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Many tissue-specific adult stem cell lineages maintain a balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase Set1 regulates early-stage male germ cells in Drosophila. Early-stage germline-specific knockdown of Set1 results in temporally progressive defects, arising as germ cell loss and developing into overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage non-cell-autonomously. Additionally, wild-type Set1, but not the catalytically inactive Set1, rescues the Set1 knockdown phenotypes, highlighting the functional importance of the methyltransferase activity of Set1. Further, RNA-sequencing experiments reveal key signaling pathway components, such as the JAK-STAT pathway gene Stat92E and the BMP pathway gene Mad, which are upregulated upon Set1 knockdown. Genetic interaction assays support the functional relationships between Set1 and JAK-STAT or BMP pathways, as both Stat92E and Mad mutations suppress the Set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The phenotype of germ cell loss followed by over-proliferation when inhibiting a histone methyltransferase also raises concerns about using their inhibitors in cancer therapy.
Sujet(s)
Différenciation cellulaire , Protéines de Drosophila , Drosophila melanogaster , Cellules germinales , Histone-lysine N-methyltransferase , Transduction du signal , Animaux , Mâle , Différenciation cellulaire/génétique , Protéines de Drosophila/métabolisme , Protéines de Drosophila/génétique , Transduction du signal/génétique , Histone-lysine N-methyltransferase/métabolisme , Histone-lysine N-methyltransferase/génétique , Cellules germinales/métabolisme , Cellules germinales/cytologie , Drosophila melanogaster/métabolisme , Drosophila melanogaster/génétique , Cellules souches/métabolisme , Cellules souches/cytologie , Facteurs de transcription STAT/métabolisme , Facteurs de transcription STAT/génétique , Janus kinases/métabolisme , Janus kinases/génétique , Prolifération cellulaire/génétique , Lignage cellulaire/génétique , Régulation de l'expression des gènes au cours du développementRÉSUMÉ
Aneuploidy is nearly ubiquitous in tumor genomes, but the role of aneuploidy in the early stages of cancer evolution remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigated how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Previous work implicated p53 activation as a downstream response to aneuploidy induction. We found that simple aneuploidy, characterized by 1-3 gained or lost chromosomes, resulted in little or modest p53 activation and cell cycle arrest when compared with more complex aneuploid cells. Single-cell RNA sequencing analysis revealed that the degree of p53 activation was strongly correlated with karyotype complexity. Single-cell tracking showed that cells could continue to divide despite the observation of one to a few lagging chromosomes. Unexpectedly, colonoids with simple aneuploidy exhibited impaired differentiation after niche factor withdrawal. These findings demonstrate that simple aneuploid cells can escape p53 surveillance and may contribute to niche factor-independent growth of cancer-initiating colon stem cells.
Sujet(s)
Aneuploïdie , Différenciation cellulaire , Prolifération cellulaire , Organoïdes , Protéine p53 suppresseur de tumeur , Humains , Protéine p53 suppresseur de tumeur/métabolisme , Protéine p53 suppresseur de tumeur/génétique , Organoïdes/métabolisme , Côlon/métabolisme , Intestins , Cellules souches tumorales/métabolisme , Cellules souches tumorales/anatomopathologie , Points de contrôle du cycle cellulaire/génétique , Transformation cellulaire néoplasique/génétiqueRÉSUMÉ
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.
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Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI). Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r < -0.5), 27 were consistently not associated with age (height in children), sex or race. Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.
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Many cell types come from tissue-specific adult stem cells that maintain the balance between proliferation and differentiation. Here, we study how the H3K4me3 methyltransferase, Set1, regulates early-stage male germ cell proliferation and differentiation in Drosophila. Early-stage germline-specific knockdown of set1 results in a temporally progressed defects, arising as germ cell loss and developing to overpopulated early-stage germ cells. These germline defects also impact the niche architecture and cyst stem cell lineage in a non-cell-autonomous manner. Additionally, wild-type Set1, but not the catalytically inactive Set1, could rescue the set1 knockdown phenotypes, highlighting the functional importance of the methyl-transferase activity of the Set1 enzyme. Further, RNA-seq experiments reveal key signaling pathway components, such as the JAK-STAT pathway gene stat92E and the BMP pathway gene mad, that are upregulated upon set1 knockdown. Genetic interaction assays support the functional relationships between set1 and JAK-STAT or BMP pathways, as mutations of both the stat92E and mad genes suppress the set1 knockdown phenotypes. These findings enhance our understanding of the balance between proliferation and differentiation in an adult stem cell lineage. The germ cell loss followed by over-proliferation phenotypes when inhibiting a histone methyl-transferase raise concerns about using their inhibitors in cancer therapy.
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Population-based association studies have identified many genetic risk loci for coronary artery disease (CAD), but it is often unclear how genes within these loci are linked to CAD. Here, we perform interaction proteomics for 11 CAD-risk genes to map their protein-protein interactions (PPIs) in human vascular cells and elucidate their roles in CAD. The resulting PPI networks contain interactions that are outside of known biology in the vasculature and are enriched for genes involved in immunity-related and arterial-wall-specific mechanisms. Several PPI networks derived from smooth muscle cells are significantly enriched for genetic variants associated with CAD and related vascular phenotypes. Furthermore, the networks identify 61 genes that are found in genetic loci associated with risk of CAD, prioritizing them as the causal candidates within these loci. These findings indicate that the PPI networks we have generated are a rich resource for guiding future research into the molecular pathogenesis of CAD.
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Maladie des artères coronaires , Humains , Maladie des artères coronaires/génétique , Cartes d'interactions protéiques , Réseaux de régulation génique , Locus génétiques , ProtéomiqueRÉSUMÉ
Schlemm's canal (SC) is central in intraocular pressure regulation but requires much characterization. It has distinct inner and outer walls, each composed of Schlemm's canal endothelial cells (SECs) with different morphologies and functions. Recent transcriptomic studies of the anterior segment added important knowledge, but were limited in power by SEC numbers or did not focus on SC. To gain a more comprehensive understanding of SC biology, we performed bulk RNA sequencing on C57BL/6J SC, blood vessel, and lymphatic endothelial cells from limbal tissue (~4500 SECs). We also analyzed mouse limbal tissues by single-cell and single-nucleus RNA sequencing (C57BL/6J and 129/Sj strains), successfully sequencing 903 individual SECs. Together, these datasets confirm that SC has molecular characteristics of both blood and lymphatic endothelia with a lymphatic phenotype predominating. SECs are enriched in pathways that regulate cell-cell junction formation pointing to the importance of junctions in determining SC fluid permeability. Importantly, and for the first time, our analyses characterize 3 molecular classes of SECs, molecularly distinguishing inner wall from outer wall SECs and discovering two inner wall cell states that likely result from local environmental differences. Further, and based on ligand and receptor expression patterns, we document key interactions between SECs and cells of the adjacent trabecular meshwork (TM) drainage tissue. Also, we present cell type expression for a collection of human glaucoma genes. These data provide a new molecular foundation that will enable the functional dissection of key homeostatic processes mediated by SECs as well as the development of new glaucoma therapeutics.
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BACKGROUND AND PURPOSE: Vertebral compression fracture represents a major health burden for the aging populations globally. However, limited studies exist on the relative efficacy and safety of surgical interventions for vertebral compression fracture. Here, we aim to compare clinical and patient-reported outcomes following vertebral augmentation using balloon kyphoplasty, vertebroplasty, and SpineJack vertebral implant. MATERIALS AND METHODS: An institutional review board-approved, retrospective, multi-institutional review of patients undergoing vertebral augmentation with kyphoplasty, vertebroplasty, and/or a SpineJack vertebral implant was performed between 2018 and 2021. Primary outcomes included pre- and postprocedural pain ratings and vertebral body height restoration. The secondary outcome was a change in the local kyphotic angle. The Kruskal-Wallis test was used to compare outcomes across 3 treatment options. Complications were reviewed during and 30-90 days after the procedure. RESULTS: Vertebral augmentation of 344 vertebral compression fracture levels was performed during the study period. Sixty-seven patients had 79 kyphoplasty procedures (55% women; mean age, 64.2 [SD, 12.3] years). Seventy-four patients underwent a mean of 84 vertebroplasty procedures (51% women; mean age, 63.5 [SD, 12.8] years), and 61 patients had a mean of 67 SpineJack vertebral implant procedures (57.4% women; mean age, 68.3 [SD, 10.6] years). Following kyphoplasty, vertebroplasty, and SpineJack vertebral implant, pain scores improved significantly (P < .001). Resting pain improvement was similar across the 3 procedures, whereas improvement of "worst pain" was significantly better following a SpineJack vertebral implant compared with kyphoplasty and vertebroplasty (P < .001). Patients with a SpineJack vertebral implant had greater improvement in vertebral body height restoration and local kyphotic angle compared with those undergoing kyphoplasty and vertebroplasty. Adjacent level fractures (6.7% incidence) occurred similarly in the 3 procedure types. There were no other peri- or postoperative complications. CONCLUSIONS: The SpineJack vertebral implant showed equivalent pain improvement compared with vertebroplasty and kyphoplasty, but it had superior vertebral body height restoration and local kyphotic angle improvement. This study supports the SpineJack vertebral implant as a safe and effective alternative (adjunct) for vertebral augmentation, especially in patients with moderate-to-severe vertebral compression fractures for greater improvement in vertebral body height restoration.
Sujet(s)
Fractures par compression , Cyphoplastie , Fractures ostéoporotiques , Fractures du rachis , Vertébroplastie , Humains , Femelle , Adulte d'âge moyen , Sujet âgé , Mâle , Cyphoplastie/méthodes , Fractures par compression/imagerie diagnostique , Fractures par compression/chirurgie , Fractures du rachis/imagerie diagnostique , Fractures du rachis/chirurgie , Fractures du rachis/complications , Études rétrospectives , Résultat thérapeutique , Ciments osseux/usage thérapeutique , Vertébroplastie/méthodes , Douleur/traitement médicamenteux , Douleur/étiologie , Fractures ostéoporotiques/chirurgieRÉSUMÉ
Aneuploidy, a near ubiquitous genetic feature of tumors, is a context-dependent driver of cancer evolution; however, the mechanistic basis of this role remains unclear. Here, by inducing heterogeneous aneuploidy in non-transformed human colon organoids (colonoids), we investigate how the effects of aneuploidy on cell growth and differentiation may promote malignant transformation. Single-cell RNA sequencing reveals that the gene expression signature across over 100 unique aneuploid karyotypes is enriched with p53 responsive genes. The primary driver of p53 activation is karyotype complexity. Complex aneuploid cells with multiple unbalanced chromosomes activate p53 and undergo G1 cell-cycle arrest, independent of DNA damage and without evidence of senescence. By contrast, simple aneuploid cells with 1-3 chromosomes gained or lost continue to proliferate, demonstrated by single cell tracking in colonoids. Notably, simple aneuploid cells exhibit impaired differentiation when niche factors are withdrawn. These findings suggest that while complex aneuploid cells are eliminated from the normal epithelium due to p53 activation, simple aneuploid cells can escape this checkpoint and may contribute to niche factor-independent growth of cancer-initiating cells.
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Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.
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Regulatory T cells (Treg) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating Treg (TIL-Treg) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific Treg derived from a murine tumor model. We identified 10 subsets of human TIL-Treg, most of which have high concordance with murine TIL-Treg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in Treg suppression, including LAG3. Functionally, the OX40hiGITRhi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-Treg correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-Treg-expressing T cell receptors that are specific for TAA fully develop a distinct TH1-like signature over a 2-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression of TBX21 (Tbet), IFNG, and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific TH1-like Treg subset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1-responding tumors. These findings demonstrate that TIL-Treg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-Treg may positively contribute to antitumor responses.
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Carcinome pulmonaire non à petites cellules , Tumeurs du poumon , Humains , Animaux , Souris , Tumeurs du poumon/génétique , Granzymes , Transduction du signal , Analyse sur cellule uniqueRÉSUMÉ
MOTIVATION: Single-cell sequencing technology has become a routine in studying many biological problems. A core step of analyzing single-cell data is the assignment of cell clusters to specific cell types. Reference-based methods are proposed for predicting cell types for single-cell clusters. However, the scalability and lack of preprocessed reference datasets prevent them from being practical and easy to use. RESULTS: Here, we introduce a reference-based cell annotation web server, CellAnn, which is super-fast and easy to use. CellAnn contains a comprehensive reference database with 204 human and 191 mouse single-cell datasets. These reference datasets cover 32 organs. Furthermore, we developed a cluster-to-cluster alignment method to transfer cell labels from the reference to the query datasets, which is superior to the existing methods with higher accuracy and higher scalability. Finally, CellAnn is an online tool that integrates all the procedures in cell annotation, including reference searching, transferring cell labels, visualizing results, and harmonizing cell annotation labels. Through the user-friendly interface, users can identify the best annotation by cross-validating with multiple reference datasets. We believe that CellAnn can greatly facilitate single-cell sequencing data analysis. AVAILABILITY AND IMPLEMENTATION: The web server is available at www.cellann.io, and the source code is available at https://github.com/Pinlyu3/CellAnn_shinyapp.
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Ordinateurs , Logiciel , Humains , Animaux , Souris , Bases de données factuelles , Analyse sur cellule uniqueRÉSUMÉ
Genome-wide association studies (GWASs) are a valuable tool for understanding the biology of complex human traits and diseases, but associated variants rarely point directly to causal genes. In the present study, we introduce a new method, polygenic priority score (PoPS), that learns trait-relevant gene features, such as cell-type-specific expression, to prioritize genes at GWAS loci. Using a large evaluation set of genes with fine-mapped coding variants, we show that PoPS and the closest gene individually outperform other gene prioritization methods, but observe the best overall performance by combining PoPS with orthogonal methods. Using this combined approach, we prioritize 10,642 unique gene-trait pairs across 113 complex traits and diseases with high precision, finding not only well-established gene-trait relationships but nominating new genes at unresolved loci, such as LGR4 for estimated glomerular filtration rate and CCR7 for deep vein thrombosis. Overall, we demonstrate that PoPS provides a powerful addition to the gene prioritization toolbox.
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Hérédité multifactorielle , Locus de caractère quantitatif , Humains , Hérédité multifactorielle/génétique , Locus de caractère quantitatif/génétique , Étude d'association pangénomique/méthodes , Prédisposition génétique à une maladie/génétique , Phénotype , Polymorphisme de nucléotide simple/génétiqueRÉSUMÉ
Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.
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The impact of genome organization on the control of gene expression persists as a major challenge in regulatory biology. Most efforts have focused on the role of CTCF-enriched boundary elements and TADs, which enable long-range DNA-DNA associations via loop extrusion processes. However, there is increasing evidence for long-range chromatin loops between promoters and distal enhancers formed through specific DNA sequences, including tethering elements, which bind the GAGA-associated factor (GAF). Previous studies showed that GAF possesses amyloid properties in vitro, bridging separate DNA molecules. In this study, we investigated whether GAF functions as a looping factor in Drosophila development. We employed Micro-C assays to examine the impact of defined GAF mutants on genome topology. These studies suggest that the N-terminal POZ/BTB oligomerization domain is important for long-range associations of distant GAGA-rich tethering elements, particularly those responsible for promoter-promoter interactions that coordinate the activities of distant paralogous genes.
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Protéines de Drosophila , Drosophila , Animaux , Chromatine/génétique , ADN/métabolisme , Protéines de liaison à l'ADN/génétique , Drosophila/génétique , Protéines de Drosophila/génétique , Protéines de Drosophila/métabolisme , Éléments activateurs (génétique) , Facteurs de transcription/génétique , Facteurs de transcription/métabolismeRÉSUMÉ
BRAF mutations are a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on the clinical course and treatment response in adult glioma remain unclear. Here, we characterize a multi-institutional cohort of more than 300 patients (>200 adults) with BRAF-mutated glioma using clinical, pathological/molecular, and outcome data. We observed that adult and pediatric BRAF-mutant gliomas harbor distinct clinical and molecular features, with a higher prevalence of BRAFV600E (Class I) and BRAF fusions in pediatric tumors. BRAFV600E alterations were associated with improved survival in adults with glioma overall, though not in glioblastoma. Other genomic alterations observed within functional classes were consistent with the putative roles of those BRAF mutation classes in glioma pathogenesis. In our adult cohort, BRAFV600E alterations conferred sensitivity to targeted therapies. Overall, this large cohort of BRAF-altered adult gliomas demonstrates a broad range of molecular alterations with implications for treatment sensitivity and survival.
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How pioneer factors interface with chromatin to promote accessibility for transcription control is poorly understood in vivo. Here, we directly visualize chromatin association by the prototypical GAGA pioneer factor (GAF) in live Drosophila hemocytes. Single-particle tracking reveals that most GAF is chromatin bound, with a stable-binding fraction showing nucleosome-like confinement residing on chromatin for more than 2 min, far longer than the dynamic range of most transcription factors. These kinetic properties require the full complement of GAF's DNA-binding, multimerization and intrinsically disordered domains, and are autonomous from recruited chromatin remodelers NURF and PBAP, whose activities primarily benefit GAF's neighbors such as Heat Shock Factor. Evaluation of GAF kinetics together with its endogenous abundance indicates that, despite on-off dynamics, GAF constitutively and fully occupies major chromatin targets, thereby providing a temporal mechanism that sustains open chromatin for transcriptional responses to homeostatic, environmental and developmental signals.
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Protéines de Drosophila , Facteurs de transcription , Animaux , Chromatine , Protéines de liaison à l'ADN/métabolisme , Drosophila/génétique , Protéines de Drosophila/génétique , Protéines de Drosophila/métabolisme , Cinétique , Facteurs de transcription/métabolismeRÉSUMÉ
BACKGROUND: Asian American (AsAm) representation is lacking in conversations surrounding cultural humility in healthcare. We aimed to investigate US medical student perspectives on AsAm patient inclusion in cultural humility training in medical education. METHODS: This qualitative study analyzed free-text responses to an optional, open-ended question presented at the conclusion of an online survey assessing medical student experiences with and perceptions regarding AsAm patients in their medical education. This survey was distributed to a convenience sample of nine US medical schools. Medical students who completed at least one clinical rotation were eligible to participate in the survey. Qualitative analysis of free-text responses was conducted in an iterative process to generate emergent themes. RESULTS: There was a total of 195 optional free-text responses from 688 participants (28%). Motivation to learn about AsAm population included shared identity and desire to better serve the AsAm population in their local community and future careers. Topics of interest included healthcare-related cultural preferences, healthcare delivery strategies, and health disparities for the AsAm population and other minority patients. Students reported that they drew on personal experiences and some pre-clinical or clinical exposures to learn about AsAm patients. Respondents cited the lack of exposure in the medical school curriculum and clinical experiences as the main challenge to learning about AsAm health and provided suggestions for the delivery of this education in their pre-clinical and clinical education. Respondents emphasized that AsAms are treated as a monolith in medical education and healthcare, despite their heterogeneity. CONCLUSIONS: Medical students identified a need and interest for greater inclusion of AsAm topics in medical education on cultural humility and minority health.
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Enseignement médical premier cycle , Enseignement médical , Étudiant médecine , , Programme d'études , HumainsRÉSUMÉ
COVID-19 pathogenesis is associated with an exuberant inflammatory response. However, the tissue injury pattern and immune response in solid-organ transplant recipients (SOTRs) taking immunosuppressive therapy have not been well characterized. Here, we perform both cfDNA and cytokine profiling on plasma samples to map tissue damage, including allograft injury and delineate underlying immunopathology. We identified injuries from multiple-tissue types, including hematopoietic cells, vascular endothelium, hepatocyte, adipocyte, pancreas, kidney, heart, and lung in SOTRs with COVID-19 that correlates with disease severity. SOTRs with COVID-19 have higher plasma levels of cytokines such as IFN-λ1, IFN-γ, IL-15, IL-18 IL-1RA, IL-6, MCP-2, and TNF-α as compared to healthy controls, and the levels of GM-CSF, IL-15, IL-6, IL-8, and IL-10 were associated with disease severity in SOTRs. Strikingly, IFN-λ and IP-10 were markedly increased in SOTRs compared to immunocompetent patients with COVID-19. Correlation analyses showed a strong association between monocyte-derived cfDNA and inflammatory cytokines/chemokines in SOTRs with COVID-19. Moreover, compared to other respiratory viral infections, COVID-19 induced pronounced injury in hematopoietic, vascular endothelial and endocrine tissues. Allograft injury, measured as donor-derived cfDNA was elevated in SOTRs with COVID-19, including allografts distant from the primary site of infection. Allograft injury correlated with inflammatory cytokines and cfDNA from immune cells. Furthermore, longitudinal analysis identified a gradual decrease of cfDNA and inflammatory cytokine levels in patients with a favorable outcome. Our findings highlight distinct tissue injury and cytokine features in SOTRs with COVID-19 that correlate with disease severity.
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The SpineJack implant system was recently FDA approved for treatment of vertebral compression fractures (VCF), however United States-based outcomes data is lacking. We sought to examine the safety and clinical outcomes following vertebral augmentation using the SpineJack implant for treatment of VCF in a U.S. patient population. An IRB-approved, retrospective study of SpineJack implants used in vertebral augmentation was performed from 11/2018 to 2/2020. Outcome objectives included pain improvement, vertebral body height (VH) restoration, improvement in local kyphotic angle (LKA), and incidence of adjacent level fractures (ALF). Complications were reviewed to assess safety of the procedure. Thirty patients with VCF (60% female; mean [SD] age of 62.7 [±12.8] years) underwent a total of 53 vertebral augmentations with 106 SpineJack implants. Worst pain scores decreased significantly from 8.7 to 4.3 (95%CI of the change [Δ]: 4.3-4.4; p < 0.001). Middle and anterior VH significantly increased from 13.1 ± 0.2 to 15.9 ± 0.2 mm (95%CI Δ: 2.6-2.9 mm; p < 0.001) and 15.6 ± 0.2 to 16.8 ± 0.2 mm (95%CI Δ: 1.1-1.4 mm; p < 0.001), respectively. LKA was significantly decreased from 10.0 ± 2.1 to 7.4 ± 2.1 degrees (95%CI Δ: 2.4-2.8 degrees; p < 0.001). Four patients (13%) sustained ten ALF over a median (IQR) follow up period of 94 (17.5-203) days. There were no major adverse events during the follow up period. To summarize, vertebral augmentation with SpineJack implants of patients with VCF resulted in significantly decreased pain, restored VH, and improved LKA, without major adverse events. However, 13% of patients sustained ALF during a median follow up period of 3 months.