The cycling and aging mouse female reproductive tract at single-cell resolution.

The female reproductive tract (FRT) undergoes extensive remodeling during reproductive cycling. This recurrent remodeling and how it shapes organ-specific aging remains poorly explored. Using single-cell and spatial transcriptomics, we systematically characterized morphological and gene expression changes occurring in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrous cycle, during decidualization, and into aging. These analyses reveal that fibroblasts play central-and highly organ-specific-roles in FRT remodeling by orchestrating extracellular matrix (ECM) reorganization and inflammation. Our results suggest a model wherein recurrent FRT remodeling over reproductive lifespan drives the gradual, age-related development of fibrosis and chronic inflammation. This hypothesis was directly tested using chemical ablation of cycling, which reduced fibrotic accumulation during aging. Our atlas provides extensive detail into how estrus, pregnancy, and aging shape the organs of the female reproductive tract and reveals the unexpected cost of the recurrent remodeling required for reproduction.

Bioactive Bismuth Compounds: Is Their Toxicity a Barrier to Therapeutic Use?

Bismuth compounds are considered relatively non-toxic, with their low solubility in aqueous solutions (e.g., biological fluids) being the major contributing factor to this property. Bismuth derivatives are widely used for the treatment of peptic ulcers, functional dyspepsia, and chronic gastritis. Moreover, the properties of bismuth compounds have also been extensively explored in two main fields of action: antimicrobial and anticancer. Despite the clinical interest of bismuth-based drugs, several side effects have also been reported. In fact, excessive acute ingestion of bismuth, or abuse for an extended period of time, can lead to toxicity. However, evidence has demonstrated that the discontinuation of these compounds usually reverses their toxic effects. Notwithstanding, the continuously growing use of bismuth products suggests that it is indeed part of our environment and our daily lives, which urges a more in-depth review and investigation into its possible undesired activities. Therefore, this review aims to update the pharmaco-toxicological properties of bismuth compounds. A special focus will be given to in vitro, in vivo, and clinical studies exploring their toxicity.

Clonal heterogeneity in ER+ breast cancer reveals the proteasome and PKC as potential therapeutic targets.

Intratumoral heterogeneity impacts the success or failure of anti-cancer therapies. Here, we investigated the evolution and mechanistic heterogeneity in clonal populations of cell models for estrogen receptor positive breast cancer. To this end, we established barcoded models of luminal breast cancer and rendered them resistant to commonly applied first line endocrine therapies. By isolating single clones from the resistant cell pools and characterizing replicates of individual clones we observed inter- (between cell lines) and intra-tumor (between different clones from the same cell line) heterogeneity. Molecular characterization at RNA and phospho-proteomic levels revealed private clonal activation of the unfolded protein response and respective sensitivity to inhibition of the proteasome, and potentially shared sensitivities for repression of protein kinase C. Our in vitro findings are consistent with tumor-heterogeneity that is observed in breast cancer patients thus highlighting the need to uncover heterogeneity at an individual patient level and to adjust therapies accordingly.

Do mammals have menopause?

Semantics and lack of data have clouded our understanding about menopause in non-human mammals. The traditional definition of menopause based on the last menstrual bleed is limited and hinders cross-species comparison. Here, we redefine it as the permanent cessation of ovulation and show menopause to be widespread across mammalian orders.

Chylothorax associated with pulmonary compressive atelectasis in an emperor tamarin (Saguinus imperator).

Chylothorax is the accumulation of lymph in the thoracic cavity, and it has never been reported in neotropical primates. An emperor tamarin died and at necropsy chylothorax associated with pulmonary compressive atelectasis was diagnosed. Idiopathic chylothorax can be a cause of respiratory insufficiency and death in tamarins.

Low level of antioxidant capacity biomarkers but not target overexpression predicts vulnerability to ROS-inducing drugs.

Despite a strong rationale for why cancer cells are susceptible to redox-targeting drugs, such drugs often face tumor resistance or dose-limiting toxicity in preclinical and clinical studies. An important reason is the lack of specific biomarkers to better select susceptible cancer entities and stratify patients. Using a large panel of lung cancer cell lines, we identified a set of "antioxidant-capacity" biomarkers (ACB), which were tightly repressed, partly by STAT3 and STAT5A/B in sensitive cells, rendering them susceptible to multiple redox-targeting and ferroptosis-inducing drugs. Contrary to expectation, constitutively low ACB expression was not associated with an increased steady state level of reactive oxygen species (ROS) but a high level of nitric oxide, which is required to sustain high replication rates. Using ACBs, we identified cancer entities with a high percentage of patients with favorable ACB expression pattern, making it likely that more responders to ROS-inducing drugs could be stratified for clinical trials.

Adherence to the CONSORT statement of randomized clinical trials on ART restorations in children: current status and reporting characteristics.

Appropriate research reports are important to facilitate the evaluation of studies and the decision-making by dentists and policymakers. This meta-research study assessed the conformity of randomized clinical trials (RCTs) on atraumatic restorative treatment (ART) restorations with the CONSORT recommendations and their risk of bias (RoB). Cochrane Library, MEDLINE, BBO, LILACS, Scopus, and Web of Science databases were searched from April 2019 to June 2021 for RCTs that assessed the longevity of ART restorations in children. A specific tool was used to assess adherence to the CONSORT recommendations; RoB was evaluated with the Cochrane risk-of-bias tool. Descriptive analyses included the number of studies by journal, follow-up period, country, and quality assessments. A total of 2,181 papers were retrieved and 36 of them were analyzed qualitatively. The overall CONSORT mean score (CONms) was 22.52 ± 6.17 out of 32 points. The best described items were intervention and outcomes, whereas allocation concealment was described in only 22% of the papers. Significant differences in CONms were detected in the analysis by country and publication dates. High CONms were observed in recently published papers (26.7 ± 3.1) when compared to first ART studies (18.1 ± 4.6; p < 0.001). RoB was low in four studies, unclear in 11, and high in 21. Adherence of the papers to the CONSORT recommendations was not fully achieved and most of the papers had unclear and high RoB (PROSPERO registration #CRD42020201460).

Adherence to the CONSORT statement of randomized clinical trials on ART restorations in children: current status and reporting characteristics

Abstract: Appropriate research reports are important to facilitate the evaluation of studies and the decision-making by dentists and policymakers. This meta-research study assessed the conformity of randomized clinical trials (RCTs) on atraumatic restorative treatment (ART) restorations with the CONSORT recommendations and their risk of bias (RoB). Cochrane Library, MEDLINE, BBO, LILACS, Scopus, and Web of Science databases were searched from April 2019 to June 2021 for RCTs that assessed the longevity of ART restorations in children. A specific tool was used to assess adherence to the CONSORT recommendations; RoB was evaluated with the Cochrane risk-of-bias tool. Descriptive analyses included the number of studies by journal, follow-up period, country, and quality assessments. A total of 2,181 papers were retrieved and 36 of them were analyzed qualitatively. The overall CONSORT mean score (CONms) was 22.52 ± 6.17 out of 32 points. The best described items were intervention and outcomes, whereas allocation concealment was described in only 22% of the papers. Significant differences in CONms were detected in the analysis by country and publication dates. High CONms were observed in recently published papers (26.7 ± 3.1) when compared to first ART studies (18.1 ± 4.6; p < 0.001). RoB was low in four studies, unclear in 11, and high in 21. Adherence of the papers to the CONSORT recommendations was not fully achieved and most of the papers had unclear and high RoB (PROSPERO registration #CRD42020201460).

Signatures of TSPAN8 variants associated with human metabolic regulation and diseases.

Here, with the example of common copy number variation (CNV) in the TSPAN8 gene, we present an important piece of work in the field of CNV detection, that is, CNV association with complex human traits such as 1H NMR metabolomic phenotypes and an example of functional characterization of CNVs among human induced pluripotent stem cells (HipSci). We report TSPAN8 exon 11 (ENSE00003720745) as a pleiotropic locus associated with metabolomic regulation and show that its biology is associated with several metabolic diseases such as type 2 diabetes (T2D) and cancer. Our results further demonstrate the power of multivariate association models over univariate methods and define metabolomic signatures for variants in TSPAN8.

Fast identification of differential distributions in single-cell RNA-sequencing data with waddR.

MOTIVATION: Single-cell gene expression distributions measured by single-cell RNA-sequencing (scRNA-seq) often display complex differences between samples. These differences are biologically meaningful but cannot be identified using standard methods for differential expression. RESULTS: Here, we derive and implement a flexible and fast differential distribution testing procedure based on the 2-Wasserstein distance. Our method is able to detect any type of difference in distribution between conditions. To interpret distributional differences, we decompose the 2-Wasserstein distance into terms that capture the relative contribution of changes in mean, variance and shape to the overall difference. Finally, we derive mathematical generalizations that allow our method to be used in a broad range of disciplines other than scRNA-seq or bioinformatics. AVAILABILITY AND IMPLEMENTATION: Our methods are implemented in the R/Bioconductor package waddR, which is freely available at https://github.com/goncalves-lab/waddR, along with documentation and examples. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Quality of Work Life and Contribution to Productivity: Assessing the Moderator Effects of Burnout Syndrome.

This study is focused on assessing the effects of burnout as a moderator of the relationship between employees' quality of work life (QWL) and their perceptions of their contribution to the organization's productivity by integrating the QWL factors into the trichotomy of (de)motivators of productivity in the workplace. The empirical findings resulting from an OLS multiple regression, with interaction terms, applied to a survey administered at 514 employees in 6 European countries, point out two important insights: (i) QWL hygiene factors (e.g., safe work environment and occupational healthcare) positively and significantly influence the contribution to productivity; and (ii) burnout de-motivator factors (that is, low effectiveness, cynicism, and emotional exhaustion) significantly moderate the relationship between QWL and the contribution to productivity. Combining burnout with other QWL components, such as occupational health, safe work, and appropriate salary, new insights are provided concerning the restricting (i.e., low effectiveness and cynicism) and catalyzing (emotional exhaustion) burnout components of contribution to productivity. These findings are particularly relevant given the increased weight of burnout, mental disorders and absenteeism in the labor market, affecting individuals' quality of life and organizations' performance and costs.

Quality of Work Life and Organizational Performance: Workers' Feelings of Contributing, or Not, to the Organization's Productivity.

This is a pioneering study on the relationship between quality of work life and the employee's perception of their contribution to organizational performance. It unveils the importance of subjective and behavioral components of quality of work life and their influence on the formation of the collaborator's individual desire to contribute to strengthening the organization's productivity. The results obtained indicate that for workers: feeling their supervisors' support through listening to their concerns and by sensing they take them on board; being integrated in a good work environment; and feeling respected both as professionals and as people; positively influence their feeling of contributing to organizational performance. The results are particularly relevant given the increased weight of services in the labor market, together with intensified automation and digitalization of collaborators' functions. The findings also contribute to the ongoing debate about the need for more work on the subjective and behavioral components of so-called smart and learning organizations, rather than focusing exclusively on remuneration as the factor stimulating organizational productivity based on the collaborator's contribution.

Publisher Correction: Molecular and functional variation in iPSC-derived sensory neurons.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single-cell reconstruction of the early maternal-fetal interface in humans.

During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success.

Prevalência de depressão e fatores associados em mulheres atendidas pela Estratégia de Saúde da Família / Prevalence of depression and associated factors in women covered by Family Health Strategy

RESUMO Objetivo Avaliar a prevalência de depressão e os fatores associados em mulheres de 20 a 59 anos de áreas cobertas pela Estratégia de Saúde da Família de município da Zona da Mata Mineira. Métodos Trata-se de um estudo transversal, com mulheres de 20 a 59 anos cadastradas em duas Unidades de Saúde da Família, que utilizou um questionário contendo variáveis sociodemográficas, apoio social, autoavaliação de estado de saúde, estilo de vida, morbidade e saúde da mulher. O desfecho depressão foi avaliado segundo o Patients Health Questionnaire-9 (PHQ-9). Resultados Das 1.958 mulheres incluídas nesta análise, 28,5% encontram-se na faixa etária entre 30 e 39 anos; 15,4% não concluíram o ensino elementar; 54,5% não trabalham ou nunca trabalharam; 44,2% declararam não ser da raça branca. Fatores associados à ocorrência de depressão na população estudada: possuir baixa escolaridade, trabalhar atualmente e ter doença mental prévia. Como fatores de proteção observaram-se: ser casada ou viver com companheiro, realizar atividades físicas regularmente e relatar autoavaliação positiva de saúde. Conclusão Os resultados deste estudo revelam prevalência de depressão de 19,7% nas mulheres de 20 a 59 anos de áreas cobertas pela Estratégia de Saúde da Família, apontando para a necessidade de um cuidado especial na atenção primária à saúde às mulheres com baixa escolaridade, que trabalham, apresentam doença mental e não praticam exercícios físicos, de modo que se possa reduzir o sofrimento e promover a saúde. Ressalta-se a lacuna na utilização de instrumentos de rastreamento dos casos de depressão na atenção primária.

ABSTRACT Objective To assess the prevalence of depression and its associated factors in women aged 20 to 59 years at some areas with the coverage of Family Health Strategy in a city located at Zona da Mata Mineira. Methods It is a cross-sectional study with women aged 20-59 enrolled in two Primary Health Care Units making use of a questionnaire containing socio-demographic variables, social support, self-assessment of general health status, lifestyle, morbidity and women's health. Depression was evaluated according to Patients Health Questionnaire-9 (PHQ-9). Results From 1,958 women included in this analysis, 28,5% are aged 30-39; 15,4% did not finish High School; 54,5% do not work or have never worked and 44,2% defined themselves as not white. Factors associated with depression episodes in the population studied: lower educational background, currently having a job, previous diagnosis of psychiatric disorders. Protective factors which were observed: being married or living with a partner, practicing physical activities in a regular basis and reporting positive self-assessed health. Conclusion The results of this study reveal a prevalence of depression of 19.7% in women aged 20 to 59 years covered by the Family Health Strategy, pointing to the need for special care in primary health care for women with low schooling, who work, have mental illness, and do not exercise so that they can reduce suffering and promote health. It was observed a significant gap related to managing specific tools designed to screening depressive episodes in primary care.

Molecular and functional variation in iPSC-derived sensory neurons.

Induced pluripotent stem cells (iPSCs), and cells derived from them, have become key tools for modeling biological processes, particularly in cell types that are difficult to obtain from living donors. Here we present a map of regulatory variants in iPSC-derived neurons, based on 123 differentiations of iPSCs to a sensory neuronal fate. Gene expression was more variable across cultures than in primary dorsal root ganglion, particularly for genes related to nervous system development. Using single-cell RNA-sequencing, we found that the number of neuronal versus contaminating cells was influenced by iPSC culture conditions before differentiation. Despite high differentiation-induced variability, our allele-specific method detected thousands of quantitative trait loci (QTLs) that influenced gene expression, chromatin accessibility, and RNA splicing. On the basis of these detected QTLs, we estimate that recall-by-genotype studies that use iPSC-derived cells will require cells from at least 20-80 individuals to detect the effects of regulatory variants with moderately large effect sizes.

Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs.

This corrects the article DOI: 10.1038/nature22403.

Common genetic variation drives molecular heterogeneity in human iPSCs.

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Regulatory Divergence of Transcript Isoforms in a Mammalian Model System.

Phenotypic differences between species are driven by changes in gene expression and, by extension, by modifications in the regulation of the transcriptome. Investigation of mammalian transcriptome divergence has been restricted to analysis of bulk gene expression levels and gene-internal splicing. Using allele-specific expression analysis in inter-strain hybrids of Mus musculus, we determined the contribution of multiple cellular regulatory systems to transcriptome divergence, including: alternative promoter usage, transcription start site selection, cassette exon usage, alternative last exon usage, and alternative polyadenylation site choice. Between mouse strains, a fifth of genes have variations in isoform usage that contribute to transcriptomic changes, half of which alter encoded amino acid sequence. Virtually all divergence in isoform usage altered the post-transcriptional regulatory instructions in gene UTRs. Furthermore, most genes with isoform differences between strains contain changes originating from multiple regulatory systems. This result indicates widespread cross-talk and coordination exists among different regulatory systems. Overall, isoform usage diverges in parallel with and independently to gene expression evolution, and the cis and trans regulatory contribution to each differs significantly.

Fgf and Esrrb integrate epigenetic and transcriptional networks that regulate self-renewal of trophoblast stem cells.

Esrrb (oestrogen-related receptor beta) is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome using mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.