Introduction
Despite the propagation of virtual mental health services for vulnerable groups during COVID-19 pandemic, the implementation and evaluation of remote evidence-based practices (EBP) to ...manage them in low- and middle-income countries remains scarce. In the current study, we describe and evaluate the implementation process and clinical impact of brief, remote, manualized EBP for crisis intervention and suicide risk management among healthcare workers attending patients with COVID-19 (COVID-19-HCWs) in Mexico.
Methods
The implementation process comprised community engagement of volunteer mental health specialists, creation of new clinical teams with different disciplines and skills, intervention systematization through manuals and education through 4-h remote training as main strategies. Mexican COVID-19-HCWs who had used a free 24-h helpline rated their pre- and post-intervention emotional distress. Therapists recorded patients’ pre-intervention diagnosis, severity, and suicide risk, the techniques used in each case, and their post-treatment perception of COVID-19-HCWs’ improvement at the end of the intervention.
Results
All techniques included in the intervention manual were employed at least in one case (
n
= 51). At the beginning of the intervention, 65.9% of the COVID-19-HCWs were considered moderately ill or worse according to Clinical Global Impression-Severity (CGI-S) scores, whereas at the end, 79.4% of them were perceived as much or very much improved according to CGI-Improvement scores (CGI-I), and their emotional distress had been significantly reduced (
p
< 0.001).
Discussion
This prospective study provides evidence that implementation of remote EBP is feasible and useful to reduce emotional distress and suicide risk among COVID-19-HCWs from a middle-income country. However, this study was limited by lack of a control group, improvement ratings provided by therapists and non-anonymous satisfaction ratings.
In COVID‐19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre‐existing autoimmune conditions can therefore be at increased risk of severe COVID‐19 and/or ...associated sequelae, yet SARS‐CoV‐2 infection in this group has been little studied. Here, we performed single‐cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS‐CoV‐2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell–cell communication that substantially shape the immune response under SARS‐CoV‐2 infection. While enrichment of HLA‐DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type‐I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS‐CoV‐2 in patients with pre‐existing autoimmunity, highlighting important considerations for disease treatment and follow‐up.
Patients with autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) display diverging and aberrant immune responses to SARS‐CoV‐2 infection, including widespread alterations in immune cell composition and T‐cell clonal expansion as well as in gene expression patterns, transcription factor activity, and cell–cell communication.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete ...genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients.
The RNA polymerase II-associated protein 1 (RPAP1) is conserved across metazoa and required for stem cell differentiation in plants; however, very little is known about its mechanism of action or its ...role in mammalian cells. Here, we report that RPAP1 is essential for the expression of cell identity genes and for cell viability. Depletion of RPAP1 triggers cell de-differentiation, facilitates reprogramming toward pluripotency, and impairs differentiation. Mechanistically, we show that RPAP1 is essential for the interaction between RNA polymerase II (RNA Pol II) and Mediator, as well as for the recruitment of important regulators, such as the Mediator-specific RNA Pol II factor Gdown1 and the C-terminal domain (CTD) phosphatase RPAP2. In agreement, depletion of RPAP1 diminishes the loading of total and Ser5-phosphorylated RNA Pol II on many genes, with super-enhancer-driven genes among the most significantly downregulated. We conclude that Mediator/RPAP1/RNA Pol II is an ancient module, conserved from plants to mammals, critical for establishing and maintaining cell identity.
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•RPAP1 is an RNA Pol II regulator, conserved from plants to mammals•RPAP1 depletion erases cell identity gene expression, triggering de-differentiation•Mechanistically, RPAP1 is critical for the Mediator-RNA Pol II interaction•RPAP1 preferentially contributes to enhancer-driven gene transcription
Lynch et al. report a regulator of RNA Pol II called RPAP1, displaying functional conservation from plants to mammals. RPAP1 is required to establish and maintain cell identity. Mechanistically, RPAP1 is critical for the Mediator-RNA Pol II interaction, thereby preserving normal transcription at enhancer-driven genes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
STUDY QUESTION
Does endometrium harbour functionally active microorganisms and whether the microbial composition differs between proliferative and mid-secretory phases?
SUMMARY ANSWER
...Endometrium harbours functionally alive microorganisms including bacteria, viruses, archaea and fungi whose composition and metabolic functions change along the menstrual cycle.
WHAT IS KNOWN ALREADY
Resident microbes in the endometrium have been detected, where microbial dysfunction has been associated with reproductive health and disease. Nevertheless, the core microorganismal composition in healthy endometrium is not determined and whether the identified bacterial DNA sequences refer to alive/functionally active microbes is not clear. Furthermore, whether there are cyclical changes in the microbial composition remains an open issue.
STUDY DESIGN, SIZE, DURATION
RNA sequencing (RNAseq) data from 14 endometrial paired samples from healthy women, 7 samples from the mid-secretory phase and 7 samples from the consecutive proliferative phase were analysed for the microbial RNA sequences.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The raw RNAseq data were converted into FASTQ format using SRA Toolkit. The unmapped reads to human sequences were aligned to the reference database Kraken2 and visualised with Krona software. Menstrual phase taxonomic differences were performed by R package metagenomeSeq. The functional analysis of endometrial microbiota was obtained with HUMANn2 and the comparison between menstrual phases was conducted by one-way ANOVA. Human RNAseq analysis was performed using miARma-Seq and the functional enrichment analysis was carried out using gene set enrichment analysis (GSEA; HumanCyc). The integration of metabolic pathways between host and microbes was investigated. The developed method of active microbiota mapping was validated in independent sample set.
MAIN RESULTS AND THE ROLE OF CHANCE
With the novel metatranscriptomic approach, we mapped the entire alive microbiota composing of >5300 microorganisms within the endometrium of healthy women. Microbes such as bacteria, fungi, viruses and archaea were identified. The validation of three independent endometrial samples from different ethnicity confirmed the findings. Significant differences in the microbial abundances in the mid-secretory vs. proliferative phases were detected with possible metabolic activity in the host-microbiota crosstalk in receptive phase endometrium, specifically in the prostanoid biosynthesis pathway and L-tryptophan metabolism.
LARGE SCALE DATA
The raw RNAseq data used in the current study are available at GEO GSE86491 and at BioProject PRJNA379542.
LIMITATIONS, REASONS FOR CAUTION
These pioneering results should be confirmed in a bigger sample size.
WIDER IMPLICATIONS OF THE FINDINGS
Our study confirms the presence of active microbes, bacteria, fungi, viruses and archaea in the healthy human endometrium with implications in receptive phase endometrial functions, meaning that microbial dysfunction could impair the metabolic pathways important for endometrial receptivity. The results of this study contribute to the better understanding of endometrial microbiota composition in healthy women and its possible role in endometrial functions. In addition, our novel methodological pipeline for analysing alive microbes with transcriptional and metabolic activities could serve to inspire new analysis approaches in reproductive medicine.
STUDY FUNDING/COMPETING INTERESTS
This work is supported by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO) and European Regional Development Fund (FEDER): grants RYC-2016-21199 and ENDORE SAF2017-87526-R; FEDER/Junta de Andalucía-Consejería de Economía y Conocimiento: MENDO (B-CTS-500-UGR18) and by the University of Granada Plan Propio de Investigación 2016 - Excellence actions: Unit of Excellence on Exercise and Health (UCEES) (SOMM17/6107/UGR). A.S.-L. and N.M.M. are funded by the Spanish Ministry of Science, Innovation and Universities (PRE2018-0854409 and FPU19/01638). S.A. has received honoraria for lectures from Merck. The funder had no role in this study.
Prp40 and early events in splice site definition Becerra, Soraya; Andrés-León, Eduardo; Prieto-Sánchez, Silvia ...
Wiley interdisciplinary reviews. RNA,
01/2016, Volume:
7, Issue:
1
Journal Article
Peer reviewed
The alternative splicing (AS) of precursor messenger RNA (pre‐mRNA) is a tightly regulated process through which introns are removed to leave the resulting exons in the mRNA appropriately aligned and ...ligated. The AS of pre‐mRNA is a key mechanism for increasing the complexity of proteins encoded in the genome. In humans, more than 90% of genes undergo AS, underscoring the importance of this process in RNA biogenesis. As such, AS misregulation underlies multiple human diseases. The splicing reaction is catalyzed by the spliceosome, a highly dynamic complex that assembles at or near the intron/exon boundaries and undergoes sequential conformational and compositional changes during splicing. The initial recognition of splice sites defines the exons that are going to be removed, which is a critical step in the highly regulated splicing process. Although the available lines of evidence are increasing, the molecular mechanisms governing AS, including the initial interactions occurring at intron/exon boundaries, and the factors that modulate these critical connections by functioning as a scaffold for active‐site RNAs or proteins, remain poorly understood. In this review, we summarize the major hallmarks of the initial steps in the splicing process and the role of auxiliary factors that contribute to the assembly of the spliceosomal complex. We also discuss the role of the essential yeast Prp40 protein and its mammalian homologs in the specificity of this pre‐mRNA processing event. In addition, we provide the first exhaustive phylogenetic analysis of the molecular evolution of Prp40 family members. WIREs RNA 2016, 7:17–32. doi: 10.1002/wrna.1312
This article is categorized under:
RNA Processing > Splicing Mechanisms
RNA Processing > Splicing Regulation/Alternative Splicing
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The absence of the mouse cell surface receptor CD38 in
mice suggests that this receptor acts as a positive regulator of inflammatory and autoimmune responses. Here, we report that, in the context of ...the chronic graft-
-host disease (cGVHD) lupus inducible model, the transfer of B6.C-H2bm12/KhEg(bm12) spleen cells into co-isogenic
B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells, and T-bet
CD11c
B cells, were observed in
mice than in WT mice, while the expansion of Treg cells and Tfr cells was normal, suggesting that the ability of
B cells to respond to allogeneic help from bm12 CD4
T cells is greatly diminished. The frequencies of T-bet
CD11c
B cells, which are considered the precursors of the autoantibody-secreting cells, correlate with anti-ssDNA autoantibody serum levels, IL-27, and sCD40L. Proteomics profiling of the spleens from WT cGVHD mice reflects a STAT1-driven type I IFN signature, which is absent in
cGVHD mice. Kidney, spleen, and liver inflammation was mild and resolved faster in
cGVHD mice than in WT cGVHD mice. We conclude that CD38 in B cells functions as a modulator receptor that controls autoimmune responses.
Cancer is a complex disease in which unrestrained cell proliferation results in tumour development. Extensive research into the molecular mechanisms underlying tumorigenesis has led to the ...characterization of oncogenes and tumour suppressors that are key elements in cancer growth and progression, as well as that of other important elements like microRNAs. These genes and miRNAs appear to be constitutively deregulated in cancer. To identify signatures of miRNA-mRNA interactions potentially conserved in essential cancer pathways, we have conducted an integrative analysis of transcriptomic data, also taking into account methylation and copy number alterations. We analysed 18,605 raw transcriptome samples from The Cancer Genome Atlas covering 15 of the most common types of human tumours. From this global transcriptome study, we recovered known cancer-associated miRNA-targets and importantly, we identified new potential targets from miRNA families, also analysing the phenotypic outcomes of these genes/mRNAs in terms of survival. Further analyses could lead to novel approaches in cancer therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The identification of novel biomarkers for early breast cancer detection would be a great advance. Because of their role in tumorigenesis and stability in body fluids, microRNAs (miRNAs) are emerging ...as a promising diagnostic tool. Our aim was to identify miRNAs deregulated in breast tumors and evaluate the potential of circulating miRNAs in breast cancer detection.
We conducted miRNA expression profiling of 1919 human miRNAs in paraffin-embedded tissue from 122 breast tumors and 11 healthy breast tissue samples. Differential expression analysis was performed, and a microarray classifier was generated. The most relevant miRNAs were analyzed in plasma from 26 healthy individuals and 83 patients with breast cancer (36 before and 47 after treatment) and validated in 116 healthy individuals and 114 patients before treatment.
We identified a large number of miRNAs deregulated in breast cancer and generated a 25-miRNA microarray classifier that discriminated breast tumors with high diagnostic sensitivity and specificity. Ten miRNAs were selected for further investigation, of which 4 (miR-505-5p, miR-125b-5p, miR-21-5p, and miR-96-5p) were significantly overexpressed in pretreated patients with breast cancer compared with healthy individuals in 2 different series of plasma. MiR-505-5p and miR-96-5p were the most valuable biomarkers (area under the curve 0.72). Moreover, the expression levels of miR-3656, miR-505-5p, and miR-21-5p were decreased in a group of treated patients.
Circulating miRNAs reflect the presence of breast tumors. The identification of deregulated miRNAs in plasma of patients with breast cancer supports the use of circulating miRNAs as a method for early breast cancer detection.
Large-scale RNAseq has substantially changed the transcriptomics field, as it enables an unprecedented amount of high resolution data to be acquired. However, the analysis of these data still poses a ...challenge to the research community. Many tools have been developed to overcome this problem, and to facilitate the study of miRNA expression profiles and those of their target genes. While a few of these enable both kinds of analysis to be performed, they also present certain limitations in terms of their requirements and/or the restrictions on data uploading. To avoid these restraints, we have developed a suite that offers the identification of miRNA, mRNA and circRNAs that can be applied to any sequenced organism. Additionally, it enables differential expression, miRNA-mRNA target prediction and/or functional analysis. The miARma-Seq pipeline is presented as a stand-alone tool that is both easy to install and flexible in terms of its use, and that brings together well-established software in a single bundle. Our suite can analyze a large number of samples due to its multithread design. By testing miARma-Seq in validated datasets, we demonstrate here the benefits that can be gained from this tool by making it readily accessible to the research community.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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