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Histone H3 lysine 9 (H3K9) methylation must be regulated to prevent inappropriate heterochromatin formation. Regulation of the conserved fission yeast H3K9 methyltransferase Clr4 (Suv39h) involves an automethylation-induced conformational switch and interaction of its catalytic SET domain with mono-ubiquitinated histone H3 lysine 14 (H3K14ub), a modification catalyzed by the Cul4 subunit of the CLRC complex. Using reconstituted CLRC, we show that Clr4 catalytic pocket serves as a substrate receptor for Cul4-dependent H3K14 ubiquitination. H3K14ub activates Clr4 to catalyze cis methylation of H3K9 on the same histone tail, while Clr4 automethylation enables H3K14ub-bound Clr4 to methylate H3K9 on an unmodified H3 tail in trans. Crosslinking and structural modeling reveal interactions between Clr4 chromo and SET domains, and between the chromodomain and H3K14ub, suggesting that the chromodomain reads H3K9me3 and H3K14ub to allosterically regulate Clr4 activity. H3K14 ubiquitination therefore regulates Clr4 by promoting its recruitment and by positioning H3K9 in the active site.

Histone H3 lysine 9 (H3K9) methylation must be regulated to prevent inappropriate heterochromatin for-mation. Regulation of the conserved fission yeast H3K9 methyltransferase Clr4 (Suv39h) involves an au-tomethylation-induced conformational switch and interaction of its catalytic SET domain with mono-ubiquitinated histone H3 lysine 14 (H3K14ub), a modification catalyzed by the Cul4 subunit of the CLRC complex. Using reconstituted CLRC, we show that Clr4 catalytic pocket serves as a substrate receptor for Cul4-dependent H3K14 ubiquitination. H3K14ub activates Clr4 to catalyze cis methylation of H3K9 on the same histone tail, while Clr4 automethylation enables H3K14ub-bound Clr4 to methylate H3K9 on an un-modified H3 tail in trans. Crosslinking and structural modeling reveal interactions between Clr4 chromo and SET domains, and between the chromodomain and H3K14ub, suggesting that the chromodomain reads H3K9me3 and H3K14ub to allosterically regulate Clr4 activity. H3K14 ubiquitination therefore regu-lates Clr4 by promoting its recruitment and by positioning H3K9 in the active site.Histone H3 lysine 9 (H3K9) methylation must be regulated to prevent inappropriate heterochromatin for-mation. Regulation of the conserved fission yeast H3K9 methyltransferase Clr4 (Suv39h) involves an au-tomethylation-induced conformational switch and interaction of its catalytic SET domain with mono-ubiquitinated histone H3 lysine 14 (H3K14ub), a modification catalyzed by the Cul4 subunit of the CLRC complex. Using reconstituted CLRC, we show that Clr4 catalytic pocket serves as a substrate receptor for Cul4-dependent H3K14 ubiquitination. H3K14ub activates Clr4 to catalyze cis methylation of H3K9 on the same histone tail, while Clr4 automethylation enables H3K14ub-bound Clr4 to methylate H3K9 on an un-modified H3 tail in trans. Crosslinking and structural modeling reveal interactions between Clr4 chromo and SET domains, and between the chromodomain and H3K14ub, suggesting that the chromodomain reads H3K9me3 and H3K14ub to allosterically regulate Clr4 activity. H3K14 ubiquitination therefore regu-lates Clr4 by promoting its recruitment and by positioning H3K9 in the active site.

We use a spatially explicit biogeochemical end-to-end ecosystem model, Atlantis, to simulate impacts from the Deepwater Horizon oil spill and subsequent recovery of fish guilds. Dose-response relationships with expected oil concentrations were utilized to estimate the impact on fish growth and mortality rates. We also examine the effects of fisheries closures and impacts on recruitment. We validate predictions of the model by comparing population trends and age structure before and after the oil spill with fisheries independent data. The model suggests that recruitment effects and fishery closures had little influence on biomass dynamics. However, at the assumed level of oil concentrations and toxicity, impacts on fish mortality and growth rates were large and commensurate with observations. Sensitivity analysis suggests the biomass of large reef fish decreased by 25% to 50% in areas most affected by the spill, and biomass of large demersal fish decreased even more, by 40% to 70%. Impacts on reef and demersal forage caused starvation mortality in predators and increased reliance on pelagic forage. Impacts on the food web translated effects of the spill far away from the oiled area. Effects on age structure suggest possible delayed impacts on fishery yields. Recovery of high-turnover populations generally is predicted to occur within 10 years, but some slower-growing populations may take 30+ years to fully recover.

Systemic lupus erythematosus (SLE) is characterized by the expansion of extrafollicular pathogenic B cells derived from newly activated naive cells. Although these cells express distinct markers, their epigenetic architecture and how it contributes to SLE remain poorly understood. To address this, we determined the DNA methylomes, chromatin accessibility profiles and transcriptomes from five human B cell subsets, including a newly defined effector B cell subset, from subjects with SLE and healthy controls. Our data define a differentiation hierarchy for the subsets and elucidate the epigenetic and transcriptional differences between effector and memory B cells. Importantly, an SLE molecular signature was already established in resting naive cells and was dominated by enrichment of accessible chromatin in motifs for AP-1 and EGR transcription factors. Together, these factors acted in synergy with T-BET to shape the epigenome of expanded SLE effector B cell subsets. Thus, our data define the molecular foundation of pathogenic B cell dysfunction in SLE. Systemic lupus erythematosus (SLE) is characterized by autoantibodies produced by pathogenic B cells. Boss, Sanz and colleagues show that SLE-associated epigenetic changes exist in gene regulatory programs in resting naive B cells, before their differentiation into antibody-producing plasma cells.

Cancer cells characteristically consume glucose through Warburg metabolism 1 , a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells 2 – 4 . However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME. Positron emission tomography measurements of nutrient uptake in cells of the tumour microenvironment reveal cell-intrinsic partitioning in which glucose uptake is higher in myeloid cells, whereas glutamine is preferentially acquired by cancer cells.

Recent research indicates that some young people initially learn about sexual choking through Internet memes. Thus, a qualitative content analysis was performed on 316 visual and textual memes collected from various social media websites and online searches to assess salient categories related to choking during sex. We identified nine main categories: communication, gendered dynamics, choking as dangerous, choking as sexy, sexualization of the nonsexual, shame and worry, romance/rough sex juxtaposition, choking and religious references, instructional/informational. Given that memes, through their humor, can make difficult topics more palatable and minimize potential harm in the phenomenon they depict, more concerted, synergistic effort that integrates media literacy into sexuality education programming on the potential risks that may ensue for those engaging in sexual choking is warranted.

Background In addition to systemic gender disparities, women in surgery encounter interpersonal microaggressions. The objective of this study is to describe the most common forms of microaggressions reported by women in surgery. Methods We conducted a scoping review using PubMed/MEDLINE, Ovid, and Web of Science to describe the international, indexed English-language literature on gender-based microaggressions experienced by female surgeons, surgical trainees, and medical students in surgery. After screening by title, abstract, and full-text, 37 articles were retained for data extraction and analysis. Microaggressions were analyzed using the Sexist Microaggression Experience and Stress Scale (MESS) framework and stratified by country of origin. Results Gender-based microaggression publications most commonly originated from the United States ( n  = 27 articles), Canada ( n  = 3), and India ( n  = 2). Gender-based microaggressions were classified into environmental invalidations ( n  = 20), being treated like a second-class citizen ( n  = 18), assumptions of traditional gender roles ( n  = 12), sexual objectification ( n  = 11), assumptions of inferiority (n = 10), being forced to leave gender at the door ( n  = 8), and experiencing sexist language ( n  = 6). Additionally, attendings were more frequently reported to experience microaggressions than surgical trainees and medical students, but more articles reported data on attendings ( n  = 16) than surgical trainees ( n  = 10) or students ( n  = 4). Conclusion While recent advancements have opened the field of surgery to women, there is still a lack of female representation, and persistent microaggressions may perpetuate this gender disparity. Addressing microaggressions against female surgeons is essential to achieving gender equity in surgical practice.

HIV-1 infection disproportionately affects women in sub-Saharan Africa, where areas of high HIV-1 prevalence and Schistosoma haematobium endemicity largely overlap. Female genital schistosomiasis (FGS), an inflammatory disease caused by S. haematobium egg deposition in the genital tract, has been associated with prevalent HIV-1 infection. Elevated levels of the chemokines MIP-1α (CCL-3), MIP-1β (CCL-4), IP-10 (CXCL-10), and IL-8 (CXCL-8) in cervicovaginal lavage (CVL) have been associated with HIV-1 acquisition. We hypothesize that levels of cervicovaginal cytokines may be raised in FGS and could provide a causal mechanism for the association between FGS and HIV-1. In the cross-sectional BILHIV study, specimens were collected from 603 female participants who were aged 18–31 years, sexually active, not pregnant and participated in the HPTN 071 (PopART) HIV-1 prevention trial in Zambia. Participants self-collected urine, and vaginal and cervical swabs, while CVLs were clinically obtained. Microscopy and Schistosoma circulating anodic antigen (CAA) were performed on urine. Genital samples were examined for parasite-specific DNA by PCR. Women with FGS (n=28), defined as a positive Schistosoma PCR from any genital sample were frequency age-matched with 159 FGS negative (defined as negative Schistosoma PCR, urine CAA, urine microscopy, and colposcopy imaging) women. Participants with probable FGS (n=25) (defined as the presence of either urine CAA or microscopy in combination with one of four clinical findings suggestive of FGS on colposcope-obtained photographs) were also included, for a total sample size of 212. The concentrations of 17 soluble cytokines and chemokines were quantified by a multiplex bead-based immunoassay. There was no difference in the concentrations of cytokines or chemokines between participants with and without FGS. An exploratory analysis of those women with a higher FGS burden, defined by ≥2 genital specimens with detectable Schistosoma DNA (n=15) showed, after adjusting for potential confounders, a higher Th2 (IL-4, IL-5, and IL-13) and pro-inflammatory (IL-15) expression pattern in comparison to FGS negative women, with differences unlikely to be due to chance (p=0.037 for IL-4 and p<0.001 for IL-5 after adjusting for multiple testing). FGS may alter the female genital tract immune environment, but larger studies in areas of varying endemicity are needed to evaluate the association with HIV-1 vulnerability.

Objective Although there is a growing recognition of the importance of active communication behaviours from the incoming clinician receiving a patient handover, there are currently no agreed-upon measures to objectively describe those behaviours. This study sought to identify differences in incoming clinician communication behaviours across levels of clinical training for physicians and nurses. Methods Handover observations were conducted during shift changes for attending physicians, resident physicians, registered nurses and nurse practitioners in three medical intensive care units from July 2011 to August 2012. Measures were the number of interjections from the incoming clinician and the communication mode of those interjections. Each collaborative cross-check, a specific type of interactive question, was subsequently classified by level of assertiveness. Results 133 patient handovers were analysed. Statistical differences were found in both measures. Higher levels of training were associated with fewer interjections, and a higher proportion of interactive questioning to detect erroneous assessments and actions by the incoming provider. All groups were observed to use the least assertive level of a collaborative cross-check, which contributed to misunderstandings. Nurses used less assertive collaborative cross-checks than physicians. Conclusions Differences across clinician type and levels of clinical training were found in both measures during patient handovers. The findings suggest that training could enable physicians and nurses to learn communication competencies during patient handovers which were used more frequently by more experienced practitioners, including interjecting less frequently and using interactive questioning strategies to clarify understanding, and assertively question the appropriateness of diagnoses, treatment plans and prognoses. Accompanying cultural change initiatives might be required to routinely employ these strategies in the clinical setting, particularly for nursing personnel.

One of the long-standing mysteries of evolutionary genomics is the source of the wide phylogenetic diversity in genome nucleotide composition (G + C versus A + T), which must be a consequence of interspecific differences in mutation bias, the efficiency of selection for different nucleotides or a combination of the two. We demonstrate that although genomic G + C composition is strongly driven by mutation bias, it is also substantially modified by direct selection and/or as a by-product of biased gene conversion. Moreover, G + C composition at fourfold redundant sites is consistently elevated above the neutral expectation—more so than for any other class of sites. Genome-wide nucleotide composition varies greatly among species. Here, the authors show that genomic G + C composition is driven by mutation bias but is also modified by natural selection or biased gene conversion.