IMPORTANCE: Antisocial behavior (ASB) places a large burden on perpetrators, survivors, and society. Twin studies indicate that half of the variation in this trait is genetic. Specific causal genetic ...variants have, however, not been identified. OBJECTIVES: To estimate the single-nucleotide polymorphism–based heritability of ASB; to identify novel genetic risk variants, genes, or biological pathways; to test for pleiotropic associations with other psychiatric traits; and to reevaluate the candidate gene era data through the Broad Antisocial Behavior Consortium. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association data from 5 large population-based cohorts and 3 target samples with genome-wide genotype and ASB data were used for meta-analysis from March 1, 2014, to May 1, 2016. All data sets used quantitative phenotypes, except for the Finnish Crime Study, which applied a case-control design (370 patients and 5850 control individuals). MAIN OUTCOME AND MEASURES: This study adopted relatively broad inclusion criteria to achieve a quantitative measure of ASB derived from multiple measures, maximizing the sample size over different age ranges. RESULTS: The discovery samples comprised 16 400 individuals, whereas the target samples consisted of 9381 individuals (all individuals were of European descent), including child and adult samples (mean age range, 6.7-56.1 years). Three promising loci with sex-discordant associations were found (8535 female individuals, chromosome 1: rs2764450, chromosome 11: rs11215217; 7772 male individuals, chromosome X, rs41456347). Polygenic risk score analyses showed prognostication of antisocial phenotypes in an independent Finnish Crime Study (2536 male individuals and 3684 female individuals) and shared genetic origin with conduct problems in a population-based sample (394 male individuals and 431 female individuals) but not with conduct disorder in a substance-dependent sample (950 male individuals and 1386 female individuals) (R2 = 0.0017 in the most optimal model, P = 0.03). Significant inverse genetic correlation of ASB with educational attainment (r = –0.52, P = .005) was detected. CONCLUSIONS AND RELEVANCE: The Broad Antisocial Behavior Consortium entails the largest collaboration to date on the genetic architecture of ASB, and the first results suggest that ASB may be highly polygenic and has potential heterogeneous genetic effects across sex.
Temperature is an important control factor for biologics biomanufacturing in precision fermentation. Here, we explored a highly responsive low temperature-inducible genetic system (LowTempGAL) in the ...model yeast Saccharomyces cerevisiae. Two temperature biosensors, a heat-inducible degron and a heat-inducible protein aggregation domain, were used to regulate the GAL activator Gal4p, rendering the leaky LowTempGAL systems. Boolean-type induction was achieved by implementing a second-layer control through low-temperature-mediated repression on GAL repressor gene GAL80, but suffered delayed response to low-temperature triggers and a weak response at 30°C. Application potentials were validated for protein and small molecule production. Proteomics analysis suggested that residual Gal80p and Gal4p insufficiency caused suboptimal induction. 'Turbo' mechanisms were engineered through incorporating a basal Gal4p expression and a galactose-independent Gal80p-supressing Gal3p mutant (Gal3Cp). Varying Gal3Cp configurations, we deployed the LowTempGAL systems capable for a rapid stringent high-level induction upon the shift from a high temperature (37-33°C) to a low temperature (≤30°C). Overall, we present a synthetic biology procedure that leverages 'leaky' biosensors to deploy highly responsive Boolean-type genetic circuits. The key lies in optimisation of the intricate layout of the multi-factor system. The LowTempGAL systems may be applicable in non-conventional yeast platforms for precision biomanufacturing.
To investigate how biologically relevant markers change in response to antiangiogenic therapy in metastatic clear cell renal cancer (mRCC) and correlate these changes with outcome.
The study used ...sequential tumor tissue and functional imaging (taken at baseline and 12-16 weeks) obtained from three similar phase II studies. All three studies investigated the role of VEGF tyrosine kinase inhibitors (TKI) before planned nephrectomy in untreated mRCC (n = 85). The effect of targeted therapy on ten biomarkers was measured from sequential tissue. Comparative genomic hybridization (CGH) array and DNA methylation profiling (MethylCap-seq) was performed in matched frozen pairs. Biomarker expression was correlated with early progression (progression as best response) and delayed progression (between 12-16 weeks).
VEGF TKI treatment caused a significant reduction in vessel density (CD31), phospho-S6K expression, PDL-1 expression, and FOXP3 expression (P < 0.05 for each). It also caused a significant increase in cytoplasmic FGF-2, MET receptor expression in vessels, Fuhrman tumor grade, and Ki-67 (P < 0.05 for each). Higher levels of Ki-67 and CD31 were associated with delayed progression (P < 0.05). Multiple samples (n = 5) from the same tumor showed marked heterogeneity of tumor grade, which increased significantly with treatment. Array CGH showed extensive intrapatient variability, which did not occur in DNA methylation analysis.
TKI treatment is associated with dynamic changes in relevant biomarkers, despite significant heterogeneity in chromosomal and protein, but not epigenetic expression. Changes to Ki-67 expression and tumor grade indicate that treatment is associated with an increase in the aggressive phenotype of the tumor.
The effect of high-frequency (< 20 days) wind on the intraseasonal sea surface temperature (SST) anomaly associated with the Madden-Julian oscillation (MJO) is examined by diagnosing reanalysis and ...outputs from a set of oceanic general circulation model (OGCM) experiments. Warm SST anomaly (SSTA) ahead of MJO convective center induces anomalous boundary-layer convergence, favoring the eastward propagation of the MJO. To understand the key physical processes contributing to the warm SSTA, the mixed-layer heat budget equation is diagnosed. The time change of SSTA (
∂
T
/
∂
t
) mostly comes from shortwave radiative heating, while latent heat flux (LHF) plays the secondary role. Due to the strong nonlinearity of LHF, the high-frequency (< 20 days) wind may affect the intraseasonal LHF variability via interacting with the background state, resulting in changes in intraseasonal SSTA. Our diagnosis shows that the upscale feedback associated with high-frequency wind variability accounts for around 23% of the intraseasonal LHF in the intraseasonal SST warming region, supporting the growth of
∂
T
/
∂
t
. Sensitivity experiments are then designed using an OGCM that simulates the upper-ocean temperature well, to verify the high-frequency wind effect on the intraseasonal SST variability. Once the high-frequency component of surface winds is removed in the model integration, the amplitudes of intraseasonal LHF and
∂
T
/
∂
t
are decreased, leading to reduced SSTA. The modeling results confirm the positive role of high-frequency wind in supporting the tropical intraseasonal SST variation. The findings of this study suggest that an accurate representation of high-frequency disturbances and their interaction with other components are crucial for MJO simulation and prediction.
Extensive neurogenetic analysis has shown that memory formation depends critically on cAMP-protein kinase A (PKA) signaling. Details of how this pathway is involved in memory formation, however, ...remain to be fully elucidated. From a large-scale behavioral screen in Drosophila, we identified the yu mutant to be defective in one-day memory after spaced training. The yu mutation disrupts a gene encoding an A-kinase anchoring protein (AKAP). AKAPs comprise a family of proteins, which determine the subcellular localization of PKAs and thereby critically restrict cAMP signaling within a cell. Further behavioral characterizations revealed that long-term memory (LTM) was disrupted specifically in the yu mutant, whereas learning, short-term memory and anesthesia-resistant memory all appeared normal. Another independently isolated mutation of the yu gene failed to complement the LTM defect associated with the yu mutation, and this phenotypic defect could be rescued by induced acute expression of a yu⁺ transgene, suggesting that yu functions physiologically during memory formation. AKAP Yu is expressed preferentially in the mushroom body (MB) neuroanatomical structure, and expression of a yu⁺ transgene to the MB, but not to other brain regions, is sufficient to rescue the LTM defect of the yu mutant. These observations lead us to conclude that proper localization of PKA by Yu AKAP in MB neurons is required for the formation of LTM.
PurposeThe Seek and Treat for Optimal Prevention of HIV/AIDS (STOP HIV/AIDS) Program Evaluation (SHAPE) study is a longitudinal cohort developed to monitor the progress of an HIV testing and ...treatment expansion programme across the province of British Columbia (BC). The study considers how sociostructural determinants such as gender, age, sexual identity, geography, income and ethnicity influence engagement in HIV care.ParticipantsBetween January 2016 and September 2018, 644 BC residents who were at least 19 years old and diagnosed with HIV were enrolled in the study and completed a baseline survey. Participants will complete two additional follow-up surveys (18 months apart) about their HIV care experiences, with clinical follow-up ongoing.Findings to dateAnalyses on baseline data have found high levels of HIV care engagement and treatment success among SHAPE participants, with 95% of participants receiving antiretroviral therapy and 90% having achieved viral suppression. However, persistent disparities in HIV treatment outcomes related to age, injection drug use and housing stability have been identified and require further attention when delivering services to marginalised groups.Future plansOur research will examine how engagement in HIV care evolves over time, continuing to identify barriers and facilitators for promoting equitable access to treatment and care among people living with HIV. A qualitative research project, currently in the formative phase, will compliment quantitative analyses by taking a strengths-based approach to exploring experiences of engagement and re-engagement in HIV treatment among individuals who have experienced delayed treatment initiation or treatment interruptions.
DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts ...all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (
< 9.3x10
) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to
, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to
, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (
) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
► DNA methylation of
Trip10 changes during lineage-specific differentiation of MSCs. ►
In vitro DNA methylated
Trip10 facilitates MSC-to-neuron differentiation. ► DNA methylation is visualized in ...live cells by the two-component reporter system.
Epigenetic regulation of gene expression by DNA methylation and histone modification controls cell fate during development and homeostasis in adulthood. Aberrant epigenetic modifications may lead to abnormal development, even diseases. We have found that
Trip10 (thyroid hormone receptor interactor 10), an adaptor protein involved in diverse functions, is epigenetically regulated during lineage-specific induction of human bone marrow-derived mesenchymal stem cells (MSCs). To determine whether DNA methylation-induced gene silencing is sufficient to restrict cell fate changes, we applied an
in
vitro
method to specifically methylate the promoter of
Trip10. Our hypothesis was that the methylation status of the
Trip10 promoter in MSCs alters the differentiation preference of MSCs. Transfection of
in vitro-methylated
Trip10 promoter DNA into MSCs resulted in progressive accumulation of cytosine methylation at the endogenous
Trip10 promoter, reduced
Trip10 expression, and accelerated MSC-to-neuron and MSC-to-osteocyte differentiation. A two-component EGFP reporter gene system was established to confirm the level of transcriptional silencing and visualize the targeted DNA methylation. EGFP expression induced in the reporter system by targeted
Trip10 methylation was reversed by adding 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, confirming that the suppressed
Trip10 expression and disrupted MSC differentiation resulted from the
in vitro-introduced methylations in the
Trip10 promoter. With this targeted DNA methylation and reporter system, we are able to monitor the progression of locus-specific DNA methylation
in vivo and correlate such changes with potential functional changes. Using this approach, we have established a new role for
Trip10, showing that the level of
Trip10 expression is associated with the maintenance and differentiation of MSCs.
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