Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to ...date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain.
We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis-acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism.
We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions.
In 1920, the psychiatrist Abraham Myerson published a self-help book titled The Nervous Housewife. In his book, he argued that the living conditions in urban-industrial America were responsible for a ...significant increase in the number of housewives who suffered from nervous symptoms. He also warned that women were consequently becoming increasingly discontent with the role and were beginning to desire a life outside motherhood and housewifery. Accordingly, The Nervous Housewife offered housewives and their husbands directions on how to improve her living conditions. This would allow readers to manage and prevent the emergence of nervous symptoms so that women would continue to desire a life as housewife and mother. Throughout the 1920s, Myerson would continue to publish health advice for housewives on how they could manage and eliminate their nervous symptoms. This article analyzes how Myerson connected the everyday experiences and conditions of the housewife's life to her nervousness in his texts and reveals how his motivation was to keep women satisfied with what he deemed was their proper societal role, that of housewife and mother. In doing so, it will also compare his work to other self-help texts on nervousness to illuminate how his how-to guide was innovative, while examining both scholarly and popular reviews of his book to reveal what his peers and readers perceived as the benefits of his advice.
Summary
In the 1940s, Abraham Myerson’s work on drinking norms in the USA was central to reorienting the approach medical and scientific experts adopted when studying and treating alcoholism. A ...leading psychiatrist and neurologist from Boston, Myerson argued that tensions between alcohol’s ability to satisfy a pleasure-seeking drive and the rise of asceticism had generated ambivalent social attitudes, traditions and expectations towards drinking. This article explores how Myerson identified and employed social factors to uncover the relationship between ambivalent drinking norms, one’s gender, ethnic or religious background, and whether one would drink to excess. In doing so, it will illuminate how Myerson’s innovative efforts to highlight the role of social attitudes and traditions in alcoholism ultimately helped shape the approach of medical science to the alcohol problem.
Geographically isolated wetlands (GIWs), those surrounded by uplands, exchange materials, energy, and organisms with other elements in hydrological and habitat networks, contributing to landscape ...functions, such as flow generation, nutrient and sediment retention, and biodiversity support. GIWs constitute most of the wetlands in many North American landscapes, provide a disproportionately large fraction of wetland edges where many functions are enhanced, and form complexes with other water bodies to create spatial and temporal heterogeneity in the timing, flow paths, and magnitude of network connectivity. These attributes signal a critical role for GIWs in sustaining a portfolio of landscape functions, but legal protections remain weak despite preferential loss from many landscapes. GIWs lack persistent surface water connections, but this condition does not imply the absence of hydrological, biogeochemical, and biological exchanges with nearby and downstream waters. Although hydrological and biogeochemical connectivity is often episodic or slow (e.g., via groundwater), hydrologic continuity and limited evaporative solute enrichment suggest both flow generation and solute and sediment retention. Similarly, whereas biological connectivity usually requires overland dispersal, numerous organisms, including many rare or threatened species, use both GIWs and downstream waters at different times or life stages, suggesting that GIWs are critical elements of landscape habitat mosaics. Indeed, weaker hydrologic connectivity with downstream waters and constrained biological connectivity with other landscape elements are precisely what enhances some GIW functions and enables others. Based on analysis of wetland geography and synthesis of wetland functions, we argue that sustaining landscape functions requires conserving the entire continuum of wetland connectivity, including GIWs.
The purported migrations that have formed the peoples of Britain have been the focus of generations of scholarly controversy. However, this has not benefited from direct analyses of ancient genomes. ...Here we report nine ancient genomes (∼ 1 ×) of individuals from northern Britain: seven from a Roman era York cemetery, bookended by earlier Iron-Age and later Anglo-Saxon burials. Six of the Roman genomes show affinity with modern British Celtic populations, particularly Welsh, but significantly diverge from populations from Yorkshire and other eastern English samples. They also show similarity with the earlier Iron-Age genome, suggesting population continuity, but differ from the later Anglo-Saxon genome. This pattern concords with profound impact of migrations in the Anglo-Saxon period. Strikingly, one Roman skeleton shows a clear signal of exogenous origin, with affinities pointing towards the Middle East, confirming the cosmopolitan character of the Empire, even at its northernmost fringes.
Wetlands provide numerous ecosystem services, from habitat provision to pollutant removal, floodwater storage, and microclimate regulation. Delivery of particular services relies on specific ...ecological functions, and thus to varying degree on wetland ecological condition, commonly quantified as departure from minimally impacted reference sites. Condition assessments are widely adopted as regulatory indicators of ecosystem function, and for some services (e.g., habitat) links between condition and function are often direct. For others, however, links are more tenuous, and using condition alone to enumerate ecosystem value (e.g., for compensatory mitigation) may underestimate important services. Hydrologic function affects many services cited in support of wetland protection both directly (floodwater retention, microclimate regulation) and indirectly (biogeochemical cycling, pollutant removal). We investigated links between condition and hydrologic function to test the hypothesis, embedded in regulatory assessment of wetland value, that condition predicts function. Condition was assessed using rapid and intensive approaches, including Florida's official wetland assessment tool, in 11 isolated forested wetlands in north Florida (USA) spanning a land use intensity gradient. Hydrologic function was assessed using hydrologic regime (mean, variance, and rates of change of water depth), and measurements of groundwater exchange and evapotranspiration (ET). Despite a wide range in condition, no systematic variation in hydrologic regime was observed; indeed reference sites spanned the full range of variation. In contrast, ET was affected by land use, with higher rates in intensive (agriculture and urban) landscapes in response to higher leaf area. ET determines latent heat exchange, which regulates microclimate, a valuable service in urban heat islands. Higher ET also indicates higher productivity and thus carbon cycling. Groundwater exchange regularly reversed flow direction at all sites in response to rainfall. This buffering effect on regional aquifer levels, an underappreciated service of isolated wetlands, was provided regardless of condition. Intensive landscapes may benefit most from the hydrologic services that wetlands provide because that is where certain services (floodwater storage, microclimate regulation) are realized. While the portfolio of wetland services clearly changes with disturbance, our results support a revised approach to wetland valuation that recognizes the services that accrue from sustained or enhanced functions in these "working wetlands."
Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to ...systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1 -mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10–15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of “cancer-selective paralog dependency” may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits.
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Tissue growth in bioscaffolds is influenced significantly by pore geometry, but how this geometric dependence emerges from dynamic cellular processes such as cell proliferation and ...cell migration remains poorly understood. Here we investigate the influence of pore size on the time required to bridge pores in thin 3D-printed scaffolds. Experimentally, new tissue infills the pores continually from their perimeter under strong curvature control, which leads the tissue front to round off with time. Despite the varied shapes assumed by the tissue during this evolution, we find that time to bridge a pore simply increases linearly with the overall pore size. To disentangle the biological influence of cell behaviour and the mechanistic influence of geometry in this experimental observation, we propose a simple reaction–diffusion model of tissue growth based on Porous-Fisher invasion of cells into the pores. First, this model provides a good qualitative representation of the evolution of the tissue; new tissue in the model grows at an effective rate that depends on the local curvature of the tissue substrate. Second, the model suggests that a linear dependence of bridging time with pore size arises due to geometric reasons alone, not to differences in cell behaviours across pores of different sizes. Our analysis suggests that tissue growth dynamics in these experimental constructs is dominated by mechanistic crowding effects that influence collective cell proliferation and migration processes, and that can be predicted by simple reaction–diffusion models of cells that have robust, consistent behaviours.
Recent U.S. Supreme Court rulings have limited federal protections for geographically isolated wetlands (GIWs) except where a “significant nexus” to a navigable water body is demonstrated. Geographic ...isolation does not imply GIWs are hydrologically disconnected; indeed, wetland‐groundwater interactions may yield important controls on regional hydrology. Differences in specific yield (Sy) between uplands and inundated GIWs drive differences in water level responses to precipitation and evapotranspiration, leading to frequent reversals in hydraulic gradients that cause GIWs to act as both groundwater sinks and sources. These reversals are predicted to buffer surficial aquifer dynamics and thus base flow delivery, a process we refer to as landscape hydrologic capacitance. To test this hypothesis, we connected models of soil moisture, upland water table, and wetland stage to simulate hydrology of a low‐relief landscape with GIWs, and explored the influences of total wetland area, individual wetland size, climate, and soil texture on water table and base flow variation. Increasing total wetland area and decreasing individual wetland size substantially decreased water table and base flow variation (e.g., reducing base flow standard deviation by as much as 50%). GIWs also decreased the frequency of extremely high and low water tables and base flow deliveries. For the same total wetland area, landscapes with fewer (i.e., larger) wetlands exhibited markedly lower hydrologic capacitance than those with more (i.e., smaller) wetlands, highlighting the importance of small GIWs to regional hydrology. Our results suggest that GIWs buffer dynamics of the surficial aquifer and stream base flow, providing an indirect but significant nexus to the regional hydrologic system.
Key Points
GIWs act as hydrologic sinks and sources in response to climate
GIWs effects on regional water table and base flow were modeled
GIWs buffer surficial aquifer variation, impacting stream base flow
The mobilization and transport of per- and poly-fluoroalkyl substances (PFASs) via surface runoff (runoff) from aqueous film-forming foam (AFFF)-contaminated soils during rainfall, flooding, or ...irrigation has not been thoroughly evaluated, and the effectiveness of carbonaceous sorbents in limiting PFASs in runoff is similarly unquantified. Here, laboratory-scale rainfall simulations evaluate PFAS losses in runoff and in leaching to groundwater (leachate) from AFFF-contaminated soils varying in texture, PFAS composition and concentration, and remediation treatment. Leaching dominated PFAS losses in soils with a concentration of ∑PFAS = 0.2–2 mg/kg. However, with higher soil PFAS concentrations (∑PFAS = 31 mg/kg), leachate volumes were negligible and runoff dominated losses. The concentration and variety of PFASs were far greater in leachates regardless of the initial concentrations in soil. Losses of PFASs were dependent on the C-chain length for leachates and more on the initial concentration in soil for runoff. Suspended materials did not meaningfully contribute to runoff losses. While concentrations of most PFASs declined significantly after the first rainfall event, desorption and transport in both runoff and leachates persisted over several rainfall events. Finally, results showed that sorption to AC mostly occurred during, not prior to, rainfall events and that 1% w/w AC substantially reduced losses in runoff and leachates from all soils.
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