh is produced in the anterior pituitary gland, is a major stimulant of ACTH and GH secretion, acts synergistically with CRH, opposes corticotroph cell proliferation and is downregulated in pituitary adenomas.
Extinction is defined as the loss of cell type-specific gene expression that occurs in somatic cell hybrids derived by fusion of cells with dissimilar phenotypes. To explore the basis of this dominant-negative regulation, we have studied the activities of the control elements of the liver-specific gene encoding tyrosine aminotransferase (TAT) in hepatoma/fibroblast hybrid crosses. We show that extinction in complete somatic cell hybrids is accompanied by the loss of activity of all known cell type-specific control elements of the TAT gene. This inactivity is the result of first, lack of expression of genes coding for the transcriptional activators HNF4 and HNF3[~ and HNF33,, which bind to essential elements of the enhancers; and second, loss of in vivo binding and activity of ubiquitous factors to these enhancers, including CREB, which is the target for repression by the tissue-specific extinguisher locus TSE1. Complete extinction of TAT gene activity is therefore a multifactorial process affecting all three enhancers controlling liver-specific and hormone-inducible expression. It results from lack of activation, rather than active repression, and involves both post-translational modification and loss of essential transcriptional activators.
We have characterized cDNA clones representing mouse CREB (cyclic AMP responsive element binding protein) mRNA isoforms. These include CREBA and CREBa, of which the rat and human homologues have been previously identified. Both encode proteins with CREbinding activity and identical transactivation potential. The additional CREB mRNA isoforms potentially encode CREB related proteins. From the structural organization of the mouse CREB gene we conclude that the multiple transcripts are generated by alternative splicing. Furthermore we show that specific CREB mRNA isoforms are expressed at a high level in the adult testis. Expression of these isoforms is induced after commencement of spermatogenesis. In situ hybridization suggests that this expression occurs predominantly in the primary spermatocytes. Comparison of the CREB gene with the recently isolated CREM (cAMP responsive element modulator) cDNAs illustrates that the two genes have arisen by gene duplication and have diverged to encode transcriptional activators and repressors of the cAMP signal transduction pathway.
Cyclic AMP treatment of hepatoma cells leads to increased protein binding at the cyclic AMP response element (CRE) of the tyrosine aminotransferase (TAT) gene in vivo, as revealed by genomic footprinting, whereas no increase is observed at the CRE of the phosphoenolpyruvate carboxykinase (PEPCK) gene. Several criteria establish that the 43 kDa CREB protein is interacting with both of these sites. Two classes of CRE with different affinity for CREB are described. One class, including the TATCRE, is characterized by asymmetric and weak binding sites (CGTCA), whereas the second class containing symmetrical TGACGTCA sites shows a much higher binding affinity for CREB. Both classes show an increase in binding after phosphorylation of CREB by protein kinase A (PKA). An in vivo phosphorylation-dependent change in binding of CREB increases the occupancy of weak binding sites used for transactivation, such as the TATCRE, while high affinity sites may have constitutive binding of transcriptionally active and inactive CREB dimers, as demonstrated by in vivo footprinting at the PEPCK CRE. Thus, lower basal level and higher relative stimulation of transcription by cyclic AMP through low affinity CREs should result, allowing finely tuned control of gene activation.
The tissue-specific extinguisher locus TSE1, a dominant negative regulator of transcription in somatic cell hybrids, acts via a cAMP response element (CRE) to repress activity of a hepatocyte-specific enhancer. Guided by the antagonism between TSE1 and cAMP-mediated signal transduction, we identified the regulatory subunit Rlα of protein kinase A (PKA) as the product of the TSE1 locus. The evidence derives from concordant expression of Tlα mRNA and TSE1 genetic activity, high resolution mapping of the RIα gene and TSE1 on human chromosome 17, and the ability of a transfected RIα cDNA to generate a phenocopy of TSE1-mediated extinction. The mechanism of TSE1/RIα-mediated extinction involves repression of basal PKA activity, reduced phosphorylation of CREB at Ser-133, and a corresponding reduction of in vivo protein binding at the target CRE.
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