The links are still missing: Revisiting the role of RNA as a guide for chromatin-associated proteins.

A new study in Molecular Cell by Guo et al.1 and two studies in Cell Reports by Healy et al.2 and by Hall Hickman and Jenner3 show how PRC2 and other chromatin regulators do not appear to bind RNA in vivo, challenging the importance of RNA for their function.

Getting ahead in the social sciences: How parenthood and publishing contribute to gender gaps in academic career advancement.

How do parenthood and publishing contribute to gender gaps in academic career advancement? While extensive research examines the causes of gender disparities in science, technology, engineering, and mathematics (STEM) careers, we know much less about the factors that constrain women's advancement in the social sciences. Combining detailed career- and administrative register data on 976 Danish social scientists in Business and Management, Economics, Political Science, Psychology, and Sociology (5703 person-years) that obtained a PhD degree between 2000 and 2015, we estimate gender differences in attainment of senior research positions and parse out how publication outputs, parenthood and parental leave contribute to these differences. Our approach is advantageous over previous longitudinal studies in that we track the careers and publication outputs of graduates from the outset of their PhD education and match this data with time-sensitive information on each individual's publication activities and family situation. In discrete time-event history models, we observe a ∼24 per cent female disadvantage in advancement likelihoods within the first 7 years after PhD graduation, with gender differences increasing over the observation period. A decomposition indicates that variations in publishing, parenthood and parental leave account for ∼ 40 per cent of the gender gap in career advancement, suggesting that other factors, including recruitment disparities, asymmetries in social capital and experiences of unequal treatment at work, may also constrain women's careers.

COOLAIR and PRC2 function in parallel to silence FLC during vernalization.

Noncoding transcription induces chromatin changes that can mediate environmental responsiveness, but the causes and consequences of these mechanisms are still unclear. Here, we investigate how antisense transcription (termed COOLAIR) interfaces with Polycomb Repressive Complex 2 (PRC2) silencing during winter-induced epigenetic regulation of Arabidopsis FLOWERING LOCUS C (FLC). We use genetic and chromatin analyses on lines ineffective or hyperactive for the antisense pathway in combination with computational modeling to define the mechanisms underlying FLC repression. Our results show that FLC is silenced through pathways that function with different dynamics: a COOLAIR transcription-mediated pathway capable of fast response and in parallel a slow PRC2 switching mechanism that maintains each allele in an epigenetically silenced state. Components of both the COOLAIR and PRC2 pathways are regulated by a common transcriptional regulator (NTL8), which accumulates by reduced dilution due to slow growth at low temperature. The parallel activities of the regulatory steps, and their control by temperature-dependent growth dynamics, create a flexible system for registering widely fluctuating natural temperature conditions that change year on year, and yet ensure robust epigenetic silencing of FLC.

Management of Recurrent Venous Thromboembolism in Severe Immune Thrombocytopenia: A Case Report and a Review of the Literature.

We report a case of a 58-year-old man with recurrent unprovoked deep vein thrombosis (DVT) and severe immune thrombocytopenia (ITP) with a platelet count of 19 × 109/L. We further review studies reporting venous thromboembolism (VTE) in patients with severe ITP (≤ 35 × 109/L) and identified 14 patients highlighting VTE risk factors and management of these patients. The present case had several risk factors for VTE (previous DVT, obesity, heterozygosity for factor V Leiden mutation, and previous splenectomy). The patient was initially treated with low-molecular-weight heparin followed by long-term apixaban treatment. The literature review together with our case demonstrates that VTE in severe ITP (≤ 35 × 109/L) can occur in patients with VTE risk factors and antithrombotic management of these patients can be achieved without bleeding depending on severity of thrombocytopenia either by full or reduced dose of anticoagulation together with ITP therapy.

Distinct accessory roles of Arabidopsis VEL proteins in Polycomb silencing.

Polycomb repressive complex 2 (PRC2) mediates epigenetic silencing of target genes in animals and plants. In Arabidopsis, PRC2 is required for the cold-induced epigenetic silencing of the FLC floral repressor locus to align flowering with spring. During this process, PRC2 relies on VEL accessory factors, including the constitutively expressed VRN5 and the cold-induced VIN3. The VEL proteins are physically associated with PRC2, but their individual functions remain unclear. Here, we show an intimate association between recombinant VRN5 and multiple components within a reconstituted PRC2, dependent on a compact conformation of VRN5 central domains. Key residues mediating this compact conformation are conserved among VRN5 orthologs across the plant kingdom. In contrast, VIN3 interacts with VAL1, a transcriptional repressor that binds directly to FLC These associations differentially affect their role in H3K27me deposition: Both proteins are required for H3K27me3, but only VRN5 is necessary for H3K27me2. Although originally defined as vernalization regulators, VIN3 and VRN5 coassociate with many targets in the Arabidopsis genome that are modified with H3K27me3. Our work therefore reveals the distinct accessory roles for VEL proteins in conferring cold-induced silencing on FLC, with broad relevance for PRC2 targets generally.

Galectin-1 induces a tumor-associated macrophage phenotype and upregulates indoleamine 2,3-dioxygenase-1.

Galectins are a group of carbohydrate-binding proteins with a presumed immunomodulatory role and an elusive function on antigen-presenting cells. Here we analyzed the expression of galectin-1 and found upregulation of galectin-1 in the extracellular matrix across multiple tumors. Performing an in-depth and dynamic proteomic and phosphoproteomic analysis of human macrophages stimulated with galectin-1, we show that galectin-1 induces a tumor-associated macrophage phenotype with increased expression of key immune checkpoint protein programmed cell death 1 ligand 1 (PD-L1/CD274) and immunomodulator indoleamine 2,3-dioxygenase-1 (IDO1). Galectin-1 induced IDO1 and its active metabolite kynurenine in a dose-dependent manner through JAK/STAT signaling. In a 3D organotypic tissue model system equipped with genetically engineered tumorigenic epithelial cells, we analyzed the cellular source of galectin-1 in the extracellular matrix and found that galectin-1 is derived from epithelial and stromal cells. Our results highlight the potential of targeting galectin-1 in immunotherapeutic treatment of human cancers.

Estimating social bias in data sharing behaviours: an open science experiment.

Open data sharing is critical for scientific progress. Yet, many authors refrain from sharing scientific data, even when they have promised to do so. Through a preregistered, randomized audit experiment (N = 1,634), we tested possible ethnic, gender and status-related bias in scientists' data-sharing willingness. 814 (54%) authors of papers where data were indicated to be 'available upon request' responded to our data requests, and 226 (14%) either shared or indicated willingness to share all or some data. While our preregistered hypotheses regarding bias in data-sharing willingness were not confirmed, we observed systematically lower response rates for data requests made by putatively Chinese treatments compared to putatively Anglo-Saxon treatments. Further analysis indicated a theoretically plausible heterogeneity in the causal effect of ethnicity on data-sharing. In interaction analyses, we found indications of lower responsiveness and data-sharing willingness towards male but not female data requestors with Chinese names. These disparities, which likely arise from stereotypic beliefs about male Chinese requestors' trustworthiness and deservingness, impede scientific progress by preventing the free circulation of knowledge.

Stratified care in hip arthroscopy: can we predict successful and unsuccessful outcomes? Development and external temporal validation of multivariable prediction models.

OBJECTIVE: Although hip arthroscopy is a widely adopted treatment option for hip-related pain, it is unknown whether preoperative clinical information can be used to assist surgical decision-making to avoid offering surgery to patients with limited potential for a successful outcome. We aimed to develop and validate clinical prediction models to identify patients more likely to have an unsuccessful or successful outcome 1 year post hip arthroscopy based on the patient acceptable symptom state. METHODS: Patient records were extracted from the Danish Hip Arthroscopy Registry (DHAR). A priori, 26 common clinical variables from DHAR were selected as prognostic factors, including demographics, radiographic parameters of hip morphology and self-reported measures. We used 1082 hip arthroscopy patients (surgery performed 25 April 2012 to 4 October 2017) to develop the clinical prediction models based on logistic regression analyses. The development models were internally validated using bootstrapping and shrinkage before temporal external validation was performed using 464 hip arthroscopy patients (surgery performed 5 October 2017 to 13 May 2019). RESULTS: The prediction model for unsuccessful outcomes showed best and acceptable predictive performance on the external validation dataset for all multiple imputations (Nagelkerke R2 range: 0.25-0.26) and calibration (intercept range: -0.10 to -0.11; slope range: 1.06-1.09), and acceptable discrimination (area under the curve range: 0.76-0.77). The prediction model for successful outcomes did not calibrate well, while also showing poor discrimination. CONCLUSION: Common clinical variables including demographics, radiographic parameters of hip morphology and self-reported measures were able to predict the probability of having an unsuccessful outcome 1 year after hip arthroscopy, while the model for successful outcome showed unacceptable accuracy. The externally validated prediction model can be used to support clinical evaluation and shared decision making by informing the orthopaedic surgeon and patient about the risk of an unsuccessful outcome, and thus when surgery may not be appropriate.

Pain provocation tests and clinical entities in male football players with longstanding groin pain are associated with pain intensity and disability.

BACKGROUND: Clinical examination of male football players with longstanding groin pain can be considered difficult. Pain provocation tests are used to examine and classify longstanding groin pain into clinical entities as adductor-, iliopsoas-, inguinal-, and pubic-related. It is unknown if pain provocation tests and clinical entities are associated with pain intensity and disability. OBJECTIVES: To investigate if the number of positive pain provocation tests and clinical entities are associated with pain intensity and disability, measured by the Copenhagen 5-Second Squeeze Test (5SST) and the Copenhagen Hip and Groin Outcome Score (HAGOS), respectively. DESIGN: Cross-sectional. METHOD: Forty male football players (age: mean 24 years [SD: 3.2]; height: mean 182 cm [SD: 5.7]; weight: mean 78 Kg [SD: 6.6]) with longstanding groin pain for a median of 8.5 months (IQR: 4-36) were included. The players underwent a bilateral groin examination with 33 pain provocation tests and were classified with clinical entities (0-7) based on the test findings. RESULTS: The number of positive pain provocation tests (median 10, range 2-23) correlated with pain intensity (5SST: rs = 0.70 [95% CI: 0.50, 0.83]) and disability (HAGOS subscales Sport: rs =-0.62 [95% CI: -0.81, -0.36], Pain: rs = -0.38 [95% CI: -0.69, -0.06], Symptoms: rs = 0.52 [95% CI: -0.73, -0.24], ADL: rs = -0.48 [95% CI: -0.71, -0.18]). The number of clinical entities (median 3, range: 1-7) showed similar but weaker correlations to pain intensity and disability. CONCLUSIONS: In male football players with longstanding groin pain, the number of positive pain provocation tests and clinical entities shows weak to strong correlations with pain intensity and disability. Consequently, when pain intensity and disability are severe, a higher number of pain provocation tests may be positive, and more clinical entities may be present.

Head-to-tail polymerization by VEL proteins underpins cold-induced Polycomb silencing in flowering control.

Transcriptional silencing through the Polycomb silencing machinery utilizes a "read-write" mechanism involving histone tail modifications. However, nucleation of silencing and long-term stable transmission of the silenced state also requires P-olycomb Repressive Complex 2 (PRC2) accessory proteins, whose molecular role is poorly understood. The Arabidopsis VEL proteins are accessory proteins that interact with PRC2 to nucleate and propagate silencing at the FLOWERING LOCUS C (FLC) locus, enabling early flowering in spring. Here, we report that VEL proteins contain a domain related to an atypical four-helix bundle that engages in spontaneous concentration-dependent head-to-tail polymerization to assemble dynamic biomolecular condensates. Mutations blocking polymerization of this VEL domain prevent Polycomb silencing at FLC. Plant VEL proteins thus facilitate assembly of dynamic multivalent Polycomb complexes required for inheritance of the silenced state.

Institution and gender-related differences in publication speed before and during COVID-19.

The COVID-19 pandemic elicited a substantial hike in journal submissions and a global push to get medical evidence quickly through the review process. Editorial decisions and peer-assessments were made under intensified time constraints, which may have amplified social disparities in the outcomes of peer-reviewing, especially for COVID-19 related research. This study quantifies the differential impact of the pandemic on the duration of the peer-review process for women and men and for scientists at different strata of the institutional-prestige hierarchy. Using mixed-effects regression models with observations clustered at the journal level, we analysed newly available data on the submission and acceptance dates of 78,085 medical research articles published in 2019 and 2020. We found that institution-related disparities in the average time from manuscript submission to acceptance increased marginally in 2020, although half of the observed change was driven by speedy reviews of COVID-19 research. For COVID-19 papers, we found more substantial institution-related disparities in review times in favour of authors from highly-ranked institutions. Descriptive survival plots also indicated that scientists with prestigious affiliations benefitted more from fast-track peer reviewing than did colleagues from less reputed institutions. This difference was more pronounced for journals with a single-blind review procedure compared to journals with a double-blind review procedure. Gender-related changes in the duration of the peer-review process were small and inconsistent, although we observed a minor difference in the average review time of COVID-19 papers first authored by women and men.

Global mapping of GalNAc-T isoform-specificities and O-glycosylation site-occupancy in a tissue-forming human cell line.

Mucin-type-O-glycosylation on proteins is integrally involved in human health and disease and is coordinated by an enzyme family of 20 N-acetylgalactosaminyltransferases (GalNAc-Ts). Detailed knowledge on the biological effects of site-specific O-glycosylation is limited due to lack of information on specific glycosylation enzyme activities and O-glycosylation site-occupancies. Here we present a systematic analysis of the isoform-specific targets of all GalNAc-Ts expressed within a tissue-forming human skin cell line, and demonstrate biologically significant effects of O-glycan initiation on epithelial formation. We find over 300 unique glycosylation sites across a diverse set of proteins specifically regulated by one of the GalNAc-T isoforms, consistent with their impact on the tissue phenotypes. Notably, we discover a high variability in the O-glycosylation site-occupancy of 70 glycosylated regions of secreted proteins. These findings revisit the relevance of individual O-glycosylation sites in the proteome, and provide an approach to establish which sites drive biological functions.

VAL1 acts as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC.

Polycomb (PcG) silencing is crucial for development, but how targets are specified remains incompletely understood. The cold-induced Polycomb Repressive Complex 2 (PRC2) silencing of Arabidopsis thaliana FLOWERING LOCUS C (FLC) provides an excellent system to elucidate PcG regulation. Association of the DNA binding protein VAL1 to FLC PcG nucleation regionis an important step. VAL1 co-immunoprecipitates APOPTOSIS AND SPLICING ASSOCIATED PROTEIN (ASAP) complex and PRC1. Here, we show that ASAP and PRC1 are necessary for co-transcriptional repression and chromatin regulation at FLC. ASAP mutants affect FLC transcription in warm conditions, but the rate of FLC silencing in the cold is unaffected. PRC1-mediated H2Aub accumulation increases at the FLC nucleation region during cold, but unlike the PRC2-delivered H3K27me3, does not spread across the locus. H2Aub thus involved in the transition to epigenetic silencing at FLC, facilitating H3K27me3 accumulation and long-term epigenetic memory. Overall, our work highlights the importance of VAL1 as an assembly platform co-ordinating activities necessary for epigenetic silencing at FLC.

A framework for sex, gender, and diversity analysis in research.

Funding agencies have ample room to improve their policies.

Rapid Spike in Hip Adduction Strength in Early Adolescent Footballers: A Study of 125 Elite Male Players From Youth to Senior.

PURPOSE: To investigate the differences in hip adductor and abductor muscle strength in elite male footballers from youth to senior level. METHODS: We tested 125 players from the under-13-years (U'13) to senior squads of a Danish male professional football club in this cross-sectional design study. Hip adductor and abductor force (in newtons), torque (in newton meters), normalized torque (in newton meters per body mass), and adduction-to-abduction ratio were measured using handheld dynamometry. RESULTS: Between U'13 and senior level, adductor force increased by 104%, torque by 127%, and normalized torque by 21%. Abductor force increased by 78%, torque by 126%, and normalized torque by 17%. For incremental differences between age groups, significant increases were observed between the ages of U'13 to U'14 (18%-39%) and U'14 to U'15 (19%-33%) for all strength measures (P ≤ .021). No incremental difference was observed for adductor-to-abductor ratio. CONCLUSIONS: The large increases in hip adductor and abductor strength occurring between the ages of U'13 and U'15 offer insight into the strength capabilities and stress demands in these players, which may relate to injury vulnerability, and facilitate clinicians in selecting best-suited exercise interventions.

Dissecting Context-Specific Galectin Binding Using Glycoengineered Cell Libraries.

The family of galectins has critical functions in a wide range of biological processes, primarily based on their broad interactions with proteins carrying ß-galactoside-containing glycans. To understand the diversity of functions governed by galectins, it is essential to define the binding specificity of the carbohydrate recognition domain (CRDs) of the individual galectins. The binding specificity of galectins has primarily been examined with glycoarrays, but now the ability to probe and dissect binding to defined glycans in the context of a cellular membrane is facilitated by the generations of glycoengineered cell libraries with defined glyco-phenotypes. The following section will show how galectin specificities can be probed in the natural context of cellular surfaces using glycoengineered cell libraries, and how binding to glycoproteins can be measured in solution with fluorescence anisotropy.

Author-level data confirm the widening gender gap in publishing rates during COVID-19.

Publications are essential for a successful academic career, and there is evidence that the COVID-19 pandemic has amplified existing gender disparities in the publishing process. We used longitudinal publication data on 431,207 authors in four disciplines - basic medicine, biology, chemistry and clinical medicine - to quantify the differential impact of COVID-19 on the annual publishing rates of men and women. In a difference-in-differences analysis, we estimated that the average gender difference in publication productivity increased from -0.26 in 2019 to -0.35 in 2020; this corresponds to the output of women being 17% lower than the output of men in 2109, and 24% lower in 2020. An age-group comparison showed a widening gender gap for both early-career and mid-career scientists. The increasing gender gap was most pronounced among highly productive authors and in biology and clinical medicine. Our study demonstrates the importance of reinforcing institutional commitments to diversity through policies that support the inclusion and retention of women in research.

Hip adduction strength and provoked groin pain: A comparison of long-lever squeeze testing using the ForceFrame and the Copenhagen 5-Second-Squeeze test.

OBJECTIVES: To compare long-lever squeeze testing using the ForceFrame and the Copenhagen 5-Second-Squeeze test (5SST) for assessment of hip adduction strength and provoked groin pain in elite male soccer players. DESIGN: Cross-sectional study. SETTING: Pre-season testing at facilities of a Danish professional 1st tier soccer club and academy. PARTICIPANTS: Elite male soccer players (n = 83, mean age; 16 ± 2.7 years) from U13, U14, U15, U17, U19 and senior teams cleared for full training and match participation. MAIN OUTCOME MEASURES: Maximum isometric hip adduction strength (Nm/kg) and provoked groin pain (NRS 0-10). RESULTS: Hip adduction strength was 16% lower in the ForceFrame. A Bland-Altman plot showed a systematic bias (-0.47 Nm/kg, 95% CI [-0.57; -0.38]) and lack of agreement (95% limits of agreement: -1.31; 0.39 Nm/kg). In the ForceFrame, provoked groin pain was less intense (median NRS 0 [IQR: 0-1] vs. 5SST: 1 [IQR: 0-3], p < 0.001) and reported by fewer players (NRS >0) (27% [n = 22] vs. 5SST: 61.4% [n = 51], p < 0.001). CONCLUSIONS: The ForceFrame and the 5SST lack agreement and are not interchangeable methods. This may have implications when selecting a method for screening and detecting early groin problems in male soccer players.