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Single cell methodology enables detection and quantification of transcriptional changes and unravelling dynamic aspects of the transcriptional heterogeneity not accessible using bulk sequencing approaches. We have applied single-cell RNA-sequencing (scRNA-seq) to fresh human bone marrow CD34
cells and profiled 391 single hematopoietic stem/progenitor cells (HSPCs) from healthy donors to characterize lineage- and stage-specific transcription during hematopoiesis.
Cells clustered into six distinct groups, which could be assigned to known HSPC subpopulations based on lineage specific genes. Reconstruction of differentiation trajectories in single cells revealed four committed lineages derived from HSCs, as well as dynamic expression changes underlying cell fate during early erythroid-megakaryocytic, lymphoid, and granulocyte-monocyte differentiation. A similar non-hierarchical pattern of hematopoiesis could be derived from analysis of published single-cell assay for transposase-accessible chromatin sequencsis could be derived from analysis of published single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), consistent with a sequential relationship between chromatin dynamics and regulation of gene expression during lineage commitment (first, altered chromatin conformation, then mRNA transcription). Computationally, we have reconstructed molecular trajectories connecting HSCs directly to four hematopoietic lineages. Integration of long noncoding RNA (lncRNA) expression from the same cells demonstrated mRNA transcriptome, lncRNA, and the epigenome were highly homologous in their pattern of gene activation and suppression during hematopoietic cell differentiation.There is a lack of approaches for identifying pathogenic genomic structural variants (SVs) although they play a crucial role in many diseases. We present a mechanism-agnostic machine learning-based workflow, called SVFX, to assign pathogenicity scores to somatic and germline SVs. In particular, we generate somatic and germline training models, which include genomic, epigenomic, and conservation-based features, for SV call sets in diseased and healthy individuals. We then apply SVFX to SVs in cancer and other diseases; SVFX achieves high accuracy in identifying pathogenic SVs. Predicted pathogenic SVs in cancer cohorts are enriched among known cancer genes and many cancer-related pathways.
Despite relatively high rates of Postpartum Depression (PPD), little is known about the granting of social security benefits to women who are disabled as a result of PPD or of other postpartum mood and anxiety disorders (PMAD). This study aims to identify populations at risk for underutilization of social security benefits due to PMAD among Israeli women, with a focus on ethnic minorities.
This retrospective cohort study is based on the National Insurance Institute (NII) database. The study population included a simple 10% random sample of 79,391 female Israeli citizens who gave birth during 2008-2016 (these women delivered a total of 143,871 infants during the study period), and who had not been eligible for NII mental health disability benefits before 2008. The dependent variable was receipt of Benefit Entitlement (BE) due to mental illness within 2 years following childbirth. Maternal age at delivery, population group, Socio-Economic Status (SES), family status, employment status of the mother and her developing programs for early identification of postpartum emotional disorders among unprivileged ethnic groups, awareness regarding entitlement to a mental health disability allowance among ethnic minorities should be improved.
Despite the exceptionally high prevalence of PMAD among ethnic minorities, Bedouins and Arabs had lowest likelihood of Benefit Entitlement. In addition to developing programs for early identification of postpartum emotional disorders among unprivileged ethnic groups, awareness regarding entitlement to a mental health disability allowance among ethnic minorities should be improved.
Vaccination is an important strategy for the eradication of infectious diseases. CadF protein ofCampylobacter jejuniis one of the important factors in the pathogenesis of this bacterium. The purpose of this work was to perform a bioinformatics study to identify an epitope-based CadF vaccine, as a subunit vaccine.Full protein sequences of CadF were extracted from the NCBI and UniProt databases and subjected to in silico evaluations, including sequence analysis, allergenicity, antigenicity, epitope conservancy, and molecular docking assessments done by different servers.
The results showed that CadF was a highly conserved protein belonging to the outer member proteins superfamily. Among the evaluated epitopes, LSDSLALRL was identified as an antigenic and non-allergenic peptide with a suitable structure for vaccine development. It was also able to stimulate both T and B cells. This 9-mer peptide was located in 136-144 segment of CadF protein and interacted with both HLA-A 0101 and HLA-DRB1 0101 alleles. Overall, the obtained theoretical results showed that CadF protein could be used for designing and evaluating a new effective vaccine againstC. jejuni.
The results showed that CadF was a highly conserved protein belonging to the outer member proteins superfamily. Among the evaluated epitopes, LSDSLALRL was identified as an antigenic and non-allergenic peptide with a suitable structure for vaccine development. It was also able to stimulate both T and B cells. This 9-mer peptide was located in 136-144 segment of CadF protein and interacted with both HLA-A 0101 and HLA-DRB1 0101 alleles. Overall, the obtained theoretical results showed that CadF protein could be used for designing and evaluating a new effective vaccine against C. jejuni.
Osteoporosis (OP) has the characteristics of the decline in bone mineral density and worsening of bone quality, contributing to a higher risk of fractures. Some microRNAs (miRNAs) have been validated as possible mediators of osteoblast differentiation. We herein aimed to clarify whether miR-497-5p regulates the differentiation of osteoblasts in MC3T3-E1 cells.
The expression of miR-497-5p in OP patients and controls was measured by RT-qPCR, and its expression changes during osteoblast differentiation were determined as well. The effects of miR-497-5p on the differentiation of MC3T3-E1 cells were studied using MTT, ALR staining, and ARS staining. The target gene of miR-497-5p was predicted by TargetScan, and the effects of its target gene on differentiation and the pathway involved were investigated.
miR-497-5p expressed poorly in OP patients, and its expression was upregulated during MC3T3-E1 cell differentiation. C75 cell line Overexpression of miR-497-5p promoted mineralized nodule formation and the expression of RUNX2 and OCN. miR-497-5p targeted high mobility group AT-Hook 2 (HMGA2), while the upregulation of HMGA2 inhibited osteogenesis induced by miR-497-5p mimic. miR-497-5p significantly impaired the c-Jun NH2-terminal kinase (JNK) pathway, whereas HMGA2 activated this pathway. Activation of the JNK pathway inhibited the stimulative role of miR-497-5p mimic in osteogenesis.
miR-497-5p inhibits the development of OP by promoting osteogenesis via targeting HMGA2.
miR-497-5p inhibits the development of OP by promoting osteogenesis via targeting HMGA2.
Transoral surgery (TOS), particularly transoral robotic surgery (TORS) has become the preferred modality in the United States for the treatment of early stage oropharyngeal cancer, largely due to assumptions of fewer toxicities and improved quality of life compared to primary radiotherapy (RT). However, these assumptions are based on retrospective analysis, a subset of which utilize primary RT groups not limited to T1-2 stage tumors for which transoral robotic surgery is FDA approved. Thus, there is potential for underestimating survival and overestimating toxicity, including treatment related mortality, in primary RT.
Consecutive cases of early T-stage (T1-T2) oropharyngeal cancer presenting to the London Health Sciences Centre between 2014 and 2018 treated with RT or chemoradiation (CRT) were reviewed. Patient demographics, treatment details, survival outcomes and toxicity were collected. Toxicities were retrospectively graded using the Common Terminology Criteria for Adverse Events criteria.
A total of 198 patients were identified, of which 82% were male and 73% were HPV-positive. Sixty-eight percent of patients experienced a grade 2 toxicity, 48% a grade 3 and 4% a grade 4. The most frequent toxicities were dysphagia, neutropenia and ototoxicity.The rates of gastrostomy tube dependence at 1 and 2years were 2.5% and 1% respectively. There were no grade 5 (fatal)toxicities.HPV-positive patients experienced improved 5-year overall survival (86% vs 64%, p = 0.0026).
Primary RT or CRT provides outstanding survival for early T-stage disease, with low rates of severe toxicity and feeding tube dependence. This study provides a reference for comparison for patients treated with primary transoral surgery.
Primary RT or CRT provides outstanding survival for early T-stage disease, with low rates of severe toxicity and feeding tube dependence. This study provides a reference for comparison for patients treated with primary transoral surgery.
Several recent studies suggest the possibility of a skin rash being a clinical presentation of coronavirus disease 2019 (COVID-19). The purpose of this case report is to bring attention to skin manifestations in the early stage of COVID-19 in order to support frontline physicians in their crucial activity of case identification.
The patient is an Italian 32-year-old female nurse who had several close contacts with multiple patients with COVID-19 as part of her professional workload. On March 13, 2020, the patient developed an itchy, erythematous papular rash (sparing only her face, scalp, and abdomen), which lasted for 10 days. The rash was accompanied by a feeling of general fatigue that gradually worsened over the following days and has continued for 5 months (until the end of July 2020). During the first week of remote assessment carried out by her general practitioner, the patient gradually developed a dry cough, intermittent fever, and diarrhoea and then had a positive test result for severe acute reation of COVID-19 is a key part of the strategy of case detection and case isolation. To enhance this activity, further research is needed to establish frequency, symptoms, signs, and pathogenesis of skin manifestations in patients with COVID-19.
A defining pathological hallmark of the progressive neurodegenerative disorder Alzheimer's disease (AD) is the accumulation of misfolded tau with abnormal post-translational modifications (PTMs). These include phosphorylation at Threonine 231 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is recognized to play a central role in pathogenesis of AD, the precise mechanisms by which these abnormal PTMs contribute to the neural toxicity of tau is unclear.
Human 0N4R tau (wild type) was expressed in touch receptor neurons of the genetic model organism C. elegans through single-copy gene insertion. Defined mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 genome editing. These mutations included T231E, to mimic phosphorylation of a commonly observed pathological epitope, and K274/281Q, to mimic disease-associated lysine acetylation - collectively referred as "PTM-mimetics" - as well as a T231A phosphoablation mutant. Stereotypical touch response assays were used to assess behavioral defects in the transgenic strains as a function of age.
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