We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.

Carriers of heterozygous germline BAP1 mutations (BAP1 +/-) are affected by the \"BAP1 cancer syndrome.\" Although they can develop almost any cancer type, they are unusually susceptible to asbestos carcinogenesis and mesothelioma. Here we investigate why among all carcinogens, BAP1 mutations cooperate with asbestos. Asbestos carcinogenesis and mesothelioma have been linked to a chronic inflammatory process promoted by the extracellular release of the high-mobility group box 1 protein (HMGB1). We report that BAP1 +/- cells secrete increased amounts of HMGB1, and that BAP1 +/- carriers have detectable serum levels of acetylated HMGB1 that further increase when they develop mesothelioma. We linked these findings to our discovery that BAP1 forms a trimeric protein complex with HMGB1 and with histone deacetylase 1 (HDAC1) that modulates HMGB1 acetylation and its release. Reduced BAP1 levels caused increased ubiquitylation and degradation of HDAC1, leading to increased acetylation of HMGB1 and its active secretion that in turn promoted mesothelial cell transformation.

The complex pathophysiology of autism spectrum disorder encompasses interactions between genetic and environmental factors. On the one hand, hundreds of genes, converging at the functional level on selective biological domains such as epigenetic regulation and synaptic function, have been identified to be either causative or risk factors of autism. On the other hand, exposure to chemicals that are widespread in the environment, such as endocrine disruptors, has been associated with adverse effects on human health, including neurodevelopmental disorders. Interestingly, experimental results suggest an overlap in the regulatory pathways perturbed by genetic mutations and environmental factors, depicting convergences and complex interplays between genetic susceptibility and toxic insults. The pervasive nature of chemical exposure poses pivotal challenges for neurotoxicological studies, regulatory agencies, and policy makers. This highlights an emerging need of developing new integrative models, including biomonitoring, epidemiology, experimental, and computational tools, able to capture real-life scenarios encompassing the interaction between chronic exposure to mixture of substances and individuals\' genetic backgrounds. In this review, we address the intertwined roles of genetic lesions and environmental insults. Specifically, we outline the transformative potential of stem cell models, coupled with omics analytical approaches at increasingly single cell resolution, as converging tools to experimentally dissect the pathogenic mechanisms underlying neurodevelopmental disorders, as well as to improve developmental neurotoxicology risk assessment.

BACKGROUND: Quality is a powerful engine in rice value chain upgrading. However, there is no consensus on how \"rice quality\" should be defined and measured in the rice sector.
UNASSIGNED: We adopt a Lancasterian definition of rice quality as a bundle of intrinsic and extrinsic attributes. We then review how rice quality is (i) perceived and defined by consumers and industry stakeholders in rice value chains in Southeast and South Asia; (ii) measured and defined by food technologists; and (iii) predicted through genetics.
CONCLUSIONS: Consumers are heterogeneous with respect to their perceived differentiation of rice quality among regions, countries, cities, and urbanization levels. Premium quality is defined by nutritional benefits, softness and aroma in Southeast Asia, and by the physical appearance of the grains (uniformity, whiteness, slenderness), satiety, and aroma in South Asia. These trends are found to be consistent with industry perceptions and have important implications for regional and national breeding programs in terms of tailoring germplasm to regions and rice varieties to specific local market segments. Because rice is traded internationally, there is a need to standardize definitions of rice quality. However, food technologists have not reached unanimity on quality classes and measurement; routine indicators need to be complemented by descriptive profiles elicited through sensory evaluation panels. Finally, because rice quality is controlled by multiple interacting genes expressed through environmental conditions, predicting grain quality requires associating genetic information with grain quality phenotypes in different environments.

The role of genetics in relation to attachment is of continued interest to developmental psychology. Recent research has attempted to disentangle genetic main effects, environmental effects, and gene and environment (G × E) interactions in the development of attachment security/insecurity and disorganization. We systematically reviewed associations between gene markers and attachment, including G × E interactions, identifying 27 eligible studies. Inconsistent results emerged for associations between both gene effects and G × E interactions on attachment organization. Where G × E interactions used attachment as the environmental factor in the interaction, we observed more consistent results for differential susceptibility of G × E interactions on offspring behavior. Small sample size and heterogeneity in measurement of environmental factors impacted on comparability of studies. From these results, we propose that the future of research into the role of genetic effects in attachment lies in further exploration of G × E interactions, particularly where attachment acts as an environmental factor impacting on other child developmental outcomes emerging from the caregiving environment, consistent with differential susceptibility approaches to developmental psychopathology. In addition, from a methodological perspective, establishing the role of gene markers in such models will require a shift toward contemporary genomics, including genome-wide analysis (including novel genes and chromosomal loci), and epigenetic individual variations.

Despite advances in genetic research, causal variants affecting risk for schizophrenia remain poorly characterized, and the top 108 loci identified through genome-wide association studies (GWAS) explain only 3.4% of variance in risk profiles. Such work is defining the highly complex nature of this condition, with omnigenic models of schizophrenia suggesting that gene regulatory networks are sufficiently interconnected such that altered expression of any \"peripheral\" gene in a relevant cell type has the capacity to indirectly modulate the expression of \"core\" schizophrenia-associated genes. This wealth of associated genes with small effect sizes makes identifying new druggable targets difficult, and current pharmacological treatments for schizophrenia can involve serious side effects. However, the fact that the majority of schizophrenia genome-wide associated variants fall within non-coding DNA is suggestive of their potential to modulate gene regulation. This would be consistent with risks that can be mediated in a \"gene × environment\" (G × E) manner. Stress and trauma can alter the regulation of key brain-related pathways over the lifetime of an individual, including modulation of brain development, and neurochemistry in the adult. Recent studies demonstrate a significant overlap between psychotic symptoms and trauma, ranging from prior trauma contributing to psychosis, as well as trauma in response to the experience of psychosis itself or in response to treatment. Given the known effects of trauma on both CNS gene expression and severity of psychosis symptoms, it may be that pharmacological treatment alone risks leaving individuals with a highly stressful and unresolved environmental component that continues to act in a \"G × E\" manner, with the likelihood that this would negatively impact recovery and relapse risk. This review aims to cover the recent advances elucidating the complex genetic architecture of schizophrenia, as well as the long-term effects of early life trauma on brain function and future mental health risk. Further, the evidence demonstrating the role of ongoing responses to trauma or heightened stress sensitivity, and their impact on the course of illness and recovery, is presented. Finally, the need for trauma-informed approaches and psychological therapy-based interventions is discussed, and a brief overview of the evidence to determine their utility is presented.

The environment may modulate genetic influences on behavioral expression. We investigated whether the physical rearing environment modulates anxiety and exploratory behavior in four populations, representing three species, of the striped mouse Rhabdomys. One population originated from an arid, open habitat and the others from grassy, covered habitats, and two species occurred in sympatry. We raised captive individuals of all populations in treatments that simulated cover or no cover for two generations and investigated the behavior of resulting adults in an open-field, light-dark and startle response tests. We expected that, when raised without cover, the arid population would be less anxious and more exploratory than grassland populations, but found the opposite in the open-field test only. We also expected that all individuals would be anxious and less exploratory when raised under cover, which was the case for anxiety in a light-dark test, but individuals from the no cover treatment were more anxious in the open-field test. Only one population × treatment interaction was detected in which the arid population was least exploratory. Therefore, the physical rearing environment had less of an influence than phylogeny on the development of anxiety and exploration in Rhabdomys.

While genetic factors are a major etiological contributor to autism spectrum disorder (ASD), evidence also supports a role for environmental factors. Herein, we will discuss two such factors that have been associated with a significant proportion of ASD risk: prenatal stress exposure and maternal immune dysregulation, and how sex and gender relate to these factors.
Recent evidence suggests that maternal stress susceptibility interacts with prenatal stress exposure to affect offspring neurodevelopment. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. Animal models have been developed to explore pathophysiology targeting both of these factors, with limited sex-specific effects observed. While prenatal stress and maternal immune dysregulation are associated with ASD, most cases of these prenatal exposures do not result in ASD, suggesting interaction with multiple other risks. We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, as well as potential mitigating factors. Sex differences of these risks have been understudied but are crucial for understanding the higher prevalence of ASD in boys. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential points for prevention or intervention, and for a personalized medicine approach for this subset of environmental-associated ASD cases.

Exposure to chronic stress, either repeated severe acute or moderate sustained stress, is one of the strongest risk factors for the development of psychopathologies such as post-traumatic stress disorder and depression. Chronic stress is linked with several lasting biological consequences, particularly to the stress endocrine system but also affecting intermediate phenotypes such as brain structure and function, immune function, and behavior. Although genetic predisposition confers a proportion of the risk, the most relevant molecular mechanisms determining those susceptible and resilient to the effects of stress and trauma may be epigenetic. Epigenetics refers to the mechanisms that regulate genomic information by dynamically changing the patterns of transcription and translation of genes. Mounting evidence from preclinical rodent and clinical population studies strongly support that epigenetic modifications can occur in response to traumatic and chronic stress. Here, we discuss this literature examining stress-induced epigenetic changes in preclinical models and clinical cohorts of stress and trauma occurring early in life or in adulthood. We highlight that a complex relationship between the timing of environmental stressors and genetic predispositions likely mediate the response to chronic stress over time, and that a better understanding of epigenetic changes is needed by further investigations in longitudinal and postmortem brain clinical cohorts.

The interaction between the serotonin transporter (SERT) linked polymorphic region (5-HTTLPR) and adverse early life stressing (ELS) events is associated with enhanced stress susceptibility and risk to develop mental disorders like major depression, anxiety, and aggressiveness. In particular, human short allele carriers are at increased risk. This 5-HTTLPR polymorphism is absent in the rodent SERT gene, but heterozygous SERT knockout rodents (SERT+/-) show several similarities to the human S-allele carrier, therefore creating an animal model of the human situation. Many rodent studies investigated ELS interactions in SERT knockout rodents combined with ELS. However, underlying neuromolecular mechanisms of the (mal)adaptive responses to adversity displayed by SERT rodents remain to be elucidated. Here, we provide a comprehensive review including studies describing mechanisms underlying SERT variation × ELS interactions in rodents. Alterations at the level of translation and transcription but also epigenetic alterations considerably contribute to underlying mechanisms of SERT variation × ELS interactions. In particular, SERT+/- rodents exposed to adverse early rearing environment may be of high translational and predictive value to the more stress sensitive human short-allele carrier, considering the similarity in neurochemical alterations. Therefore, SERT+/- rodents are highly relevant in research that aims to unravel the complex psychopathology of mental disorders. So far, most studies fail to show solid evidence for increased vulnerability to develop affective-like behavior after ELS in SERT+/- rodents. Several reasons may underlie these failures, e.g., (1) stressors used might not be optimal or severe enough to induce maladaptations, (2) effects in females are not sufficiently studied, and (3) few studies include both behavioral manifestations and molecular correlates of ELS-induced effects in SERT+/- rodents. Of course, one should not exclude the (although unlikely) possibility of SERT+/- rodents not being sensitive to ELS. In conclusion, future studies addressing ELS-induced effects in the SERT+/- rodents should extensively study both long-term behavioral and (epi)genetic aspects in both sexes. Finally, further research is warranted using more severe stressors in animal models. From there on, we should be able to draw solid conclusions whether the SERT+/- exposed to ELS is a suitable translational animal model for studying 5-HTTLPR polymorphism and stress interactions.