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Background/Objectives: All 11 metallothionein protein-coding genes are located on human chromosome 16q13. It is unique among human genetics to have an entire pathway's genes clustered in a short chromosomal region. Since solid tumors, particularly high-grade serous ovarian cancer (HGSC), exhibit high rates of monoallelic aneuploidy, this region is commonly lost. Studies have not yet been performed to determine what vulnerability may be created in cancer cells with low metallothionein expression. Here, a screen of FDA-approved cancer small molecule drugs for those best targeting low metallothionein ovarian cancer was completed. Methods: Screening methods were tested and compared using vehicle-treated negative controls and cadmium chloride, a positive control for cell loss selective for low metallothionein cells. CAOV3 cells, which are unique in their expression of only two metallothionein isoforms, were used, with or without shRNA knockdown of the predominantly expressed MT2A gene. A library of FDA-approved molecules was then screened. Results: The optimal assay utilized Hoechst 33342 nuclear staining and mechanized fluorescent microscope counting of cell content. Encorafenib, an RAF inhibitor, was identified as the most selective for enhanced cytotoxicity in MT2A knockdown cells compared to scrambled controls. Conclusions: The nuclear stain Hoechst 33342, assessed by fluorescence microscopy, provides a low variance, moderate throughput platform for cancer cell loss screens. Low metallothionein ovarian cancer cells exhibit a vulnerability to the RAF inhibitor encorafenib. [ABSTRACT FROM AUTHOR]

Abstract Background Previous studies assessing the hypothesis that the construct of ‘aberrant salience’ is associated with psychosis and psychotic symptoms showed conflicting results. For this reason, the association between measures to index aberrant salience and subclinical psychotic symptoms in a general population sample was analysed. In addition, genetic vulnerability was added to the analysis as a modifier to test the hypothesis that modification by genetic vulnerability may explain variability in the results. Methods The TwinssCan project obtained data from general population twins (N = 887). CAPE (Community Assessment of Psychic Experience) scores were used to index psychotic experiences. Aberrant salience was assessed with white noise task and ambiguous situations task. Results Measures of aberrant salience were not associated with psychotic experiences, nor was there evidence for an interaction with genetic predisposition in this association (Z = 1.08, p = 0.282). Conclusions Various studies including the present could not replicate the association between aberrant salience and psychotic experiences in general population samples. The conflicting findings might be explained by moderation by genetic vulnerability, but results are inconsistent. If there was evidence for a main effect or interaction, this was in the positive symptom scale only. On the other hand, the association was more robust in so-called ‘ultra-high risk’ patients and first episode psychosis patients. Thus, this association may represent a state-dependent association, present only at the more severe end of the psychosis spectrum.

Background Genetic vulnerability to mental disorders has been associated with coronavirus disease-19 (COVID-19) outcomes. We explored whether polygenic risk scores (PRSs) for several mental disorders predicted poorer clinical and psychological COVID-19 outcomes in people with pre-existing depression. Methods Data from three assessments of the Australian Genetics of Depression Study (N = 4405; 52.2 years ± 14.9; 76.2% females) were analyzed. Outcomes included COVID-19 clinical outcomes (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection and long COVID, noting the low incidence of COVID-19 cases in Australia at that time) and COVID-19 psychological outcomes (COVID-related stress and COVID-19 burnout). Predictors included PRS for depression, bipolar disorder, schizophrenia, and anxiety. The associations between these PRSs and the outcomes were assessed with adjusted linear/logistic/multinomial regressions. Mediation (N = 4338) and moderation (N = 3326) analyses were performed to explore the potential influence of anxiety symptoms and resilience on the identified associations between the PRSs and COVID-19 psychological outcomes. Results None of the selected PRS predicted SARS-CoV-2 infection or long COVID. In contrast, the depression PRS predicted higher levels of COVID-19 burnout. Anxiety symptoms fully mediated the association between the depression PRS and COVID-19 burnout. Resilience did not moderate this association. Conclusions A higher genetic risk for depression predicted higher COVID-19 burnout and this association was fully mediated by anxiety symptoms. Interventions targeting anxiety symptoms may be effective in mitigating the psychological effects of a pandemic among people with depression. [ABSTRACT FROM AUTHOR]

Background: Previous studies assessing the hypothesis that the construct of 'aberrant salience' is associated with psychosis and psychotic symptoms showed conflicting results. For this reason, the association between measures to index aberrant salience and subclinical psychotic symptoms in a general population sample was analysed. In addition, genetic vulnerability was added to the analysis as a modifier to test the hypothesis that modification by genetic vulnerability may explain variability in the results. Methods: The TwinssCan project obtained data from general population twins (N = 887). CAPE (Community Assessment of Psychic Experience) scores were used to index psychotic experiences. Aberrant salience was assessed with white noise task and ambiguous situations task. Results: Measures of aberrant salience were not associated with psychotic experiences, nor was there evidence for an interaction with genetic predisposition in this association (Z = 1.08, p = 0.282). Conclusions: Various studies including the present could not replicate the association between aberrant salience and psychotic experiences in general population samples. The conflicting findings might be explained by moderation by genetic vulnerability, but results are inconsistent. If there was evidence for a main effect or interaction, this was in the positive symptom scale only. On the other hand, the association was more robust in so-called 'ultra-high risk' patients and first episode psychosis patients. Thus, this association may represent a state-dependent association, present only at the more severe end of the psychosis spectrum. [ABSTRACT FROM AUTHOR]

Given the escalating impact of climate change on agriculture and food security, gaining insights into the evolutionary dynamics of climatic adaptation and uncovering climate-adapted variation can empower the breeding of climate-resilient crops to face future climate change. Alfalfa (Medicago sativa subsp. sativa), the queen of forages, shows remarkable adaptability across diverse global environments, making it an excellent model for investigating species responses to climate change. In this study, we performed population genomic analyses using genome resequencing data from 702 accessions of 24 Medicago species to unravel alfalfa's climatic adaptation and genetic susceptibility to future climate change. We found that interspecific genetic exchange has contributed to the gene pool of alfalfa, particularly enriching defense and stress-response genes. Intersubspecific introgression between M. sativa subsp. falcata (subsp. falcata) and alfalfa not only aids alfalfa's climatic adaptation but also introduces genetic burden. A total of 1671 genes were associated with climatic adaptation, and 5.7% of them were introgressions from subsp. falcata. By integrating climate-associated variants and climate data, we identified populations that are vulnerable to future climate change, particularly in higher latitudes of the Northern Hemisphere. These findings serve as a clarion call for targeted conservation initiatives and breeding efforts. We also identified pre-adaptive populations that demonstrate heightened resilience to climate fluctuations, illuminating a pathway for future breeding strategies. Collectively, this study enhances our understanding about the local adaptation mechanisms of alfalfa and facilitates the breeding of climate-resilient alfalfa cultivars, contributing to effective agricultural strategies for facing future climate change. Population genomic analyses are performed in thit study to unravel alfalfa's climatic adaptation and vulnerability to future climate change. It is found that intraspecific gene flow and interspecific introgression have introduced genes that facilitate adaptation to current and future climates. A total of 1671 candidate genes are identified as being associated with climatic adaptation, providing potential targets for the breeding of climate-resilient cultivars to cope with future climate change. [ABSTRACT FROM AUTHOR]

Background: According to observational research, migraine may increase the risk of Meniere's disease (MD). The two have not, however, been proven to be causally related. Methods: Using Mendelian random (MR) analysis, we aimed to evaluate any potential causal relationship between migraine and MD. We extracted singlenucleotide polymorphisms (SNPs) from large-scale genome-wide association studies (GWAS) involving European individuals, focusing on migraine and MD. The main technique used to evaluate effect estimates was inverse-variance weighting (IVW). To assess heterogeneity and pleiotropy, sensitivity analyses were carried out using weighted median, MR-Egger, simple mode, weighted mode, and MR-PRESSO. Results: There was no discernible causative link between genetic vulnerability to MD and migraine. The migraine dose not increase the prevalence of MD in the random-effects IVW method (OR = 0.551, P = 0.825). The extra weighted median analysis (OR = 0.674, P = 0.909), MR-Egger (OR = 0.068, P = 0.806), Simple mode (OR = 0.170, P = 0.737), and Weighted mode (OR = 0.219, P= 0.760) all showed largely consistent results. The MD dose not increase the prevalence of migraine in the random-effects IVW method (OR = 0.999, P = 0.020). The extra weighted median analysis (OR = 0.999, P = 0.909), MR-Egger (OR = 0.999, P = 0.806), Simple mode (OR = 0.999, P = 0.737), and Weighted mode (OR = 1.000, P = 0.760). [ABSTRACT FROM AUTHOR]

Introduction: Cannabis use disorders are global emerging problem nowadays, with high prevalence and morbidity. Cognitive impairments, and also corresponding genetic vulnerability, has been fairly replicated in individuals with cannabis dependence. However, there are few studies that assess cognitive functioning as an endophenotype or a trait marker for cannabis dependence. While the primary objective of this study was to assess the endophenotype pattern of cognitive dysfunction in cannabis dependence, assessing the association between the degree of cognitive functioning, and their socio‐demographic and clinical variables in the cannabis dependence patients and their first‐degree relatives was the secondary objective. Methodology: We compared cognitive functioning across three groups‐ patients with cannabis dependence syndrome, their 'non‐user' first‐degree relatives and healthy controls, with 30 participants in each group. Five cognitive domains‐ attention and concentration, verbal fluency, memory, visuospatial ability and executive functions were assessed. We assessed for endophenotype pattern of statistical significance in pairwise analyses of Kruskal‐Wallis test, which was corrected for multiple comparisons. Subsequently, correlation analysis to assess association of cognitive impairment with socio‐demographic and clinical variables was conducted. Results: Although impairment in attention and executive functions also was seen in patients with cannabis dependence, endophenotype pattern of statistical significance in pairwise analyses, with impairment in first‐degree relatives too, was seen in all sub‐scores of verbal fluency and verbal memory. None of the correlations were significant. Conclusion: 'Non‐user' first‐degree relatives of patients with cannabis dependence too show significant cognitive impairment. Verbal fluency and verbal memory are possible endophenotypes or trait markers for cannabis dependence syndrome. [ABSTRACT FROM AUTHOR]

Estimation of genetic diversity is a prerequisite to select genetically diverse parents. Availability and collection of genetically diverse parents contribute significantly towards the selection and utilization of promising parents in plant breeding to develop a commercial variety or hybrid. Germplasm is an important source for various qualitative and quantitative traits that may be used to introgress through combination breeding for the improvement of the existing cultivars or development of new cultivars and hybrids by using marker assisted selection. Genetic diversity refers to the variations among the alleles of a gene and it may be examined at nucleotide level in the DNA sequence. Various classical and DNA tools are available to access genetic diversity at morphological and molecular levels and can be expressed in the form of dendrogram, percentage polymorphic loci and genetic distance. Estimation of genetic diversity using molecular techniques is more reliable as it is based on highly polymorphic molecular markers which remain unaffected by the influence of environment. Genetically diverse genotypes are used as valuable source by the plant breeders for the development of new or improved crop varieties with desirable traits to cope up the biotic and abiotic stresses such as drought tolerant, salt tolerant, insect pest and disease resistance etc. This article reviews various traditional to molecular methods used in estimation of genetic diversity and their exploitations in plant breeding programme. [ABSTRACT FROM AUTHOR]

• A comprehensive genome-wide CRISPR knockout screen identified novel susceptibilities in PM cells. • Non-oncogenic stress-responsive pathways, such as DNA damage are critical gene dependencies. • Integrated analysis prioritizes CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable non-oncogene dependencies. • The results reveal overlooked aspects of PM biology and provide a blueprint for developing novel targeted therapies. Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery. This analysis has allowed us to identify with high confidence numerous known and novel gene dependencies that are surprisingly highly enriched for non-oncogenic pathways involved in response to various stress stimuli, in particular DNA damage and transcriptional dysregulation. By integrating genomic analysis with a series of in vitro and in vivo functional studies, we validate and prioritize several non-oncogene addictions conferred by CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable vulnerabilities, revealing previously unappreciated aspects of PM biology. Our findings support the growing consensus that stress-responsive non-oncogenic signaling plays a key role in the initiation and progression of PM and provide a functional blueprint for the development of unprecedented targeted therapies to combat this formidable disease. [ABSTRACT FROM AUTHOR]

Abstract Introduction While COVID-19 pandemic continues to spread worldwide, researchers have linked patterns of traits to poor disease outcomes. Risk factors for COVID-19 include asthma, elderly age, being pregnant, having any underlying diseases such as cardiovascular disease, diabetes, obesity, and experiencing lifelong systemic racism. Recently, connections to certain genes have also been found, although the susceptibility has not yet been established. We aimed to investigate the available evidence for the genetic susceptibility to COVID-19. Methods This study was a systematic review of current evidence to investigate the genetic susceptibility of COVID-19. By systematic search and utilizing the keywords in the online databases including Scopus, PubMed, Web of Science, and Science Direct, we retrieved all the related papers and reports published in English from December 2019 to September 2020. Results According to the findings, COVID-19 uses the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry. Previous studies have shown that people with ACE2 polymorphism who have type 2 transmembrane serine proteases (TMPRSS2) are at high risk of SARS-CoV-2 infection. Also, two studies have shown that males are more likely to become infected with SARS-CoV-2 than females. Besides, research has also shown that patients possessing HLA-B*15:03 genotype may become immune to the infection. Conclusion Combing through the genome, several genes related to immune system’s response were related to the severity and susceptibility to the COVID-19. In conclusion, a correlation was found between the ACE2 levels and the susceptibility to SARS-CoV-2 infection.

Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40–70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction. [ABSTRACT FROM AUTHOR]

ABSTRACT A better understanding of genetic diversity in cotton cultivars is needed to make the most of the genetic resources and guarantee continuing improvements in the breeding programs. Our objective was to evaluate the genetic diversity among cotton genotypes from the top breeding programs in Brazil and recommend hybrid combinations that would increase variability. The field experiments we conducted on three cotton genotypes from each of the following Brazilian breeding programs: EMBRAPA, MONSANTO DELTAPINE, FIBERMAX, IMA, TMG and UFU. Several phenotypic evaluations were carried out at V5, B1, full flower and full maturity. Moderate genetic divergence was observed among the genotypes from these breeding programs. Hybridization of the BRS 433 FL B2RF and FM 980 GLT genotypes would likely produce segregating populations with greater genetic variability, yield potential, lint yield and desirable fiber quality. Maturity, micronaire and fiber length were the strongest contributors to genetic divergence.

Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40–70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction.

Banana cultivation has increased significantly over the last century to meet the growing demand for this popular fruit. Originating in Southeast Asia, bananas are now produced in >135 different countries in tropical and subtropical regions of the world. Most of this expansion of production is based on a single banana variety, Cavendish, which makes up almost all the export trade grown in large-scale monocultures and a large part of the local trade and represents >40% of all bananas grown globally. Over the last century several major diseases of the banana have emerged and widely expanded their geographic ranges. Cultivars within the Cavendish variety are highly susceptible to these diseases, including yellow Sigatoka, black leaf streak, Eumusae leaf spot, freckle, Fusarium wilt tropical race 4, banana bunchy top, and the bacterial wilts Moko, Xanthomonas wilt, and banana Blood disease. This review graphically illustrates the emergence and rapid intercontinental spread of these diseases and discusses several major disease epidemics in bananas. Evidently, the large-scale monoculture based on the single variety Cavendish has resulted in an extreme level of genetic vulnerability. The resistance to diversification in the Cavendish production chain and the lack of investment in genetics and plant breeding in the recent past means that currently limited genetic solutions are available to replace the Cavendish banana with a set of market acceptable resistant varieties from a range of different genetic backgrounds. [ABSTRACT FROM AUTHOR]

Aim: Adaptation, migration and extinction of species is closely associated with climate changes and shape the distribution of biodiversity. The adaptive responses of species in the biodiversity hotspot, the Hengduan Mountains, to climate change remain poorly understood. Location: The Hengduan Mountains, southeast of the Qinghai‐Tibet Plateau. Methods: The principles of phylogeography and landscape genomics were applied to the endemic species Roscoea humeana in the Hengduan Mountains by genotyping by sequencing data. A total of 5,902 single‐nucleotide polymorphisms were used to analyse the genetic structure/diversity and changes in effective population size over time. Species distribution modelling, principal component analysis and gradient forest analysis were used to explore associations between climate change and genetic variation. Results: The population size of R. humeana rapidly increased after the Last Glacial Maximum. The contribution of climate to genetic variation was greater than that of geography. Precipitation during the warmest season played a pivotal role in the adaptation to climate changes. Loci associated with drought tolerance and anti‐ultraviolet radiation were identified, suggesting local adaptation of R. humeana to alpine environments. Main conclusions: These results suggest that the current genetic structure and diversity of R. humeana were shaped by Quaternary climate fluctuations and persistence of microrefugia in the Hengduan Mountains. The results further suggest that R. humeana can survive in future refugia within the area where the warmest quarter precipitation is higher than 560 mm, and local adaptation to drought tolerance may be beneficial for its acclimation to future climate changes. [ABSTRACT FROM AUTHOR]

Introduction: While COVID-19 pandemic continues to spread worldwide, researchers have linked patterns of traits to poor disease outcomes. Risk factors for COVID-19 include asthma, elderly age, being pregnant, having any underlying diseases such as cardiovascular disease, diabetes, obesity, and experiencing lifelong systemic racism. Recently, connections to certain genes have also been found, although the susceptibility has not yet been established. We aimed to investigate the available evidence for the genetic susceptibility to COVID-19. Methods: This study was a systematic review of current evidence to investigate the genetic susceptibility of COVID-19. By systematic search and utilizing the keywords in the online databases including Scopus, PubMed, Web of Science, and Science Direct, we retrieved all the related papers and reports published in English from December 2019 to September 2020. Results: According to the findings, COVID-19 uses the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry. Previous studies have shown that people with ACE2 polymorphism who have type 2 transmembrane serine proteases (TMPRSS2) are at high risk of SARS-CoV-2 infection. Also, two studies have shown that males are more likely to become infected with SARS-CoV-2 than females. Besides, research has also shown that patients possessing HLA-B*15:03 genotype may become immune to the infection. Conclusion: Combing through the genome, several genes related to immune system's response were related to the severity and susceptibility to the COVID-19. In conclusion, a correlation was found between the ACE2 levels and the susceptibility to SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Background and Aims: The association between perceived stress (PS) and gaming addiction (GA) is well documented. However, the mechanism for explaining this association remains unclear. Using a genetically informative design, this study aims to distinguish between the diathesis-stress and bio-ecological models of gene by environment interaction (G x E) to explain the underlying mechanism of the relationship., Methods: In total, 1,468 twins (mean age = 22.6 ± 2.8 years) completed an online survey including the GA and PS scales. Twin correlations for GA and PS were computed and univariate model-fitting analysis was conducted to determine genetic and environmental influences on GA and PS. The bivariate G x E model-fitting analysis was performed to determine the best G x E interaction model., Results: Additive genetic, shared environmental, and non-shared environmental effects were 0.70 (95%CI = 0.61, 0.77), 0.00, and 0.30 (95%CI = 0.26, 0.33), and 0.38 (95%CI = 0.24, 0.55), 0.35 (95% CI = 0.18, 0.51), and 0.22 (95%CI = 0.20, 0.26) for GA and PS, respectively. Bivariate G x E model-fitting analysis supported the diathesis-stress model, where genetic influences on GA were greater in higher levels of PS, whereas environmental influences on GA were small and constant across levels of PS., Discussion and Conclusions: The evidence for the diathesis-stress model for GA is consistent with the etiological process of many forms of psychopathology. The findings should be incorporated in clinical settings to improve the treatment of GA, and used in developments of intervention and prevention methods for GA.

A better understanding of genetic diversity in cotton cultivars is needed to make the most of the genetic resources and guarantee continuing improvements in the breeding programs. Our objective was to evaluate the genetic diversity among cotton genotypes from the top breeding programs in Brazil and recommend hybrid combinations that would increase variability. The field experiments we conducted on three cotton genotypes from each of the following Brazilian breeding programs: EMBRAPA, MONSANTO DELTAPINE, FIBERMAX, IMA, TMG and UFU. Several phenotypic evaluations were carried out at V5, B1, full flower and full maturity. Moderate genetic divergence was observed among the genotypes from these breeding programs. Hybridization of the BRS 433 FL B2RF and FM 980 GLT genotypes would likely produce segregating populations with greater genetic variability, yield potential, lint yield and desirable fiber quality. Maturity, micronaire and fiber length were the strongest contributors to genetic divergence. Keywords: Gossypium hirsutum L.; genetic vulnerability; quantitative characters.A better understanding of genetic diversity in cotton cultivars is needed to make the most of the genetic resources and guarantee continuing improvements in the breeding programs. Our objective was to evaluate the genetic diversity among cotton genotypes from the top breeding programs in Brazil and recommend hybrid combinations that would increase variability. The field experiments we conducted on three cotton genotypes from each of the following Brazilian breeding programs: EMBRAPA, MONSANTO DELTAPINE, FIBERMAX, IMA, TMG and UFU. Several phenotypic evaluations were carried out at V5, B1, full flower and full maturity. Moderate genetic divergence was observed among the genotypes from these breeding programs. Hybridization of the BRS 433 FL B2RF and FM 980 GLT genotypes would likely produce segregating populations with greater genetic variability, yield potential, lint yield and desirable fiber quality. Maturity, micronaire and fiber length were the strongest contributors to genetic divergence. [ABSTRACT FROM AUTHOR]

Background: Alcohol and tobacco are among the leading substances that are misused together and shared genetic vulnerability is likely. Increased susceptibility to nicotine self-administration has been shown in alcohol-preferring rat-lines. However, a nicotine-preferring (nP) rat-line has not been studied for alcohol preference.Objectives: To evaluate alcohol preference and intake in male and female nP rats. We hypothesized that nP rats and females would drink more ethanol than control rats and males, respectively.Methods: nP rats are being selectively outbred for high oral nicotine intake at Ege University. Seventeen nP (18th generation) and 20 naïve female and male SD rats, not previously exposed to alcohol or nicotine, were used. Twelve-week-old rats were given intermittent access to 20% ethanol in a 2-bottle-choice-procedure for six weeks. After one week withdrawal, six weeks of oral nicotine self-administration was applied.Results: nP rats drank significantly more ethanol than controls and their preference for ethanol over water was higher. Female rats' ethanol intake was higher than males'. The nP rats' nicotine preference and intake were higher than controls, and they gained less weight.Conclusion: We have shown for the first time that nP rats also have high alcohol intake. Our results support the hypothesis that shared genetic factors may underlie concurrent addiction to nicotine and alcohol and have translational value in understanding their misuse. Considering the increased vulnerability for alcohol use disorder in smokers and sex differences observed, early preventive measures in families with a history of tobacco addiction, specifically targeting female members, could have public health benefits. [ABSTRACT FROM AUTHOR]

G-quadruplexes (G4) are alternative nucleic acid structures involved in transcription, translation and replication. Aberrant G4 formation and stabilisation is linked to genome instability and cancer. G4 ligand treatment disrupts key biological processes leading to cell death. To discover genes and pathways involved with G4s and gain mechanistic insights into G4 biology, we present the first unbiased genome-wide study to systematically identify human genes that promote cell death when silenced by shRNA in the presence of G4-stabilising small molecules. Many novel genetic vulnerabilities were revealed opening up new therapeutic possibilities in cancer, which we exemplified by an orthogonal pharmacological inhibition approach that phenocopies gene silencing. We find that targeting the WEE1 cell cycle kinase or USP1 deubiquitinase in combination with G4 ligand treatment enhances cell killing. We also identify new genes and pathways regulating or interacting with G4s and demonstrate that the DDX42 DEAD-box helicase is a newly discovered G4-binding protein.

Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.

The aim of this study was to estimate the genetic base of Brazilian irrigated rice cultivars released in the period from 1965 to 2012. The genealogies of the cultivars were obtained based on information from marketing folders, websites, crossings records, and scientific articles. The following factors were calculated: relative genetic contribution (RGC), accumulated genetic contribution (AGC), frequency (in percentage) of each ancestor in the genealogy (FAG), number of ancestors that constitute each cultivar (NAC),number of ancestors responsible for 60%, 70%, 80% and 90% of the genetic base (NAGB), and average number of ancestor per cultivar (ANAC). The cultivars were also grouped based on the period of release (1965-1980, 1981-1990, 1991-2000 and 2001-2012). For each grouping, the previously described factors were also estimated. A total of 110 cultivars were studied and it was concluded that the genetic base of Brazilian irrigated rice cultivars is narrow.

Alcoholism is a pervasive societal problem, yet available pharmacotherapies fail to treat most sufferers. The type 1 corticotropin-releasing factor (CRF1) receptor has received much attention for its putative role in the progression to alcohol dependence, although at present its success in clinical trials has been limited. Two single-nucleotide polymorphisms in the rat Crhr1 promoter have been identified in the Marchigian substrain of Sardinian alcohol-preferring (msP) rats. Unlike other Wistar-derived alcohol-preferring lines, nondependent msP rats reduce their alcohol self-administration in response to CRF1 antagonists and show increased brain CRF1 expression. The current study tested the hypotheses that the A alleles in the Crhr1 promoter polymorphisms are: (1) unique to msP (vs. CRF1 antagonist-insensitive) alcohol-preferring lines and (2) associate with greater alcohol preference or intake. Two related polymorphisms were observed in which both loci on a given chromosome were either mutant variant (A) or wild-type (G) alleles within the distal Crhr1 promoter of 17/25 msP rats (68%), as compared to 0/23 Indiana P rats, 0/20 Sardinian alcohol-preferring rats bred at Scripps (Scr:sP) and 0/21 outbred Wistar rats. Alcohol consumption in msP rats did not differ according to the presence of Crhr1 A alleles, but greater alcohol preference (98%) was observed in A allele homozygous msP rats (AA) compared to msP rats with wild-type (GG, 91%) or heterozygous (GA, 91%) genotypes. The greater alcohol preference reflected decreased water intake, accompanied by reduced total calories consumed by AA rats. The data show that msP rats differentially possess mutant A variant alleles in the polymorphic promoter region of the Crhr1 gene that may differentially regulate consumption. [ABSTRACT FROM AUTHOR]

Background: Stress during the adolescent period influences postnatal maturation and behavioral patterns in adulthood. Adolescent stress-induced molecular and functional changes in neurons are the key clinical features of psychiatric disorders including schizophrenia. Objective: In the present study, we exposed genetically vulnerable mice to isolation stress to examine the molecular changes in the glutamatergic system involving N-methyl- d-aspartate (NMDA) receptors via dopaminergic disturbance in the prefrontal cortex (PFc). Results: We report that late adolescent stress in combination with Disrupted-in-Schizophrenia 1 ( DISC1) genetic risk elicited alterations in glutamatergic neurons in the PFc, such as increased expression of glutamate transporters, decreased extracellular levels of glutamate, decreased concentration of d-serine, and impaired activation of NMDA-Ca/calmodulin kinase II signaling. These changes resulted in behavioral deficits in locomotor activity, forced swim, social interaction, and novelty preference tests. The glutamatergic alterations in the PFc were prevented if the animals were treated with an atypical antipsychotic drug clozapine and a dopamine D1 agonist SKF81297, which suggests that the activation of dopaminergic neurons is involved in the regulation of the glutamatergic system. Conclusion: Our results suggest that adolescent stress combined with dopaminergic abnormalities in the PFc of genetically vulnerable mice induces glutamatergic disturbances, which leads to behavioral deficits in the young adult stage. [ABSTRACT FROM AUTHOR]

Genetic diversity is essential for crop breeding and one way to estimate it is through the concept of genetic base, which can be defined as the number of ancestors and their relative genetic contributions (RGC) to each cultivar. The RGC can be estimated through the coefficient of parentage between the ancestors and cultivars. Previous studies determined that the genetic base of Brazilian soybean was very narrow. The objective of this work was to evaluate the pedigree of 444 Brazilian soybean cultivars to estimate their genetic base. The cultivars were divided according to their release dates and according to their origin (public or private), and the genetic base for each group was also estimated. We found 60 ancestors, of which the top four (CNS, S-100, Roanoke and Tokyo, respectively) contribute 55.3% of the genetic base. Only 14 ancestors have an RGC over 1.0%, and they represent 92.4% of the genetic base. Analysis of the release dates indicated that there has been an increase in the number of ancestors over time, but the four main ancestors were the same over all periods, and their cumulative RGC increased from 46.6% to 57.6%, indicating a narrowing of the genetic base.

Studies of the association between polymorphisms of the serotonin transporter gene and fear learning have produced inconsistent results, raising questions about the strength of the relationship and the methodological conditions under which the relationship occurs. We conducted a meta-analysis of existing studies to provide an integrated statistical measure of the effect of the polymorphic region of the serotonin transporter gene (5-HTTLPR) in aversive associative learning (acquisition and extinction) in humans and rodents. The included studies were gathered through scientific database search engines. Selection criteria included experimental studies in which 5-HTTLPR and any measure of fear were considered as main variables. An effect size was calculated for each relevant experiment. 30 articles, with 33 experiments were included, 28 for acquisition, 13 for extinction. The integrated effect size (random effects model) for acquisition of fear was d = 0.33, 95 % CI [0.20, 0.50]. For extinction, the integrated effect size was d = 0.63, 95 % [CI 0.26, 1.00]. Test for publication bias was not significant neither for acquisition nor extinction. Thus, a medium but consistent effect was found between having the S allele of 5-HTTLPR and fear. The finding suggests a genetic vulnerability to anxiety in carriers of the polymorphism of the serotonin transporter that should be considered in future research. [ABSTRACT FROM AUTHOR]

Social anxiety disorder (SAD) is a disabling psychiatric disorder with a complex pathogenesis. Studies indicate a genetic component in the development of SAD, but the search for genetic mechanisms underlying this vulnerability is complicated. A focus on endophenotypes instead of the disorder itself may provide a fruitful path forward. Endophenotypes are measurable characteristics related to complex psychiatric disorders and reflective of genetically-based disease mechanisms, and could shed light on the ways by which genes contribute to the development of SAD. We review evidence for candidate MRI endophenotypes of SAD and discuss the extent to which they meet the criteria for an endophenotype, focussing on the amygdala, the medial prefrontal cortex, whole-brain functional connectivity and structural-anatomical changes. Strongest evidence is present for the primary endophenotype criterion of association between the candidate endophenotypes and SAD, while the other criteria, involving trait-stability, heritability and co-segregation of the endophenotype with the disorder within families, warrant further investigation. We highlight the potential of neuroimaging endophenotypes and stress the need for family studies into SAD endophenotypes. [ABSTRACT FROM AUTHOR]

Summary Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L , BCL2 , and MEN1 , and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies. [ABSTRACT FROM AUTHOR]

Currently, about 246 million people around the world have used an illicit drug. The reasons for this use are multiple: e.g. to augment the sensation of pleasure or to reduce the withdrawal and other aversive effects of a given substance. This raises the problem of addiction, which remains a disease of modern society. This review offers a comprehensive update of the different theories about the etiology of addictive behaviors with emphasis on the neurobiological, environmental, psychopathological, behavioural and genetic aspects of addictions, discussed from an evolutionary perspective. The main conclusion of this review is that vulnerability to drug addiction suggests an interaction between many brain systems (including the reward, decision-making, serotonergic, oxytocin, interoceptive insula, CRF, norepinephrine, dynorphin/KOR, orexin and vasopressin systems), genetic predisposition, sociocultural context, impulsivity and drugs types. Further advances in biological and psychological science are needed to address the problems of addiction at its roots. [ABSTRACT FROM AUTHOR]