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Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their level of public accessibility, and the complexity of the models used to capture clinical knowledge. CIViC (Clinical Interpretation of Variants in Cancer - www.civicdb.org ) is a fully open, free-to-use cancer variant interpretation knowledgebase that incorporates highly detailed curation of evidence obtained from peer-reviewed publications and meeting abstracts, and currently holds over 6300 Evidence Items for over 2300 variants derived from over 400 genes. CIViC has seen increased adoption by, and also undertaken collaboration with, a wide range of users and organizations involved in research. To enhance CIViC’s clinical value, regular submission to the ClinVar database and pursuit of other regulatory approvals is necessary. For this reason, a formal peer reviewed curation guideline and discussion of the underlying principles of curation is needed. We present here the CIViC knowledge model, standard operating procedures (SOP) for variant curation, and detailed examples to support community-driven curation of cancer variants.

Manually curated variant knowledgebases and their associated knowledge models are serving an increasingly important role in distributing and interpreting variants in cancer. These knowledgebases vary in their level of public accessibility, and the complexity of the models used to capture clinical knowledge. CIViC (Clinical Interpretations of Variants in Cancer - www.civicdb.org) is a fully open, free-to-use cancer variant interpretation knowledgebase that incorporates highly detailed curation of evidence obtained from peer-reviewed publications. Currently, the CIViC knowledge model consists of four main components: Genes, Variants, Evidence Items, and Assertions. Each component has an associated knowledge model and methods for curation. Gene and Variant data contextualize the genomic region(s) involved in the clinical statement. Evidence Items provide structured associations between variants and their clinically predictive/therapeutic, prognostic, diagnostic, predisposing, and functional implications. Finally, CIViC Assertions summarize collections of CIViC Evidence Items for a specific Disease, Variant, and Clinical Significance with incorporation of clinical and technical guidelines. Here we present the CIViC knowledge model, curation standard operating procedures, and detailed examples to support community-driven curation of cancer variants. Footnotes * https://civicdb.org/

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. With nearly 300 contributors, CIViC contains peer-reviewed, published literature curated and expert-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new evidence types (predisposing, oncogenic and functional). The growing CIViC knowledgebase distributes clinically-relevant cancer variant data currently representing >2500 variants in >400 genes from >2800 publications.

Tens of thousands of species are threatened with extinction as a result of human activities. Here we explore how the extinction risks of terrestrial mammals and birds might change in the next 50 years. Future population growth and economic development are forecasted to impose unprecedented levels of extinction risk on many more species worldwide, especially the large mammals of tropical Africa, Asia and South America. Yet these threats are not inevitable. Proactive international efforts to increase crop yields, minimize land clearing and habitat fragmentation, and protect natural lands could increase food security in developing nations and preserve much of Earth's remaining biodiversity.

Within germinal centers (GCs), complex and highly orchestrated molecular programs must balance proliferation, somatic hypermutation and selection to both provide effective humoral immunity and to protect against genomic instability and neoplastic transformation. In contrast to this complexity, GC B cells are canonically divided into two principal populations, dark zone (DZ) and light zone (LZ) cells. We now demonstrate that, following selection in the LZ, B cells migrated to specialized sites within the canonical DZ that contained tingible body macrophages and were sites of ongoing cell division. Proliferating DZ (DZp) cells then transited into the larger DZ to become differentiating DZ (DZd) cells before re-entering the LZ. Multidimensional analysis revealed distinct molecular programs in each population commensurate with observed compartmentalization of noncompatible functions. These data provide a new three-cell population model that both orders critical GC functions and reveals essential molecular programs of humoral adaptive immunity. Germinal centers are typically divided into dark and light zones. Clark and colleagues identify ‘gray zone’ cyclin B1 + B cell clusters as sites of ongoing cell proliferation, and these cells are distinct from dark zone B cells that undergo AID-dependent somatic hypermutation. This separation of function safeguards B cells undergoing DNA replication against potential mutagenic events that could result in neoplastic transformation.

In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet how the pre-BCR mediates these functions remains unclear. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 ligation by C-X-C motif chemokine ligand 12 activates the mitogen-activated protein kinase extracellular-signal-regulated kinase, which then directs the development of small pre- and immature B cells, including orchestrating cell cycle exit, pre-BCR repression, Igk recombination and BCR expression. In contrast, pre-BCR expression and escape from interleukin-7 have only modest effects on B cell developmental transcriptional and epigenetic programs. These data show a direct and central role for CXCR4 in orchestrating late B cell lymphopoiesis. Furthermore, in the context of previous findings, our data provide a three-receptor system sufficient to recapitulate the essential features of B lymphopoiesis in vitro. Pre-B cells undergo a transition checkpoint needed for developmental progression. Mandal and colleagues show that the CXCL12–CXCR4 signaling axis orchestrates late B cell lymphopoiesis by suppressing Myc and cyclin D genes and promoting Rag-mediated recombination of immunoglobulin light-chain genes.

When women with small ovarian reserves are subjected to assisted reproductive technologies, high doses of gonadotropins are linked to high oocyte and embryo wastage and low live birth rates. We hypothesized that excessive follicle-stimulating hormone (FSH) doses during superovulation are detrimental to ovulatory follicle function in individuals with a small ovarian reserve. To test this hypothesis, heifers with small ovarian reserves were injected twice daily for 4 days, beginning on Day 1 of the estrous cycle with 35, 70, 140, or 210 IU doses of Folltropin-V (FSH). Each heifer (n = 8) was superovulated using a Williams Latin Square Design. During each superovulation regimen, three prostaglandin F2α injections were given at 12-h interval, starting at the seventh FSH injection to regress the newly formed corpus luteum (CL). Human chorionic gonadotropin was injected 12 h after the last (8th) FSH injection to induce ovulation. Daily ultrasonography and blood sampling were used to determine the number and size of follicles and corpora lutea, uterine thickness, and circulating concentrations of estradiol, progesterone, and anti-Müllerian hormone (AMH). The highest doses of FSH did not increase AMH, progesterone, number of ovulatory-size follicles, uterine thickness, or number of CL. However, estradiol production and ovulation rate were lower for heifers given high FSH doses compared to lower doses, indicating detrimental effects on ovulatory follicle function. Summary sentence High doses of Folltropin-V in cattle with a low antral follicle count and small ovarian reserve are detrimental to ovulatory follicle function.

Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1-deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions. While inductive signals controlling germline specification are well characterized, the intrinsic factors that allow epiblast cells to respond to such signals remain largely unknown. Here the authors use in vitro differentiated primordial germ cells to show that partial retention of histone H3K4 monomethylation within relevant enhancers is important for germline competence and specification.

PurposeThe 2020 murder of George Floyd resulted in challenges to policing in the United States of America, but little is known about how police chiefs perceive them. At the same time, chiefs of police wield great influence over public perceptions of crime and disorder, the state of their profession, the laws and policies that govern the conduct of police officers and municipal public safety budgets. It is therefore critical to understand how police perceive the changes to their profession post-Floyd.Design/methodology/approachThis study surveyed a randomly selected national sample of 276 municipal chiefs of police. Items probed resignations, recruitment, efforts to defund departments, community support, officer morale, suspects’ likelihood of obeying lawful orders and career risks that could inhibit proactive police work. It examined associations between perceptions and Census Bureau region, length of tenure as chief, size of police department, population served and the urban or rural designation of the jurisdiction.FindingsChiefs overwhelmingly reported recruiting qualified candidates had become much harder, and the present risks of proactive police work encourage inaction. Chiefs of agencies in the Northeast perceived more challenges than those in the South. Respondents with more years of experience were less likely to perceive the current situation as dire. Approximately 13.5% reported an attempt to defund their department, 56.8% of which yielded some success. Our study suggests an increase in the number and scope of challenges perceived by chiefs of police. Results vary by region and police chief years of experience.Originality/valueThis study provides researchers and practitioners with the perspectives of chiefs about the post-Floyd era that influence their decisions, policies and initiatives.

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding. BRWD1 regulates over 7000 genes to repress proliferative and induce differentiation programs. However, BRWD1 does not regulate the expression of TFs required for B lymphopoiesis. Hypogammaglobulinemia patients with BRWD1 mutations have B-cell transcriptional profiles and enhancer landscapes similar to those observed in Brwd1 -/- mice. These data indicate that, in both mice and humans, BRWD1 is a master orchestrator of enhancer accessibility that cooperates with TF networks to drive late B-cell development. B-cell development is tightly regulated by transcription programs that are coordinated by transcription factors (TF) and locus accessibility. Here the authors show that, in mice and humans, the epigenetic reader BRWD1 inhibits and promotes the accessibility of enhancers for early and late B lymphopoiesis, respectively.