Elevated tph2 mRNA expression in a rat model of chronic anxiety

BACKGROUND: Allelic variations in TPH2, the gene encoding tryptophan hydroxylase 2, the rate-limiting enzyme for brain serotonin (5-HT) biosynthesis, may be genetic predictors of panic disorder and panic responses to panicogenic challenges in healthy volunteers. To test the hypothesis that tph2 mRNA is altered in chronic anxiety states, we measured tph2 expression in an established rat model of panic disorder. METHODS: We implanted 16 adult, male rats with bilateral guide cannulae and then primed them with daily injections of the corticotropin-releasing factor (CRF) receptor agonist, urocortin 1 (UCN1, 6 fmoles/100 nl per side, n = 8) or vehicle (n = 8) into the basolateral amygdaloid complex (BL) for 5 consecutive days. Anxiety-like behavior was assessed, 24 hr prior to and 48 hr following priming, in the social interaction (SI) test. A third group (n = 7) served as undisturbed home cage controls. All rats were killed 3 days after the last intra-BL injection to analyze tph2 and slc6a4 (gene encoding the serotonin transporter, SERT) mRNA expression in the dorsal raphe nucleus (DR), the main source of serotonergic projections to anxiety-related brain regions, using in situ hybridization histochemistry. RESULTS: UCN1 priming increased anxiety-related behavior in the SI test compared to vehicle-injected controls and elevated tph2, but not slc6a4, mRNA expression in DR subregions, including the ventrolateral DR/ventrolateral periaqueductal gray (DRVL/VLPAG), a subregion previously implicated in control of panic-related physiologic responses. Tph2 mRNA expression in the DRVL/VLPAG was correlated with increased anxiety-related behavior. CONCLUSION: Our data support the hypothesis that chronic anxiety states are associated with dysregulated tph2 expression

Coral adaptive capacity insufficient to halt global transition of coral reefs into net erosion under climate change

Projecting the effects of climate change on net reef calcium carbonate production is critical to understanding the future impacts on ecosystem function, but prior estimates have not included corals\u27 natural adaptive capacity to such change. Here we estimate how the ability of symbionts to evolve tolerance to heat stress, or for coral hosts to shuffle to favourable symbionts, and their combination, may influence responses to the combined impacts of ocean warming and acidification under three representative concentration pathway (RCP) emissions scenarios (RCP2.6, RCP4.5 and RCP8.5). We show that symbiont evolution and shuffling, both individually and when combined, favours persistent positive net reef calcium carbonate production. However, our projections of future net calcium carbonate production (NCCP) under climate change vary both spatially and by RCP. For example, 19%-35% of modelled coral reefs are still projected to have net positive NCCP by 2050 if symbionts can evolve increased thermal tolerance, depending on the RCP. Without symbiont adaptive capacity, the number of coral reefs with positive NCCP drops to 9%-13% by 2050. Accounting for both symbiont evolution and shuffling, we project median positive NCPP of coral reefs will still occur under low greenhouse emissions (RCP2.6) in the Indian Ocean, and even under moderate emissions (RCP4.5) in the Pacific Ocean. However, adaptive capacity will be insufficient to halt the transition of coral reefs globally into erosion by 2050 under severe emissions scenarios (RCP8.5)

Crh receptor priming in the bed nucleus of the stria terminalis induces tph2 gene expression in the dorsomedial dorsal raphe nucleus and chronic anxiety

The bed nucleus of the stria terminalis (BNST) is a nodal structure in neural circuits controlling anxiety-related defensive behavioral responses. It contains neurons expressing the stress- and anxiety-related neuropeptide corticotropin-releasing hormone (Crh) as well as Crh receptors. Repeated daily subthreshold activation of Crh receptors in the BNST is known to induce a chronic anxiety-like state, but how this affects neurotransmitter-relevant gene expression in target regions of the BNST is still unclear. Since the BNST projects heavily to the dorsal raphe nucleus (DR), the main source of brain serotonin, we here tested the hypothesis that such repeated, anxiety-inducing activation of Crh receptors in the BNST alters the expression of serotonergic genes in the DR, including tph2, the gene encoding the rate-limiting enzyme for brain serotonin synthesis, and slc6a4, the gene encoding the serotonin transporter (SERT). For 5 days, adult male Wistar rats received daily, bilateral, intra-BNST microinjections of vehicle (1% bovine serum albumin in 0.9% saline, n = 11) or behaviorally subthreshold doses of urocortin 1 (Ucn1, n = 11), a potent Crh receptor agonist. Priming with Ucn1 increased tph2 mRNA expression selectively within the anxiety-related dorsal part of the DR (DRD) and decreased social interaction (SI) time, a measure of anxiety-related defensive behavioral responses in rodents. Decreased social interaction was strongly correlated with increased tph2 mRNA expression in the DRD. Together with previous studies, our data are consistent with the hypothesis that Crh-mediated control of the BNST/DRD-serotonergic system plays a key role in the development of chronic anxiety states, possibly also contributing to stress-induced relapses in drug abuse and addiction behavior

Job requirements compared to medical school education: differences between graduates from problem-based learning and conventional curricula

Background: Problem-based Learning (PBL) has been suggested as a key educational method of knowledge acquisition to improve medical education. We sought to evaluate the differences in medical school education between graduates from PBL-based and conventional curricula and to what extent these curricula fit job requirements. Methods: Graduates from all German medical schools who graduated between 1996 and 2002 were eligible for this study. Graduates self-assessed nine competencies as required at their day-to-day work and as taught in medical school on a 6-point Likert scale. Results were compared between graduates from a PBL-based curriculum (University Witten/Herdecke) and conventional curricula. Results: Three schools were excluded because of low response rates. Baseline demographics between graduates of the PBL-based curriculum (n = 101, 49% female) and the conventional curricula (n = 4720, 49% female) were similar. No major differences were observed regarding job requirements with priorities for "Independent learning/working" and "Practical medical skills". All competencies were rated to be better taught in PBL-based curriculum compared to the conventional curricula (all p < 0.001), except for "Medical knowledge" and "Research competence". Comparing competencies required at work and taught in medical school, PBL was associated with benefits in "Interdisciplinary thinking" (Δ + 0.88), "Independent learning/working" (Δ + 0.57), "Psycho-social competence" (Δ + 0.56), "Teamwork" (Δ + 0.39) and "Problem-solving skills" (Δ + 0.36), whereas "Research competence" (Δ - 1.23) and "Business competence" (Δ - 1.44) in the PBL-based curriculum needed improvement. Conclusion: Among medical graduates in Germany, PBL demonstrated benefits with regard to competencies which were highly required in the job of physicians. Research and business competence deserve closer attention in future curricular development

Molecular Architecture of the Human Mediator–RNA Polymerase II–TFIIF Assembly

The authors perform a cryo-EM study of the 1.9 MDa human Mediator-RNA polymerase II-TFIIF assembly, which reveals the structural organization of the human transcription initiation apparatus

HD 219134 Revisited: Planet d Transit Upper Limit and Planet f Transit Nondetection with ASTERIA and TESS

HD 219134 is a K3V dwarf star with six reported radial-velocity discovered planets. The two innermost planets b and c show transits, raising the possibility of this system to be the nearest (6.53 pc), brightest (V = 5.57) example of a star with a compact multiple transiting planet system. Ground-based searches for transits of planets beyond b and c are not feasible because of the infrequent transits, long transit duration (~5 hr), shallow transit depths (<1%), and large transit time uncertainty (~half a day). We use the space-based telescopes the Arcsecond Space Telescope Enabling Research in Astrophysics (ASTERIA) and the Transiting Exoplanet Survey Satellite (TESS) to search for transits of planets f (P = 22.717 days and M sin i = 7.3 ± 0.04M_⊕) and d (P = 46.859 days and M sin i = 16.7 ± 0.64M_⊕). ASTERIA was a technology demonstration CubeSat with an opportunity for science in an extended program. ASTERIA observations of HD 219134 were designed to cover the 3σ transit windows for planets f and d via repeated visits over many months. While TESS has much higher sensitivity and more continuous time coverage than ASTERIA, only the HD 219134 f transit window fell within the TESS survey's observations. Our TESS photometric results definitively rule out planetary transits for HD 219134 f. We do not detect the Neptune-mass HD 219134 d transits and our ASTERIA data are sensitive to planets as small as 3.6 R_⊕. We provide TESS updated transit times and periods for HD 219134 b and c, which are designated TOI 1469.01 and 1469.02 respectively

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator

Country Concepts and the Rational Actor Trap: Limitations to Strategic Management of International NGOs

Growing criticism of inefficient development aid demanded new planning instruments of donors, including international NGOs (INGOs). A reorientation from isolated project-planning towards holistic country concepts and the increasing rationality of a result-orientated planning process were seen as answer. However, whether these country concepts - newly introduced by major INGOs too - have increased the efficiency of development cooperation is open to question. Firstly, there have been counteracting external factors, like the globalization of the aid business, that demanded structural changes in the composition of INGO portfolios towards growing short-term humanitarian aid; this was hardly compatible with the requirements of medium-term country planning. Secondly, the underlying vision of rationality as a remedy for the major ills of development aid was in itself a fallacy. A major change in the methodology of planning, closely connected with a shift of emphasis in the approach to development cooperation, away from project planning and service delivery, towards supporting the socio-cultural and political environment of the recipient communities, demands a reorientation of aid management: The most urgent change needed is by donors, away from the blinkers of result-orientated planning towards participative organizational cultures of learning.Des critiques croissantes de l'aide au développement inefficace exigent de nouveaux instruments de planification des bailleurs de fonds, y compris les ONG internationales (ONGI). Une réorientation de la planification des projets isolés vers des concepts holistiques de la planification de l’aide par pays ainsi que la rationalité croissante d'un processus de planification orientée vers les résultats ont été considérés comme réponse. Toutefois, si ces concepts de pays - nouvellement introduites par les grandes OING eux aussi - ont augmenté l'efficacité de la coopération au développement est ouvert à la question. Tout d'abord, il y a eu l’impact des facteurs externes, comme la mondialisation de l'entreprise de l'aide, qui a exigé des changements structurels dans la composition des portefeuilles des OING vers la croissance de l'aide humanitaire à court terme. Cela était difficilement compatible avec les exigences de l'aménagement du territoire à moyen terme. Deuxièmement, la vision sous-jacente de la rationalité accrue de la planification, concentré sur les resultats, comme un remède pour les grands maux de l'aide au développement était en soi une erreur. Un changement majeur dans la méthodologie de la planification, étroitement liée à un changement d'orientation dans l'approche de la coopération au développement, qui n’est pas concentrer sur planification du projet et la prestation de services, mais qui soutienne l'environnement socio-culturel et politique des communautés bénéficiaires, exige une réorientation de la gestion de l’aide: Le changement le plus urgent est un changement par les donateurs eux-mêmes, qui devrait implanter des cultures de collaboration étroit avec les partenaires et la population locale

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types