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Abstract Background Pain management is a major unmet need in people with rheumatoid arthritis (RA). Although many patients are treated with disease modifying anti-rheumatic drugs (DMARDS), including biologic therapies, many people with RA continue to experience significant pain. We aimed to determine whether performing a comprehensive pain evaluation is feasible in people with active RA receiving conventional DMARDs and biologic therapies. Methods The BIORA-PAIN feasibility study was an open-label, randomised trial, which recruited participants suitable for treatment with biologic therapy. The primary feasibility outcomes were recruitment, randomisation and retention of eligible participants. All participants underwent pain assessment for nociceptive, neuropathic and nociplastic pain during the 12-month study period, with quarterly assessments for VAS (Visual Analogue Scale) pain, painDETECT and QST (quantitative sensory testing). This trial was registered in clinicaltrials.gov NCT04255134. Results During the study period, 93 participants were screened of whom 25 were eligible: 13 were randomised to adalimumab and 12 to abatacept. Participant recruitment was lower than expected due to the COVID-19 pandemic. Pain assessments were practical in the clinical trial setting. An improvement was observed for VAS pain from baseline over 12 months, with a mean (SEM) of 3.7 (0.82) in the abatacept group and 2.3 (1.1) in the adalimumab group. There was a reduction in painDETECT and improvement in QST measures in both treatment groups during the study. Participant feedback included that some of the questionnaire-based pain assessments were lengthy and overlapped in their content. Adverse events were similar in both groups. There was one death due to COVID-19. Conclusions This first-ever feasibility study of a randomised controlled trial assessing distinct modalities of pain in RA met its progression criteria. This study demonstrates that it is feasible to recruit and assess participants with active RA for specific modalities of pain, including nociceptive, neuropathic and nociplastic elements. Our data suggests that it is possible to stratify people for RA based on pain features. The differences in pain outcomes between abatacept and adalimumab treated groups warrant further investigation. Trial registration NCT04255134, Registered on Feb 5, 2020.

BackgroundSocial media use has potential to facilitate the rapid dissemination of research evidence to busy health and social care practitioners. ObjectiveThis study aims to quantitatively synthesize evidence of the between- and within-group effectiveness of social media for dissemination of research evidence to health and social care practitioners. It also compared effectiveness between different social media platforms, formats, and strategies. MethodsWe searched electronic databases for articles in English that were published between January 1, 2010, and January 10, 2023, and that evaluated social media interventions for disseminating research evidence to qualified, postregistration health and social care practitioners in measures of reach, engagement, direct dissemination, or impact. Screening, data extraction, and risk of bias assessments were carried out by at least 2 independent reviewers. Meta-analyses of standardized pooled effects were carried out for between- and within-group effectiveness of social media and comparisons between platforms, formats, and strategies. Certainty of evidence for outcomes was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. ResultsIn total, 50 mixed-quality articles that were heterogeneous in design and outcome were included (n=9, 18% were randomized controlled trials [RCTs]). Reach (measured in number of practitioners, impressions, or post views) was reported in 26 studies. Engagement (measured in likes or post interactions) was evaluated in 21 studies. Direct dissemination (measured in link clicks, article views, downloads, or altmetric attention score) was analyzed in 23 studies (8 RCTs). Impact (measured in citations or measures of thinking and practice) was reported in 13 studies. Included studies almost universally indicated effects in favor of social media interventions, although effect sizes varied. Cumulative evidence indicated moderate certainty of large and moderate between-group effects of social media interventions on direct dissemination (standardized mean difference [SMD] 0.88; P=.02) and impact (SMD 0.76; P

BackgroundEffective dissemination of research to health and social care practitioners enhances clinical practice and evidence-based care. Social media use has potential to facilitate dissemination to busy practitioners. ObjectiveThis is a protocol for a systematic review that will quantitatively synthesize evidence of the effectiveness of social media, compared with no social media, for dissemination of research evidence to health and social care practitioners. Social media platforms, formats, and sharing mechanisms used for effective dissemination of research evidence will also be identified and compared. MethodsElectronic database searches (MEDLINE, PsycINFO, CINAHL, ERIC, LISTA, and OpenGrey) will be conducted from January 1, 2010, to January 10, 2023, for studies published in English. Randomized, nonrandomized, pre-post study designs or case studies evaluating the effect of social media on dissemination of research evidence to postregistration health and social care practitioners will be included. Studies that do not involve social media or dissemination or those that evaluate dissemination of nonresearch information (eg, multisource educational materials) to students or members of the public only, or without quantitative data on outcomes of interest, will be excluded. Screening will be carried out by 2 independent reviewers. Data extraction and quality assessment, using either the Cochrane tool for assessing risk of bias or the Newcastle-Ottawa Scale, will be completed by 2 independent reviewers. Outcomes of interest will be reported in 4 domains (reach, engagement, dissemination, and impact). Data synthesis will include quantitative comparisons using narrative text, tables, and figures. A meta-analysis of standardized pooled effects will be undertaken, and subgroup analyses will be applied, if appropriate. ResultsSearches and screening will be completed by the end of May 2023. Data extraction and analyses will be completed by the end of July 2023, after which findings will be synthesized and reported by the end of October 2023. ConclusionsThis systematic review will summarize the evidence for the effectiveness of social media for the dissemination of research evidence to health and social care practitioners. The limitations of the evidence may include multiple outcomes or methodological heterogeneity that limit meta-analyses, potential risk of bias in included studies, and potential publication bias. The limitations of the study design may include potential insensitivity of the electronic database search strategy. The findings from this review will inform the dissemination practice of health and care research. Trial RegistrationPROSPERO CRD42022378793; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=378793 International Registered Report Identifier (IRRID)DERR1-10.2196/45684

BackgroundThe mobile app market differs from country to country, and to date, no previous review of the content quality of smoking cessation apps has been conducted in France. ObjectiveThis study aimed to examine the general quality of the most popular smoking cessation apps in France and also determine the degree to which apps adhere to established behavioral and cognitive techniques (BCTs) proven effective in clinical practice. MethodsA systematic research of smoking cessation apps was conducted in both the Google Play Store and Apple Store in the French market. The general quality of popular apps was rated with the Mobile App Rating Scale (MARS), and the therapeutic quality was assessed with the ratio of adherence of the behavior change technique taxonomy for smoking cessation treatment. ResultsA total of 14 mobile apps met all the inclusion criteria of the content analysis. The interrater reliability varied from “substantial” (0.79) to “almost perfect” (0.9) for the two measures. The mean MARS score was 3.5 out of 5 (median 3.6, IQR 0.6 [3.2-3.8]). The findings suggest that popular apps focus primarily on the functionality dimension of the MARS scale (4.2/5). The mean number of BCTs was 22, with a large difference between apps (minimum 4, maximum 38). At least half of the apps addressed motivation (8.8/14, 63%) and advised on using behavioral skills in order to quit smoking or stay a nonsmoker (8.7/14, 62%). However, only a handful of apps gathered important information (5.9/14, 42%) in order to deliver proper advice regarding the use of approved medication or the implementation of behavioral techniques (4.3/14, 31%). The mean MARS score was positively correlated with the price (r=0.70, P=.007) and the number of BCTs used (r=0.67, P=.01). User rating was not correlated with any quality scale (P=.67). ConclusionsThe content quality of popular smoking cessation apps in France varied by app type and price. Most popular apps propose in general good quality content but lack implementation of evidence-based BCTs associated with effectiveness on smoking cessation treatment. Further research is needed to evaluate the improvement in the content quality of smoking cessation apps in France.

Abstract Background To explore associations between pets, and specifically dog ownership and sleep, health, exercise and neighbourhood. Methods Cross sectional examination of 6575 participants of the Whitehall II study aged between 59 and 79 years. We used self-assessed measurement scales of the Short Form (SF36), General Health Questionnaire (GHQ), Control, Autonomy, Self-realisation and Pleasure (CASP), Centre for Epidemiologic Studies Depression Scale (CES-D), sleep, exercise, and perceptions of local neighbourhood. In addition the Mini Mental State Examination which is administered to test global cognitive status (MMSE). Results We found 2/7 people owned a pet and of those 64% were “very” attached to their pet. Mild exercise in metabolic equivalents (MET-hours) was significantly higher in pet owners than non-owners (median 27.8 (IQR 18.1 to 41.8) vs 25.7 (IQR 16.8 to 38.7), p = 0.0001), and in dog owners than other pets (median 32.3 (IQR 20.8 to 46.1) vs 25.6 (IQR 16.8 to 38.5), p

Background: Child maltreatment is a substantial social problem that affects large numbers of children and young people in the UK, resulting in a range of significant short- and long-term psychosocial problems. Objectives: To synthesise evidence of the effectiveness, cost-effectiveness and acceptability of interventions addressing the adverse consequences of child maltreatment. Study design: For effectiveness, we included any controlled study. Other study designs were considered for economic decision modelling. For acceptability, we included any study that asked participants for their views. Participants: Children and young people up to 24 years 11 months, who had experienced maltreatment before the age of 17 years 11 months. Interventions: Any psychosocial intervention provided in any setting aiming to address the consequences of maltreatment. Main outcome measures: Psychological distress [particularly post-traumatic stress disorder (PTSD), depression and anxiety, and self-harm], behaviour, social functioning, quality of life and acceptability. Methods: Young Persons and Professional Advisory Groups guided the project, which was conducted in accordance with Cochrane Collaboration and NHS Centre for Reviews and Dissemination guidance. Departures from the published protocol were recorded and explained. Meta-analyses and cost-effectiveness analyses of available data were undertaken where possible. Results: We identified 198 effectiveness studies (including 62 randomised trials); six economic evaluations (five using trial data and one decision-analytic model); and 73 studies investigating treatment acceptability. Pooled data on cognitive–behavioural therapy (CBT) for sexual abuse suggested post-treatment reductions in PTSD [standardised mean difference (SMD) –0.44 (95% CI –4.43 to –1.53)], depression [mean difference –2.83 (95% CI –4.53 to –1.13)] and anxiety [SMD –0.23 (95% CI –0.03 to –0.42)]. No differences were observed for post-treatment sexualised behaviour, externalising behaviour, behaviour management skills of parents, or parental support to the child. Findings from attachment-focused interventions suggested improvements in secure attachment [odds ratio 0.14 (95% CI 0.03 to 0.70)] and reductions in disorganised behaviour [SMD 0.23 (95% CI 0.13 to 0.42)], but no differences in avoidant attachment or externalising behaviour. Few studies addressed the role of caregivers, or the impact of the therapist–child relationship. Economic evaluations suffered methodological limitations and provided conflicting results. As a result, decision-analytic modelling was not possible, but cost-effectiveness analysis using effectiveness data from meta-analyses was undertaken for the most promising intervention: CBT for sexual abuse. Analyses of the cost-effectiveness of CBT were limited by the lack of cost data beyond the cost of CBT itself. Conclusions: It is not possible to draw firm conclusions about which interventions are effective for children with different maltreatment profiles, which are of no benefit or are harmful, and which factors encourage people to seek therapy, accept the offer of therapy and actively engage with therapy. Little is known about the cost-effectiveness of alternative interventions. Limitations: Studies were largely conducted outside the UK. The heterogeneity of outcomes and measures seriously impacted on the ability to conduct meta-analyses. Future work: Studies are needed that assess the effectiveness of interventions within a UK context, which address the wider effects of maltreatment, as well as specific clinical outcomes. Study registration: This study is registered as PROSPERO CRD42013003889. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Cysticercosis is more common than usually thought. Fine needle aspiration cytology (FNAC) plays an important role in prompt recognition of this disease. Aims: To study the role of FNAC in the diagnosis of cysticercosis. Materials and Methods: Twenty-two patients with subcutaneous and intramuscular nodules, who were clinically diagnosed as tuberculous lymphadenitis, reactive lymphadenitis, lipoma, neurofibroma and cysticercosis were included in the present study. Results: In nine cases, a definitive diagnosis of cysticercosis was obtained in the form of fragments of parasite bladder wall and, biopsy confirmed the diagnosis. In the rest 13 cases, larval fragments could not be identified on the aspirates and the diagnosis of parasitic inflammation was suggested on the basis of other cytomorphological findings. Follow-up biopsy confirmed the diagnosis of cysticercosis. Conclusions: FNAC in cysticercosis is a low-cost outpatient procedure. The cytological diagnosis is quite straightforward in cases where the actual parasite structure is identified in the smears. However, in other cases, presence of eosinophils, histiocytes which may be in palisaded clusters or not, a typical granular dirty background, etc., are the features which should always alert the pathologist to this possibility.

von Recklinghausen neurofibromatosis (NF-1) is the most common inherited syndrome predisposing to neoplasia, particularly neural crest-derived tumors. However, lung malignancies reported in association with neurofibromatosis are sparse. We present a case of a 48-year-old man with NF-1 that manifested as carcinoma of lung, in order to discuss the linkage between these two entities.

Objective: The purpose of this study was to determine whether clinical, health-related quality of life (HRQL), and gait characteristics in adults with knee osteoarthritis (OA) differed by obesity category., Methods: This cross-sectional analysis of 823 older adults (mean age 64.6 years, SD 7.8 years) with knee OA and overweight or obesity compared clinical, HRQL, and gait outcomes among obesity classifications (overweight or class I, body mass index [BMI] 27.0-34.9; class II, BMI 35.0-39.9; class III BMI ≥40.0)., Results: Patients with class III obesity had worse Western Ontario McMasters Universities Arthritis Index knee pain (0-20) than the overweight or class I (mean 8.6 vs 7.0; difference 1.5; 95% confidence interval [CI] 1.0-2.1; P < 0.0001) and class II (mean 8.6 vs 7.4; difference 1.1; 95% CI 0.6-1.7; P = 0.0002) obesity groups. The Short Form 36 physical HRQL measure was lower in the class III obesity group compared to the overweight or class I (mean 31.0 vs 37.3; difference -6.2; 95% CI -7.8 to -4.7; P < 0.0001) and class II (mean 31.0 vs 35.0; difference -3.9; 95% CI -5.6 to -2.2; P < 0.0001) obesity groups. The class III obesity group had a base of support (cm) during gait that was wider than that for the overweight or class I (mean 14.0 vs 11.6; difference 3.3; 95% CI 2.6-4.0; P < 0.0001) and class II (mean 14.0 vs 11.6; difference 2.4; 95% CI 1.6-3.2; P < 0.0001) obesity groups., Conclusion: Among adults with knee OA, those with class III obesity had significantly higher pain levels and worse physical HRQL and gait characteristics compared to adults with overweight or class I or class II obesity., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

In the adult mouse testis, germ cells of various developmental cell states co-exist. FACS isolation of cells stained with the DNA dye Hoechst 33342 has been used for many years to sub-divide these cells based on their DNA content. This approach provides an efficient way to obtain broad categories of male germ cells: pre-meiotic spermatogonia, meiotic spermatocytes and post-meiotic spermatids. The addition of a red filter for Hoechst staining enables further sub-division of spermatocytes depending on sub-stages of meiotic prophase. However, separation of different stage spermatids using Hoechst staining alone is not possible. We recently reported a methodology, combining Hoechst staining with a second DNA dye (SYTO16) that enables the further separation of these cells into three sub-populations: round, early elongating, and late elongating spermatids (Gill et al., Cytometry A 101:529-536, 2022). This method makes it possible to obtain rapidly and simply pure fractions of male germ cells from multiple developental stages from the same animal., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

In mammals, the adult testis is the tissue with the highest diversity in gene expression. Much of that diversity is attributed to germ cells, primarily meiotic spermatocytes and postmeiotic haploid spermatids. Exploiting a newly developed cell purification method, we profiled the transcriptomes of such postmitotic germ cells of mice. We used a de novo transcriptome assembly approach and identified thousands of novel expressed transcripts characterized by features distinct from those of known genes. Novel loci tend to be short in length, monoexonic, and lowly expressed. Most novel genes have arisen recently in evolutionary time and possess low coding potential. Nonetheless, we identify several novel protein-coding genes harboring open reading frames that encode proteins containing matches to conserved protein domains. Analysis of mass-spectrometry data from adult mouse testes confirms protein production from several of these novel genes. We also examine overlap between transcripts and repetitive elements. We find that although distinct families of repeats are expressed with differing temporal dynamics during spermatogenesis, we do not observe a general mode of regulation wherein repeats drive expression of nonrepetitive sequences in a cell type-specific manner. Finally, we observe many fairly long antisense transcripts originating from canonical gene promoters, pointing to pervasive bidirectional promoter activity during spermatogenesis that is distinct and more frequent compared with somatic cells., (© 2023 Gill et al.; Published by Cold Spring Harbor Laboratory Press.)

Microscopy has long played a pivotal role in the field of assisted reproductive technology (ART). The advent of artificial intelligence (AI) has opened the door for new approaches to sperm and oocyte assessment and selection, with the potential for improved ART outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: It has been suggested that antenatal exposure to environmental endocrine disruptors is responsible for adverse trends in male reproductive health, including male infertility, impaired semen quality, cryptorchidism and testicular cancer, a condition known as testicular dysgenesis syndrome. Anogenital distance (AGD) is an anthropomorphic measure of antenatal exposure to endocrine disruptors, with higher exposure levels leading to shortened AGD. We hypothesized that exposure to endocrine disruptors could lead to changes in DNA methylation during early embryonic development, which could then persist in the sperm of infertile men with shortened AGD., Results: Using fluorescence activated cell sorting based on staining with either YO-PRO-1 (YOPRO) or chromomycin-3 (CMA3), we isolated four sperm fractions from eleven infertile men with short AGD and ten healthy semen donors. We examined DNA methylation in these sorted spermatozoa using reduced representation bisulfite sequencing. We found that fractions of spermatozoa from infertile men stained with CMA3 or YOPRO were more likely to contain transposable elements harboring an estrogen receptor response element (ERE). Abnormal sperm (as judged by high CMA3 or YOPRO staining) from infertile men shows substantial hypomethylation in estrogenic Alu sequences. Conversely, normal sperm fractions (as judged by low CMA3 or YO-PRO-1 staining) of either healthy donors or infertile patients were more likely to contain hypermethylated Alu sequences with ERE., Conclusions: Shortened AGD, as related to previous exposure to endocrine disruptors, and male infertility are accompanied by increased presence of hormonal response elements in the differentially methylated regulatory sequences of the genome of sperm fractions characterized by chromatin decondensation and apoptosis., (© 2022. The Author(s).)

During spermatogenesis, mammalian male germ cells undergo multiple developmental processes, including meiosis and post-meiotic differentiation (spermiogenesis). To understand the transitions between different cellular states it is essential to isolate pure populations of cells at different stages of development. Previous approaches enabled the isolation of cells from different stages of meiotic prophase I, but techniques to sub-fractionate unfixed, post-meiotic spermatids have been lacking. Here we report the development of a protocol enabling simultaneous isolation of cells at different stages of meiotic prophase and post-meiotic differentiation from testes of adult mice. This approach builds on existing fluorescence activated cell sorting protocols designed to purify cells in different stages of meiotic prophase I. By utilizing the specific spectral properties that two different DNA dyes (Hoechst 33342 and SYTO 16) exhibit when bound to chromatin of different stage male germ cells, we obtain highly pure populations of cells in relatively large numbers. This FACS protocol will enable immunocytological and molecular characterization studies of fractionated meiotic and haploid germ cells from both wild type and genetically mutant animals., (© 2022 Friedrich Miescher Institute for Biomedical Research. Cytometry Part A published by Wiley Periodicals LLC on behalf of International Society for Advancement of Cytometry.)

Lung cancer is the leading cause of cancer-related deaths. While the recent use of immune checkpoint inhibitors significantly improves patient outcomes, responsiveness remains restricted to a small proportion of patients. Conventional dendritic cells (DCs) play a major role in anticancer immunity. In mice, two subpopulations of DCs are found in the lung: DC2s (CD11b+Sirpα+) and DC1s (CD103+XCR1+), the latest specializing in the promotion of anticancer immune responses. However, the impact of lung cancer on DC populations and the consequent influence on the anticancer immune response remain poorly understood. To address this, DC populations were studied in murine models of Lewis Lung Carcinoma (LLC) and melanoma-induced lung metastasis (B16F10). We report that direct exposure to live or dead cancer cells impacts the capacity of DCs to differentiate into CD103+ DC1s, leading to profound alterations in CD103+ DC1 proportions in the lung. In addition, we observed the accumulation of CD103loCD11b+ DCs, which express DC2 markers IRF4 and Sirpα, high levels of T-cell inhibitory molecules PD-L1/2 and the regulatory molecule CD200. Finally, DC1s were injected in combination with an immune checkpoint inhibitor (anti-PD-1) in the B16F10 model of resistance to the anti-PD-1 immune checkpoint therapy; the co-injection restored sensitivity to immunotherapy. Thus, we demonstrate that lung tumor development leads to the accumulation of CD103loCD11b+ DCs with a regulatory potential combined with a reduced proportion of highly-specialized antitumor CD103+ DC1s, which could promote cancer growth. Additionally, promoting an anticancer DC signature could be an interesting therapeutic avenue to increase the efficacy of existing immune checkpoint inhibitors., Competing Interests: The authors have declared that no competing interests exist.

Gene-expression programs define shared and species-specific phenotypes, but their evolution remains largely uncharacterized beyond the transcriptome layer 1 . Here we report an analysis of the co-evolution of translatomes and transcriptomes using ribosome-profiling and matched RNA-sequencing data for three organs (brain, liver and testis) in five mammals (human, macaque, mouse, opossum and platypus) and a bird (chicken). Our within-species analyses reveal that translational regulation is widespread in the different organs, in particular across the spermatogenic cell types of the testis. The between-species divergence in gene expression is around 20% lower at the translatome layer than at the transcriptome layer owing to extensive buffering between the expression layers, which especially preserved old, essential and housekeeping genes. Translational upregulation specifically counterbalanced global dosage reductions during the evolution of sex chromosomes and the effects of meiotic sex-chromosome inactivation during spermatogenesis. Despite the overall prevalence of buffering, some genes evolved faster at the translatome layer-potentially indicating adaptive changes in expression; testis tissue shows the highest fraction of such genes. Further analyses incorporating mass spectrometry proteomics data establish that the co-evolution of transcriptomes and translatomes is reflected at the proteome layer. Together, our work uncovers co-evolutionary patterns and associated selective forces across the expression layers, and provides a resource for understanding their interplay in mammalian organs.

Chromatin integrity is essential for cellular homeostasis. Polycomb group proteins modulate chromatin states and transcriptionally repress developmental genes to maintain cell identity. They also repress repetitive sequences such as major satellites and constitute an alternative state of pericentromeric constitutive heterochromatin at paternal chromosomes (pat-PCH) in mouse pre-implantation embryos. Remarkably, pat-PCH contains the histone H3.3 variant, which is absent from canonical PCH at maternal chromosomes, which is marked by histone H3 lysine 9 trimethylation (H3K9me3), HP1, and ATRX proteins. Here, we show that SUMO2-modified CBX2-containing Polycomb Repressive Complex 1 (PRC1) recruits the H3.3-specific chaperone DAXX to pat-PCH, enabling H3.3 incorporation at these loci. Deficiency of Daxx or PRC1 components Ring1 and Rnf2 abrogates H3.3 incorporation, induces chromatin decompaction and breakage at PCH of exclusively paternal chromosomes, and causes their mis-segregation. Complementation assays show that DAXX-mediated H3.3 deposition is required for chromosome stability in early embryos. DAXX also regulates repression of PRC1 target genes during oogenesis and early embryogenesis. The study identifies a novel critical role for Polycomb in ensuring heterochromatin integrity and chromosome stability in mouse early development., (© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Adverse childhood experiences (ACEs) have deleterious effects on health across the lifespan. Educating health professionals for ACEs awareness and prevention facilitates quality care. Literature documents concept mapping as an effective teaching strategy used in health professions to stimulate learning and foster students' critical thinking. However, ACEs curricular concept mapping remains unexplored., Method: Content analysis with manifest coding was used to identify key concepts based on faculty narratives and discussion notes about ACEs content., Results: Major and minor themes emerged to support the ACEs Curricular Concept Map development with direct and indirect paths to culture of health and health equity., Conclusions: The ACEs Curricular Concept Map was developed to guide teaching ACEs knowledge in a Bachelor of Science in Nursing program. Future studies are needed to evaluate the impact of ACEs curricular concepts on nursing students' learning and graduates' ability to translate knowledge to practice ACEs awareness and prevention toward health equity for all. [J Nurs Educ. 2019;58(4):193-200.]., (Copyright 2019, SLACK Incorporated.)

Adverse childhood experiences (ACEs) devastate the lives of children, families and the community. Nearly 35 million children in the United States (US) have experienced one or more types of childhood trauma and nearly a third of youth between ages 12 and 17 have experienced two or more traumatic events. Adverse childhood experiences place an economic toll in the U.S., costing between $5.8 billion and $12.6 billion annually. Child maltreatment costs $124 billion, conservatively. Health Professionals play a major role to prevent and effectively intervene in ACEs. To this end, building a nursing workforce with necessary ACEs knowledge is critical as nursing graduates can make a sustainable impact as they translate knowledge in practice to improve health and health outcomes for children, families and communities. This paper describes how a College of Nursing initiated a systematic integration of ACEs knowledge across BSN curriculum from designing an ACEs Curriculum Integration Model, engaging and enabling faculty in the integration process and how ACEs concepts and contents were integrated. Suggestions are made for ongoing work and evaluations of the effects of ACEs curriculum integration., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The chromosomal program of meiotic prophase, comprising events such as laying down of meiotic cohesins, synapsis between homologs, and homologous recombination, must be preceded and enabled by the regulated induction of meiotic prophase genes. This gene regulatory program is poorly understood, particularly in organisms with a segregated germline. We characterized the gene regulatory program of meiotic prophase as it occurs in the mouse fetal ovary. By profiling gene expression in the mouse fetal ovary in mutants with whole tissue and single-cell techniques, we identified 104 genes expressed specifically in pre-meiotic to pachytene germ cells. We characterized the regulation of these genes by 1) retinoic acid (RA), which induces meiosis, 2) Dazl, which is required for germ cell competence to respond to RA, and 3) Stra8, a downstream target of RA required for the chromosomal program of meiotic prophase. Initial induction of practically all identified meiotic prophase genes requires Dazl. In the presence of Dazl, RA induces at least two pathways: one Stra8-independent, and one Stra8-dependent. Genes vary in their induction by Stra8, spanning fully Stra8-independent, partially Stra8-independent, and fully Stra8-dependent. Thus, Stra8 regulates the entirety of the chromosomal program but plays a more nuanced role in governing the gene expression program. We propose that Stra8-independent gene expression enables the stockpiling of selected meiotic structural proteins prior to the commencement of the chromosomal program. Unexpectedly, we discovered that Stra8 is required for prompt down-regulation of itself and Rec8. Germ cells that have expressed and down-regulated Stra8 are refractory to further Stra8 expression. Negative feedback of Stra8, and subsequent resistance to further Stra8 expression, may ensure a single, restricted pulse of Stra8 expression. Collectively, our findings reveal a gene regulatory logic by which germ cells prepare for the chromosomal program of meiotic prophase, and ensure that it is induced only once.

In all sexually reproducing organisms, cells of the germ line must transition from mitosis to meiosis. In mice, retinoic acid (RA), the extrinsic signal for meiotic initiation, activates transcription of Stra8, which is required for meiotic DNA replication and the subsequent processes of meiotic prophase. Here we report that RA also activates transcription of Rec8, which encodes a component of the cohesin complex that accumulates during meiotic S phase, and which is essential for chromosome synapsis and segregation. This RA induction of Rec8 occurs in parallel with the induction of Stra8, and independently of Stra8 function, and it is conserved between the sexes. Further, RA induction of Rec8, like that of Stra8, requires the germ-cell-intrinsic competence factor Dazl. Our findings strengthen the importance of RA and Dazl in the meiotic transition, provide important details about the Stra8 pathway, and open avenues to investigate early meiosis through analysis of Rec8 induction and function.

At fertilization, fusion of two differentiated gametes forms the zygote that is capable of forming all of the varied cell lineages of an organism. It is widely thought that the acquisition of totipotency involves extensive epigenetic reprogramming of the germline state into an embryonic state. However, recent data argue that this reprogramming is incomplete and that substantial epigenetic information passes from one generation to the next. In this review we summarize the changes in chromatin states that take place during mammalian gametogenesis and examine the evidence that early mammalian embryogenesis may be affected by inheritance of epigenetic information from the parental generation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Mir-290 through mir-295 (mir-290-295) is a mammalian-specific microRNA (miRNA) cluster that, in mice, is expressed specifically in early embryos and embryonic germ cells. Here, we show that mir-290-295 plays important roles in embryonic development as indicated by the partially penetrant lethality of mutant embryos. In addition, we show that in surviving mir-290-295-deficient embryos, female but not male fertility is compromised. This impairment in fertility arises from a defect in migrating primordial germ cells and occurs equally in male and female mutant animals. Male mir-290-295(-/-) mice, due to the extended proliferative lifespan of their germ cells, are able to recover from this initial germ cell loss and are fertile. Female mir-290-295(-/-) mice are unable to recover and are sterile, due to premature ovarian failure.

Mammalian oocytes and spermatozoa derive from fetal cells shared by the sexes. These primordial germ cells (PGCs) migrate to the developing somatic gonad, giving rise to oocytes or spermatozoa. These opposing sexual fates are determined not by the PGCs' own sex chromosome constitution (XX or XY), but by the sexual identity of the fetal gonad that they enter. We asked whether PGCs undergo a developmental transition that enables them to respond to feminizing or masculinizing cues from fetal ovary or testis. We conducted in vivo genetic studies of DAZL, an RNA-binding protein expressed in both ovarian and testicular germ cells. We found that germ cells in C57BL/6 Dazl--deficient fetuses-whether XX or XY--migrate to the gonad but do not develop either male or female features. Instead, they remain in a sexually undifferentiated state similar to that of migrating PGCs. Thus, germ cells in C57BL/6 Dazl-deficient fetuses do not respond to sexual cues from ovary or testis, whereas the earlier processes of germ cell specification and migration are unaffected. We propose that PGCs of both XX and XY fetuses undergo licensing, an active developmental transition that enables the resultant gametogenesis-competent cells to respond to feminizing or masculinizing cues produced by the fetal ovary or testis and hence to embark on oogenesis or spermatogenesis. In C57BL/6 mice, Dazl is required for licensing. Licensing serves as a gateway from the embryonic processes shared between the sexes--germ cell specification and migration--to the sex-specific pathways of oogenesis and spermatogenesis.

Retinoic acid (RA) is an essential extrinsic inducer of meiotic initiation in mammalian germ cells. However, RA acts too widely in mammalian development to account, by itself, for the cell-type and temporal specificity of meiotic initiation. We considered parallels to yeast, in which extrinsic and intrinsic factors combine to restrict meiotic initiation. We demonstrate that, in mouse embryos, extrinsic and intrinsic factors together regulate meiotic initiation. The mouse RNA-binding protein DAZL, which is expressed by postmigratory germ cells, is a key intrinsic factor, enabling those cells to initiate meiosis in response to RA. Within a brief developmental window, Dazl-expressing germ cells in both XX and XY embryos actively acquire the ability to interpret RA as a meiosis-inducing signal.

A ballast water short-time high temperature heat treatment technique was applied on board a car-carrier during a voyage from Egypt to Belgium. Ballast water from three tanks was subjected for a few seconds to temperatures ranging from 55 degrees C to 80 degrees C. The water was heated using the vessel's heat exchanger steam and a second heat exchanger was used to pre-heat and cool down the water. The treatment was effective at causing mortality of bacteria, phytoplankton and zooplankton. The International Maritime Organization (IMO) standard was not agreed before this study was carried out, but comparing our results gives a broad indication that the IMO standard would have been met in some of the tests for the zooplankton, in all the tests for the phytoplankton; and probably on most occasions for the bacteria. Passing the water through the pump increased the kill rate but increasing the temperature above 55 degrees C did not improve the heat treatment's efficacy.

A ship board trial of a deoxygenation method for treating ballast water was carried out during a voyage from Southampton (United Kingdom) to Manzanillo (Panama). A nutrient solution added to two ballast tanks encouraged bacterial growth, resulting in a gradual change to an anoxic environment. Samples were taken from two treated tanks and two untreated tanks to assess changes in the abundance and viability of zooplankton, phytoplankton and bacteria. The work was carried out before the International Maritime Organization (IMO) standard was agreed so only a broad indication of whether the results achieved the standard was given. For the zooplankton, the standard would have been achieved within 5 or 7 days but the phytoplankton results were inconclusive. The biological efficacy was the result of the combination of several factors, including the treatment, pump damage and an increase in the water temperature during the voyage.

In a controlled experiment groups of SPF Wistar rats were give 18 once-fortnightly doses of 0-5, 1-0 or 2-0 mg 3,4-benzpyrene (BP) suspended in infusine (I) or in carbon black (CB) + I by intratracheal instillation. Of rats examined post mortem, 1/16 given I+CB only, 0/16 given I only, 15/51 given BP in I+CB and 24/48 given BP in I developed squamous neoplasms of the lung. The incidence of tumours was significantly related to dose of BP. At the 1 or 2 mg dose levels BP in I only was more productive of tumours than BP in I+CB. Other changes encountered included squamous metaplasia of alveolar and bronchiolar epithelium (Sq.M), but not of bronchial epithelium, and cuboidal and columnar metaplasia of alveolar epithelium in the vicinity of terminal bronchioles (CCM). Sq.M was associated with exposure to BP or I+CB. CCM was strongly associated with exposure to I+CB but only weakly with exposure to BP.

SPF rats were exposed to the smoke from 10 cigarettes per week from the age of 10 weeks until they died. Survival, body weight, tumour incidence and histopathological appearances of the lungs were compared with those for untreated sham exposed rats. Two further groups were given a single dose of 3,4-benzyprene (BP) by intratracheal instillation. One of these was then exposed to the smoke of 10 cigarettes per week till death. Compared with untreated or sham exposed rats, exposure to smoke was associated with a significant reduction in incidence of mammary tumours. Exposure to smoke was associated with an increasing incidence of collections of macrophages laden with golden-brown pigment (GBM) and of areas of cuboidal or columnar metaplasia (CCM) or squamous metaplasia (Sq.M) of alveolar epithelium. In control rats there was virtually no GBM, a low incidence of CCM and Sq.M. Four out of 406 smoke exposed rats which came to post mortem had squamous neoplasms in the lungs, 3 having lesions of doubtful malignancy and one having a squamous carcinoma. In contrast, no squamous neoplasms were seen in 197 control rats. This difference was not statistically significant. The findings in rats given a single dose of BP were, in all the above respects, similar to those in untreated rats, except that one developed a squamous carcinoma of the lung. The effects of a single dose of BP followed by smoke exposure were in general similar to those of smoke exposure only. Three rats on this treatment regimen developed squamous cancers of the lung. None of the treatments increased the incidence of adenomata of the lungs. The results are discussed in relation to other studies of the effects of smoke exposure on rats and other species.

In a controlled experiment, 6 groups of SPF rats were given cigarette smoke condensate (SWS) in solid form without a vehicle once fortnightly by intratracheal instillation, at 3 dose levels with or without additional exposure to the vapour phase of smoke (VP) from 10 plain cigarettes each week. Treatment continued for life. Six other groups were similarly treated with one of 3 fractions of condensate with or without VP. Exposure to VP was associated with a significant reduction in body weight, but not signficantly with the incidence or severity of any observed pathological change in the lungs. A significant dose-related assoication was seen between SWS or its fractions and the incidence and degree of chronic respiratory disease (CRD), cuboidal or columnar metaplasia (CCM) and squamous metaplasia of alveolar epithelium (Sq.M) produced. No neoplasms, however, were elicited. A significant correlation was found between the degrees of CCM and of Sq.M produced in the 24 groups exposed to SWS or fractions. The results are discussed in the light of studies in which rats were exposed to tobacco smoke by inhalation and of studies in which the same condensate and fractions were applied to mouse skin.

The repeated intratracheal instillation of cigarette smoke condensate (SWS) in rats at close to maximum tolerated dose levels failed to induce squamous neoplasms in the lungs although such treatment was associated with an increased incidence of cuboidal/columnar metaplasia (CCM) and squamous metaplasia (Sq.M) of alveolar epithelium. With one exception, various fractions of SWS had no effect on lung tumour incidence though some were more effective than SWS in increasing the incidence of CCM and Sq.M. The exceptional fraction, Fraction P, which contains most of the polycyclic aromatic hydrocarbons of smoke and is the most effective of the fractions tested in producing tumours in mouse skin, gave rise to 4 squamous tumours of doubtful malignancy and one metastasizing squanmous carcinoma among 3 groups of 18 animals exposed at 3 different dose levels. The results are discussed in relation to the possible development of a method for comparing condensates for relative lung carcinogenicity.