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2.
Nat Commun ; 15(1): 5984, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39013946

RESUMO

Houseflies provide a good experimental model to study the initial evolutionary stages of a primary sex-determining locus because they possess different recently evolved proto-Y chromosomes that contain male-determining loci (M) with the same male-determining gene, Mdmd. We investigate M-loci genomically and cytogenetically revealing distinct molecular architectures among M-loci. M on chromosome V (MV) has two intact Mdmd copies in a palindrome. M on chromosome III (MIII) has tandem duplications containing 88 Mdmd copies (only one intact) and various repeats, including repeats that are XY-prevalent. M on chromosome II (MII) and the Y (MY) share MIII-like architecture, but with fewer repeats. MY additionally shares MV-specific sequence arrangements. Based on these data and karyograms using two probes, one derives from MIII and one Mdmd-specific, we infer evolutionary histories of polymorphic M-loci, which have arisen from unique translocations of Mdmd, embedded in larger DNA fragments, and diverged independently into regions of varying complexity.


Assuntos
Evolução Molecular , Moscas Domésticas , Animais , Masculino , Moscas Domésticas/genética , Cromossomo Y/genética , Processos de Determinação Sexual/genética , Cromossomos de Insetos/genética , Loci Gênicos , Feminino
3.
iScience ; 27(6): 109707, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38832018

RESUMO

In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12high) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2highSAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis.

4.
Horm Res Paediatr ; 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38861933

RESUMO

The 49th Annual Conference of the International Society of Pediatric and Adolescent Diabetes (ISPAD), held from October 18 to 21, 2023, in Rotterdam, Netherlands, showcased significant advancements and diversity in paediatric and adolescent diabetes research and clinical innovations. The conference, renowned for its global impact, brought together experts to discuss cutting-edge developments in the field. Highlights from the plenary sessions included ground-breaking research on immunotherapies and diabetes technologies and offering new insights into personalised treatment approaches. Keynote speakers emphasised the importance of early diagnosis, prevention and the potential of novel biomarkers in predicting disease progression. The symposia covered a broad spectrum of topics, from advancements in continuous glucose monitoring technologies to the latest in hybrid closed loop systems which promise to revolutionise diabetes management for young patients.

5.
Biostatistics ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38887902

RESUMO

Although transcriptomics data is typically used to analyze mature spliced mRNA, recent attention has focused on jointly investigating spliced and unspliced (or precursor-) mRNA, which can be used to study gene regulation and changes in gene expression production. Nonetheless, most methods for spliced/unspliced inference (such as RNA velocity tools) focus on individual samples, and rarely allow comparisons between groups of samples (e.g. healthy vs. diseased). Furthermore, this kind of inference is challenging, because spliced and unspliced mRNA abundance is characterized by a high degree of quantification uncertainty, due to the prevalence of multi-mapping reads, ie reads compatible with multiple transcripts (or genes), and/or with both their spliced and unspliced versions. Here, we present DifferentialRegulation, a Bayesian hierarchical method to discover changes between experimental conditions with respect to the relative abundance of unspliced mRNA (over the total mRNA). We model the quantification uncertainty via a latent variable approach, where reads are allocated to their gene/transcript of origin, and to the respective splice version. We designed several benchmarks where our approach shows good performance, in terms of sensitivity and error control, vs. state-of-the-art competitors. Importantly, our tool is flexible, and works with both bulk and single-cell RNA-sequencing data. DifferentialRegulation is distributed as a Bioconductor R package.

6.
PLoS Comput Biol ; 20(6): e1012174, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38900718

RESUMO

Computational biologists are frequently engaged in collaborative data analysis with wet lab researchers. These interdisciplinary projects, as necessary as they are to the scientific endeavor, can be surprisingly challenging due to cultural differences in operations and values. In this Ten Simple Rules guide, we aim to help dry lab researchers identify sources of friction and provide actionable tools to facilitate respectful, open, transparent, and rewarding collaborations.


Assuntos
Biologia Computacional , Comportamento Cooperativo , Pesquisadores , Humanos
7.
J Cell Physiol ; 2024 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-38764354

RESUMO

The tumor suppressor p14/19ARF regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). However, the role played by TTF1 in regulating the rRNA genes and in potentially controlling growth has remained unclear. We now show that TTF1 expression regulates cell growth by determining the cellular complement of ribosomes. Unexpectedly, it achieves this by acting as a "roadblock" to synthesis of the noncoding LncRNA and pRNA that we show are generated from the "Spacer Promoter" duplications present upstream of the 47S pre-rRNA promoter on the mouse and human ribosomal RNA genes. Unexpectedly, the endogenous generation of these noncoding RNAs does not induce CpG methylation or gene silencing. Rather, it acts in cis to suppress 47S preinitiation complex formation and hence de novo pre-rRNA synthesis by a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from p19ARF to cell growth suppression via the regulation of ribosome biogenesis by noncoding RNAs and validate a key cellular growth law in mammalian cells.

8.
Artigo em Inglês | MEDLINE | ID: mdl-38771897

RESUMO

The purpose of this article is to report a rare case of isolated superior ophthalmic vein thrombosis. A 74-year-old female presented to the emergency department with a sudden onset of eye pain and bulging. Ophthalmological examination was remarkable for proptosis and ptosis with chemosis of the OS. Neuroimaging demonstrated an isolated superior ophthalmic vein thrombosis secondary to presumed thrombosis of the superior vein varix. Hypercoagulable, infectious, and autoimmune lab workups were unremarkable. The patient was initiated on anticoagulation with the eventual resolution of her symptoms. Isolated superior ophthalmic vein thrombosis is an uncommon diagnosis that requires urgent evaluation to prevent vision loss. Risk factors are multifactorial with infectious being the most common etiology. Our case is unique in that there was no identifiable risk factor.

9.
Addiction ; 119(8): 1378-1386, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38685192

RESUMO

BACKGROUND AND AIMS: On 1 May 2018, Scotland introduced minimum unit pricing (MUP), a strength-based floor price below which alcohol cannot be sold, throughout all alcoholic beverages. The legislation necessitates an evaluation of its impact across a range of outcomes that will inform whether MUP will continue beyond its sixth year. We measured the impact of MUP on per-adult alcohol sales (as a proxy for consumption) after 3 years of implementation. DESIGN, SETTING AND PARTICIPANTS: Controlled interrupted time-series regression was used to assess the impact of MUP on alcohol sales in Scotland after 3 years of implementation, with England and Wales (EW) being the control group. In adjusted analyses, we included household disposable income, on-trade alcohol sales (in off-trade analyses) and substitution between drink categories (in drink category analyses) as covariates. MEASUREMENTS: Weekly data were assessed on the volume of pure alcohol sold in Scotland and EW between January 2013 and May 2021, expressed as litres of pure alcohol per adult. The impact of MUP on total (on- and off-trade combined), off-trade and on-trade alcohol sales was assessed separately. RESULTS: The introduction of MUP in Scotland was associated with a 3.0% (95% confidence interval = 1.8-4.2%) net reduction in total alcohol sales per adult after adjustment for the best available geographical control, disposable income and substitution. This reflects a 1.1% fall in Scotland in contrast to a 2.4% increase in EW. The reduction in total alcohol sales in Scotland was driven by reduced sales of beer, spirits, cider and perry. The reduction in total sales was due to reductions in sales of alcohol through the off-trade. There was no evidence of any change in on-trade alcohol sales. CONCLUSION: Minimum unit pricing has been effective in reducing population-level alcohol sales in Scotland in the 3 years since implementation.


Assuntos
Consumo de Bebidas Alcoólicas , Bebidas Alcoólicas , Comércio , Custos e Análise de Custo , Análise de Séries Temporais Interrompida , Escócia , Bebidas Alcoólicas/economia , Humanos , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/economia , Inglaterra , País de Gales
10.
bioRxiv ; 2024 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-38496482

RESUMO

ATAC-seq has emerged as a rich epigenome profiling technique, and is commonly used to identify Transcription Factors (TFs) underlying given phenomena. A number of methods can be used to identify differentially-active TFs through the accessibility of their DNA-binding motif, however little is known on the best approaches for doing so. Here we benchmark several such methods using a combination of curated datasets with various forms of short-term perturbations on known TFs, as well as semi-simulations. We include both methods specifically designed for this type of data as well as some that can be repurposed for it. We also investigate variations to these methods, and identify three particularly promising approaches (chromVAR-limma with critical adjustments, monaLisa and a combination of GC smooth quantile normalization and multivariate modeling). We further investigate the specific use of nucleosome-free fragments, the combination of top methods, and the impact of technical variation. Finally, we illustrate the use of the top methods on a novel dataset to characterize the impact on DNA accessibility of TRAnscription Factor TArgeting Chimeras (TRAFTAC), which can deplete TFs - in our case NFkB - at the protein level.

11.
Bone Joint J ; 106-B(2): 144-150, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38425304

RESUMO

Aims: The aim of this study was to determine both the incidence of, and the reoperation rate for, postoperative periprosthetic femoral fracture (POPFF) after total hip arthroplasty (THA) with either a collared cementless (CC) femoral component or a cemented polished taper-slip (PTS) femoral component. Methods: We performed a retrospective review of a consecutive series of 11,018 THAs over a ten-year period. All POPFFs were identified using regional radiograph archiving and electronic care systems. Results: A total of 11,018 THAs were implanted: 4,952 CC femoral components and 6,066 cemented PTS femoral components. Between groups, age, sex, and BMI did not differ. Overall, 91 patients (0.8%) sustained a POPFF. For all patients with a POPFF, 16.5% (15/91) were managed conservatively, 67.0% (61/91) underwent open reduction and internal fixation (ORIF), and 16.5% (15/91) underwent revision. The CC group had a lower POPFF rate compared to the PTS group (0.7% (36/4,952) vs 0.9% (55/6,066); p = 0.345). Fewer POPFFs in the CC group required surgery (0.4% (22/4,952) vs 0.9% (54/6,066); p = 0.005). Fewer POPFFs required surgery in males with a CC than males with a PTS (0.3% (7/2,121) vs 1.3% (36/2,674); p < 0.001). Conclusion: Male patients with a PTS femoral component were five times more likely to have a reoperation for POPFF. Female patients had the same incidence of reoperation with either component type. Of those having a reoperation, 80.3% (61/76) had an ORIF, which could greatly mask the size of this problem in many registries.


Assuntos
Artroplastia de Quadril , Prótese de Quadril , Fraturas Periprotéticas , Humanos , Masculino , Feminino , Artroplastia de Quadril/efeitos adversos , Fraturas Periprotéticas/epidemiologia , Fraturas Periprotéticas/etiologia , Fraturas Periprotéticas/cirurgia , Prótese de Quadril/efeitos adversos , Reoperação/efeitos adversos , Fatores de Risco , Desenho de Prótese , Cimentos Ósseos , Estudos Retrospectivos
12.
J Biomech ; 166: 112044, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38461742

RESUMO

Low-cost and field-viable methods that can simultaneously assess external kinetics and kinematics are necessary to enhance field-based biomechanical monitoring. The aim of this study was to determine the accuracy and usability of ground reaction force (GRF) profiles estimated from segmental kinematics, measured with OpenCap (a low-cost markerless motion-capture system), during common jumping movements. Full-body segmental kinematics were recorded for fifteen recreational athletes performing countermovement, squat, bilateral drop, and unilateral drop jumps, and used to estimate vertical GRFs with a mechanics-based method. Eleven distinct performance-, fatigue-, or injury-related GRF variables were then validated against a gold-standard force platform. Across jumping movements, a total of six and three GRF variables were estimated with a bias or limits of agreement <5 % respectively. Bias and limits of agreement were between 5 and 15 % for seventeen and nineteen variables respectively. Moreover, we show that estimated force variables with a bias <15 % can adequately assess the within-athlete changes in GRF variables between jumping conditions (arm swing or leg dominance). These findings indicate that using a low-cost and field-viable markerless motion capture system (OpenCap) to estimate and assess GRF profiles during common jumping movements is approaching acceptable limits of accuracy. The presented method can be used to monitor force variables of interest and examine underlying segmental kinematics. This application is a jump towards researchers and sports practitioners performing biomechanical monitoring of jumping efficiently, regularly, and extensively in field settings.


Assuntos
Fenômenos Mecânicos , Esportes , Humanos , Fenômenos Biomecânicos , Movimento , Postura
13.
J Exp Med ; 221(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38442272

RESUMO

Meningeal lymphatic vessels (MLVs) promote tissue clearance and immune surveillance in the central nervous system (CNS). Vascular endothelial growth factor-C (VEGF-C) regulates MLV development and maintenance and has therapeutic potential for treating neurological disorders. Herein, we investigated the effects of VEGF-C overexpression on brain fluid drainage and ischemic stroke outcomes in mice. Intracerebrospinal administration of an adeno-associated virus expressing mouse full-length VEGF-C (AAV-mVEGF-C) increased CSF drainage to the deep cervical lymph nodes (dCLNs) by enhancing lymphatic growth and upregulated neuroprotective signaling pathways identified by single nuclei RNA sequencing of brain cells. In a mouse model of ischemic stroke, AAV-mVEGF-C pretreatment reduced stroke injury and ameliorated motor performances in the subacute stage, associated with mitigated microglia-mediated inflammation and increased BDNF signaling in brain cells. Neuroprotective effects of VEGF-C were lost upon cauterization of the dCLN afferent lymphatics and not mimicked by acute post-stroke VEGF-C injection. We conclude that VEGF-C prophylaxis promotes multiple vascular, immune, and neural responses that culminate in a protection against neurological damage in acute ischemic stroke.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Animais , Camundongos , Fator C de Crescimento do Endotélio Vascular , Doenças Neuroinflamatórias , Drenagem
14.
Autism ; : 13623613231222656, 2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38311602

RESUMO

LAY ABSTRACT: Although research has the potential to improve autistic people's lives, lots of funding goes towards research looking at topics which autistic people say has little impact in their everyday lives. Autistic people's lives can be different depending on where they live, and Scotland is a unique country in many ways. We wanted to find out which topics autistic people in Scotland want to see research on. Our team of autistic and non-autistic researchers (including university-based and community researchers) created a survey where 225 autistic adults rated and ranked the importance of possible research topics and shared their thoughts on what topics mattered to them. The five most important topics were mental health and well-being, identifying and diagnosing autistic people, support services (including healthcare and social care), non-autistic people's knowledge and attitudes and issues impacting autistic women. The three least important topics were genetics or biological aspects of autism, autism treatments/interventions and causes of autism. Our findings indicate that autistic people in Scotland want research to focus on things that matter to their day-to-day lives. Also, the Scottish government says they will be listening to autistic people in their latest policy plans, and we believe that considering autistic people's research priorities is an important part of this. Our findings also add to growing calls for change to happen in how and what autism researchers do research on.

15.
Nature ; 626(8001): 1073-1083, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38355792

RESUMO

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies1, which involve human-specific mechanisms2-5 that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors6. Single-cell transcriptomics and comparison to independent neural stem cells7 showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids8. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3' untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.


Assuntos
Esclerose Lateral Amiotrófica , Proteína C-Reativa , Proteínas de Ligação a DNA , Degeneração Lobar Frontotemporal , Rede Nervosa , Proteínas do Tecido Nervoso , Neurônios , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteína C-Reativa/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Neuroglia/citologia , Neurônios/citologia , Neurônios/metabolismo , Reprodutibilidade dos Testes
16.
Artigo em Inglês | MEDLINE | ID: mdl-38361362

RESUMO

ISSUE ADDRESSED: Most food and nutrition programs cease within 2 years. Understanding the determinants of program sustainability is crucial to maximise output from funding, whilst allowing sufficient time for program benefits to be achieved. This study applied the Consolidated Framework for Implementation Research (CFIR) to map the barriers and enablers of successful long-term implementation of school-based nutrition and food programs. METHODS: Qualitative methods with purposive and snowball sampling were used to recruit experts who were identified as being influential in implementing and sustaining long-term (>2 years) school-based food and nutrition programs. Semi-structured interviews with global experts were conducted, transcribed verbatim and coded deductively (by applying the CFIR constructs) and inductively when required. Thematic analysis informed the development of themes. RESULTS: Interviews were conducted with 11 experts including researchers, government employees, and a consultant of an international agency, from seven countries. Forty-eight deductive codes and eight inductive codes identified six main themes: (1) funding and integrity of its source; (2) political landscape; (3) nutrition policies and their monitoring; (4) involvement of community actors; (5) adaptability of the program and (6) effective program evaluation. Themes related mainly to the 'outer setting' domain of the CFIR. CONCLUSIONS: The CFIR highlighted pertinent factors that influence the successful long-term implementation of school-based food and nutrition programs. SO WHAT?: The findings suggest that to sustain program implementation beyond its initial funding, relationships across government departments, local organisations and communities, need to be nurtured and prioritised from the outset.

17.
Br J Haematol ; 204(3): 945-958, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38296260

RESUMO

EVI1 expression is associated with poor prognosis in myeloid leukaemia, which can result from Chr.3q alterations that juxtapose enhancers to induce EVI1 expression via long-range chromatin interactions. More often, however, EVI1 expression occurs unrelated to 3q alterations, and it remained unclear if, in these cases, EVI1 expression is similarly caused by aberrant enhancer activation. Here, we report that, in EVI1+3q- myeloid leukaemia cells, the EVI1 promoter interacts via long-range chromatin interactions with promoters of distally located, active genes, rather than with enhancer elements. Unlike in 3q+ cells, EVI1 expression and long-range interactions appear to not depend on CTCF/cohesin, though EVI1+3q- cells utilise an EVI1 promoter-proximal site to enhance its expression that is also involved in CTCF-mediated looping in 3q+ cells. Long-range interactions in 3q- cells connect EVI1 to promoters of multiple genes, whose transcription correlates with EVI1 in EVI1+3q- cell lines, suggesting a shared mechanism of transcriptional regulation. In line with this, CRISPR interference-induced silencing of two of these sites minimally, but consistently reduced EVI1 expression. Together, we provide novel evidence of features associated with EVI1 expression in 3q- leukaemia and consolidate the view that EVI1 in 3q- leukaemia is largely promoter-driven, potentially involving long-distance promoter clustering.


Assuntos
Leucemia Mieloide , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Proteínas de Ligação a DNA/genética , Cromatina , Proteína do Locus do Complexo MDS1 e EVI1/genética , Leucemia Mieloide/genética , Proto-Oncogenes
18.
Bioinformatics ; 40(2)2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38243704

RESUMO

MOTIVATION: Spatially resolved transcriptomics (SRT) enables scientists to investigate spatial context of mRNA abundance, including identifying spatially variable genes (SVGs), i.e. genes whose expression varies across the tissue. Although several methods have been proposed for this task, native SVG tools cannot jointly model biological replicates, or identify the key areas of the tissue affected by spatial variability. RESULTS: Here, we introduce DESpace, a framework, based on an original application of existing methods, to discover SVGs. In particular, our approach inputs all types of SRT data, summarizes spatial information via spatial clusters, and identifies spatially variable genes by performing differential gene expression testing between clusters. Furthermore, our framework can identify (and test) the main cluster of the tissue affected by spatial variability; this allows scientists to investigate spatial expression changes in specific areas of interest. Additionally, DESpace enables joint modeling of multiple samples (i.e. biological replicates); compared to inference based on individual samples, this approach increases statistical power, and targets SVGs with consistent spatial patterns across replicates. Overall, in our benchmarks, DESpace displays good true positive rates, controls for false positive and false discovery rates, and is computationally efficient. AVAILABILITY AND IMPLEMENTATION: DESpace is freely distributed as a Bioconductor R package at https://bioconductor.org/packages/DESpace.


Assuntos
Perfilação da Expressão Gênica , Software , Perfilação da Expressão Gênica/métodos , Benchmarking , Transcriptoma
19.
bioRxiv ; 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37090609

RESUMO

Defects in blood development frequently occur among syndromic congenital anomalies. Thrombocytopenia-Absent Radius (TAR) syndrome is a rare congenital condition with reduced platelets (hypomegakaryocytic thrombocytopenia) and forelimb anomalies, concurrent with more variable heart and kidney defects. TAR syndrome associates with hypomorphic gene function for RBM8A/Y14 that encodes a component of the exon junction complex involved in mRNA splicing, transport, and nonsense-mediated decay. How perturbing a general mRNA-processing factor causes the selective TAR Syndrome phenotypes remains unknown. Here, we connect zebrafish rbm8a perturbation to early hematopoietic defects via attenuated non-canonical Wnt/Planar Cell Polarity (PCP) signaling that controls developmental cell re-arrangements. In hypomorphic rbm8a zebrafish, we observe a significant reduction of cd41-positive thrombocytes. rbm8a-mutant zebrafish embryos accumulate mRNAs with individual retained introns, a hallmark of defective nonsense-mediated decay; affected mRNAs include transcripts for non-canonical Wnt/PCP pathway components. We establish that rbm8a-mutant embryos show convergent extension defects and that reduced rbm8a function interacts with perturbations in non-canonical Wnt/PCP pathway genes wnt5b, wnt11f2, fzd7a, and vangl2. Using live-imaging, we found reduced rbm8a function impairs the architecture of the lateral plate mesoderm (LPM) that forms hematopoietic, cardiovascular, kidney, and forelimb skeleton progenitors as affected in TAR Syndrome. Both mutants for rbm8a and for the PCP gene vangl2 feature impaired expression of early hematopoietic/endothelial genes including runx1 and the megakaryocyte regulator gfi1aa. Together, our data propose aberrant LPM patterning and hematopoietic defects as consequence of attenuated non-canonical Wnt/PCP signaling upon reduced rbm8a function. These results also link TAR Syndrome to a potential LPM origin and a developmental mechanism.

20.
Clin Exp Immunol ; 215(2): 177-189, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-37917972

RESUMO

Patients with decompensated liver cirrhosis, in particular those classified as Childs-Pugh class C, are at increased risk of severe coronavirus disease-2019 (COVID-19) upon infection with severe acute respiratory coronavirus 2 (SARS-CoV-2). The biological mechanisms underlying this are unknown. We aimed to examine the levels of serum intrinsic antiviral proteins as well as alterations in the innate antiviral immune response in patients with decompensated liver cirrhosis. Serum from 53 SARS-CoV-2 unexposed and unvaccinated individuals, with decompensated liver cirrhosis undergoing assessment for liver transplantation, were screened using SARS-CoV-2 pseudoparticle and SARS-CoV-2 virus assays. The ability of serum to inhibit interferon (IFN) signalling was assessed using a cell-based reporter assay. Severity of liver disease was assessed using two clinical scoring systems, the Child-Pugh class and the MELD-Na score. In the presence of serum from SARS-CoV-2 unexposed patients with decompensated liver cirrhosis there was no association between SARS-CoV-2 pseudoparticle infection or live SARS-CoV-2 virus infection and severity of liver disease. Type I IFNs are a key component of the innate antiviral response. Serum from patients with decompensated liver cirrhosis contained elevated levels of auto-antibodies capable of binding IFN-α2b compared to healthy controls. High MELD-Na scores were associated with the ability of these auto-antibodies to neutralize type I IFN signalling by IFN-α2b but not IFN-ß1a. Our results demonstrate that neutralizing auto-antibodies targeting IFN-α2b are increased in patients with high MELD-Na scores. The presence of neutralizing type I IFN-specific auto-antibodies may increase the likelihood of viral infections, including severe COVID-19, in patients with decompensated liver cirrhosis.


Assuntos
COVID-19 , Interferon Tipo I , Hepatopatias , Transplante de Fígado , Humanos , Anticorpos , Cirrose Hepática
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