The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood ...trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.
Genetics of schizophrenia in the South African Xhosa Gulsuner, S; Stein, D J; Susser, E S ...
Science (American Association for the Advancement of Science),
01/2020, Letnik:
367, Številka:
6477
Journal Article
Recenzirano
Odprti dostop
Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of ...schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.
Abstract
With the conclusion of the third observing run for Advanced LIGO/Virgo (O3), we present a detailed analysis of both triggered and serendipitous observations of 17 gravitational-wave (GW) ...events (7 triggered and 10 purely serendipitous) from the Searches After Gravitational-waves Using ARizona Observatories (SAGUARO) program. We searched a total of 4935 deg
2
down to a median 5
σ
transient detection depth of 21.1 AB mag using the Mt. Lemmon 1.5 m telescope, the discovery engine for SAGUARO. In addition to triggered events within 24 hr, our transient search encompassed a time interval following GW events of <120 hr, providing observations on ∼1/2 of the events accessible to the Mt. Lemmon 1.5 m telescope. We covered 2.1%–86% of the LVC total probability (
P
total
) for individual events, with a median
P
total
≈ 8% within <120 hr. Following improvements to our pipeline and the addition of serendipitous observations, we find a total of seven new optical candidates across five GW events, which we are unable to rule out after searching for additional information and comparing to kilonova models. Using both publicly available and our own late-time data, we investigated a total of 252 optical candidates for these 17 events, finding that only 65% were followed up in some capacity by the community. Of the total 252 candidates, we are able to rule out an additional 12 previously reported counterpart candidates. In light of these results, we discuss lessons learned from the SAGUARO GW counterpart search. We discuss how community coordination of observations and candidate follow-up, as well as the role of archival data, are crucial to improving the efficiency of follow-up efforts and preventing unnecessary duplication of effort with limited electromagnetic resources.
An attempt is made to synthesize the geological properties, water quality attributes and aspects of the ecology of south-east Australian estuaries so as to provide a framework for addressing coastal ...management issues. The approach is based on the underlying causal factors of geology and morphology and more immediate environmental factors (e.g. salinity and sediments) which are associated with ecological distributions, species richness and fisheries catch. This ‘broad brush’ approach seeks to maximize reality and generality, albeit at the expense of precision and local variability in individual circumstances. It disregards small-scale ecological patterns as noise. Unlike in the Northern Hemisphere, conditions in temperate Australia are characterized by irregular flood and fire regimes that strongly influence estuary hydrology and nutrient inputs. Three main types of estuary (tide-dominated, wave-dominated and intermittently closed) are recognized based on geological criteria and having particular entrance conditions that control tidal exchange. Four zones (marine flood-tidal delta, central mud basin, fluvial delta and riverine channel/alluvial plain) are also recognized common to each type of estuary. These zones correspond to mappable sedimentary environments in all estuaries and have characteristic water quality, nutrient cycling/primary productivity signatures and ecosystems. The ecology of a zone is modified by (a) estuary type which determines the salinity regime; (b) stage of sediment filling (evolutionary maturity) which controls the spatial distribution/size of the zones; and (c) impacts of various forms of development. By using the zones/habitats as a common currency among all estuaries, it is possible to link ecological aspects such as species richness and commercial fisheries production so as to compare different estuaries or within-estuary zones.
Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The ...genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.
High development cost, low development success, cost‐disciplined health‐care policies, and intense competition demand an efficient drug development process. New compounds need to bring value to ...patients by being safe, efficacious, and cost‐effective as compared with existing treatment options. Model‐based meta‐analysis (MBMA) facilitates integration and utilization of summary‐level efficacy and safety data, providing a quantitative framework for comparative efficacy and safety assessment.1,2 This Commentary discusses the application and limitations of MBMA in drug development.
Clinical Pharmacology & Therapeutics (2011) 90 6, 766–769. doi:10.1038/clpt.2011.242
Abstract
We present a comprehensive analysis of 653 optical candidate counterparts reported during the third gravitational-wave (GW) observing run. Our sample concentrates on candidates from the 15 ...events (published in GWTC-2, GWTC-3, or not retracted on GraceDB) that had a >1% chance of including a neutron star in order to assess their viability as true kilonovae. In particular, we leverage tools available in real time, including pre-merger detections and cross-matching with catalogs (i.e., point-source, variable-star, quasar and host-galaxy redshift data sets), to eliminate 65% of candidates in our sample. We further employ spectroscopic classifications, late-time detections, and light-curve behavior analyses and conclude that 66 candidates remain viable kilonovae. These candidates lack sufficient information to determine their classifications, and the majority would require luminosities greater than that of AT 2017gfo. Pre-merger detections in public photometric survey data and comparison of cataloged host-galaxy redshifts with the GW event distances are critical to incorporate into vetting procedures, as these tools eliminated >20% and >30% of candidates, respectively. We expect that such tools that leverage archival information will significantly reduce the strain on spectroscopic and photometric follow-up resources in future observing runs. Finally, we discuss the critical role prompt updates from GW astronomers to the EM community play in reducing the number of candidates requiring vetting.
Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although ...genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.
An accurate estimate of carbon fluxes associated with tropical deforestation from the last two decades is needed to balance the global carbon budget. Several studies have already estimated carbon ...emissions from tropical deforestation, but the estimates vary greatly and are difficult to compare due to differences in data sources, assumptions, and methodologies. In this paper, we review the different estimates and datasets, and the various challenges associated with comparing them and with accurately estimating carbon emissions from deforestation. We performed a simulation study over legal Amazonia to illustrate some of these major issues. Our analysis demonstrates the importance of considering land‐cover dynamics following deforestation, including the fluxes from reclearing of secondary vegetation, the decay of product and slash pools, and the fluxes from regrowing forest. It also suggests that accurate carbon‐flux estimates will need to consider historical land‐cover changes for at least the previous 20 years. However, this result is highly sensitive to estimates of the partitioning of cleared carbon into instantaneous burning vs. long‐timescale slash pools. We also show that carbon flux estimates based on ‘committed flux’ calculations, as used by a few studies, are not comparable with the ‘annual balance’ calculation method used by other studies.
Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been ...reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.
PDF
