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Scientific Reports Jul 2024The intestinal epithelium dynamically controls cell cycle, yet no experimental platform exists for directly analyzing cell cycle phases in non-immortalized human...
The intestinal epithelium dynamically controls cell cycle, yet no experimental platform exists for directly analyzing cell cycle phases in non-immortalized human intestinal epithelial cells (IECs). Here, we present two reporters and a complete platform for analyzing cell cycle phases in live primary human IECs. We interrogate the transcriptional identity of IECs grown on soft collagen, develop two fluorescent cell cycle reporter IEC lines, design and 3D print a collagen press to make chamber slides for optimal imaging while supporting primary human IEC growth, live image cell cycle dynamics, then assemble a computational pipeline building upon free-to-use programs for semi-automated analysis of cell cycle phases. The PIP-FUCCI construct allows for assigning cell cycle phase from a single image of living cells, and our PIP-H2A construct allows for semi-automated direct quantification of cell cycle phase lengths using our publicly available computational pipeline. Treating PIP-FUCCI IECs with oligomycin demonstrates that inhibiting mitochondrial respiration lengthens G1 phase, and PIP-H2A cells allow us to measure that oligomycin differentially lengthens S and G2/M phases across heterogeneous IECs. These platforms provide opportunities for future studies on pharmaceutical effects on the intestinal epithelium, cell cycle regulation, and more.
Topics: Humans; Epithelial Cells; Intestinal Mucosa; Cell Cycle; Oligomycins; Cells, Cultured
PubMed: 38956443
DOI: 10.1038/s41598-024-66042-9 -
Scientific Reports Jul 2024Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are reported to cause stress cardiomyopathy (SC). This study...
Risk of stress cardiomyopathy associated with selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors: a real-world pharmacovigilance analysis.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are reported to cause stress cardiomyopathy (SC). This study evaluated the association between SSRI/SNRI use and the occurrence of cardiomyopathy in the publicly available U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. Disproportionate analysis and likelihood ratio tests were used to identify risk associated with SSRIs or SNRIs and the incidence of SC, using data from between from 2012 to 2022 acquired from the FAERS database. The study identified 132 individual case safety reports (ICSRs) of SC associated with SSRIs or SNRIs. Venlafaxine (48%) and fluoxetine (27%) were the most common antidepressants of the ICSRs. Approximately 80% of SC cases were reported in females, with individuals aged 45-65 years identified as a high-risk population. Both venlafaxine (ratio-scale information component [RSIC] 2.54, 95% CI 2.06-3.04) and fluoxetine (RSIC 3.20, 95% CI 2.31-4.47) were associated with SC, with likelihood ratio estimates of 3.55 (p = 0.02) for venlafaxine and 4.82 (p = 0.008) for fluoxetine. The median time to cardiomyopathy onset was 20 days, with hospitalization reported in 48.33% of patients. Venlafaxine and fluoxetine were associated with SC risk, particularly in middle-aged women. Caution should be exercised when using SSRIs or SNRIs combined with other serotonergic medications.
Topics: Humans; Female; Selective Serotonin Reuptake Inhibitors; Male; Pharmacovigilance; Middle Aged; Aged; Serotonin and Noradrenaline Reuptake Inhibitors; Takotsubo Cardiomyopathy; Adverse Drug Reaction Reporting Systems; Adult; United States; Venlafaxine Hydrochloride; Fluoxetine; Databases, Factual; Risk Factors
PubMed: 38956425
DOI: 10.1038/s41598-024-66155-1 -
Acta Pharmacologica Sinica Jul 2024Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's...
Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.
PubMed: 38956416
DOI: 10.1038/s41401-024-01326-4 -
Scientific Data Jul 2024Teratoma, due to its remarkable ability to differentiate into multiple cell lineages, is a valuable model for studying human embryonic development. The similarity of the...
Teratoma, due to its remarkable ability to differentiate into multiple cell lineages, is a valuable model for studying human embryonic development. The similarity of the gene expression and chromatin accessibility patterns in these cells to those observed in vivo further underscores its potential as a research tool. Notably, teratomas derived from human naïve (pre-implantation epiblast-like) pluripotent stem cells (PSCs) have larger embryonic cell diversity and contain extraembryonic lineages, making them more suitable to study developmental processes. However, the cell type-specific epigenetic profiles of naïve PSC teratomas have not been yet characterized. Using single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq), we analyzed 66,384 cell profiles from five teratomas derived from human naïve PSCs and their post-implantation epiblast-like (primed) counterparts. We observed 17 distinct cell types from both embryonic and extraembryonic lineages, resembling the corresponding cell types in human fetal tissues. Additionally, we identified key transcription factors specific to different cell types. Our dataset provides a resource for investigating gene regulatory programs in a relevant model of human embryonic development.
Topics: Humans; Teratoma; Pluripotent Stem Cells; Chromatin; Single-Cell Analysis; Cell Lineage; Transcription Factors
PubMed: 38956385
DOI: 10.1038/s41597-024-03558-9 -
Tracking-seq reveals the heterogeneity of off-target effects in CRISPR-Cas9-mediated genome editing.Nature Biotechnology Jul 2024The continued development of novel genome editors calls for a universal method to analyze their off-target effects. Here we describe a versatile method, called...
The continued development of novel genome editors calls for a universal method to analyze their off-target effects. Here we describe a versatile method, called Tracking-seq, for in situ identification of off-target effects that is broadly applicable to common genome-editing tools, including Cas9, base editors and prime editors. Through tracking replication protein A (RPA)-bound single-stranded DNA followed by strand-specific library construction, Tracking-seq requires a low cell input and is suitable for in vitro, ex vivo and in vivo genome editing, providing a sensitive and practical genome-wide approach for off-target detection in various scenarios. We show, using the same guide RNA, that Tracking-seq detects heterogeneity in off-target effects between different editor modalities and between different cell types, underscoring the necessity of direct measurement in the original system.
PubMed: 38956324
DOI: 10.1038/s41587-024-02307-y -
Scientific Reports Jul 2024This study aims to explore the risk factors associated with frozen shoulder (FS) and develop a predictive model for diagnosing FS, in order to facilitate early detection...
This study aims to explore the risk factors associated with frozen shoulder (FS) and develop a predictive model for diagnosing FS, in order to facilitate early detection of the condition. A total of 103 patients diagnosed with FS and admitted to the Department of Joint Surgery at Suining Central Hospital between October 2021 and October 2023 were consecutively included in the study. Additionally, 309 individuals without shoulder joint diseases, matched for age and gender, who visited the department during the same time, were included as the control group.The complete recording of clinical data for all patients was followed by the utilization of statistical tests such as the Mann-Whitney U test, sample t test, and chi-square test to compare different groups. Additionally, multivariate binary logistic regression analysis was employed to identify risk factors associated with the occurrence of FS in patients, leading to the establishment of a prediction model and derivation of a simplified equation. The diagnostic effectiveness of individual indicators and prediction models was assessed through the use of receiver operating characteristic (ROC) curve analysis. In the sample of 103 individuals, 35 were identified as male and 68 as female, with an average age range of 40-70 years (mean age: 54.20 ± 6.82 years). The analysis conducted between different groups revealed that individuals with a low body mass index (BMI), in conjunction with other factors such as diabetes, cervical spondylosis, atherosclerosis, and hyperlipidemia, were more susceptible to developing FS. Logistic regression analysis further indicated that low BMI, diabetes, cervical spondylosis, and hyperlipidemia were significant risk factors for the occurrence of FS. These variables were subsequently incorporated into a predictive model, resulting in the creation of a simplified equation.The ROC curve demonstrated that the combined indicators in the predictive model exhibited superior diagnostic efficacy compared to single indicators, as evidenced by an area under the curve of 0.787, sensitivity of 62.1%, and specificity of 82.2%. Low BMI, diabetes, cervical spondylosis, and hyperlipidemia are significant risk factors associated with the occurrence of FS. Moreover, the utilization of a prediction model has demonstrated superior capability in forecasting the likelihood of FS compared to relying solely on individual indicators. This finding holds potential in offering valuable insights for the early diagnosis of FS.
Topics: Humans; Male; Female; Bursitis; Middle Aged; Risk Factors; Aged; Adult; ROC Curve; Body Mass Index; Logistic Models
PubMed: 38956312
DOI: 10.1038/s41598-024-66360-y -
Scientific Reports Jul 2024This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic...
This study aims to identify factors influencing the alleviation of knee joint symptoms in patients with rheumatoid arthritis treated with biologic or target synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Among 2321 patients who started b/tsDMARDs between 2010 and 2023, we focused on 295 patients who had knee swelling or tenderness at the initiation of b/tsDMARDs and continued b/tsDMARDs at least 3 months, with recorded knee symptoms 6 months later. Symptom relief after 6 months was 78.2% for interleukin 6 (IL-6) inhibitors, 68.6% for Janus kinase (JAK) inhibitors, 65.8% for tumor necrosis factor (TNF) inhibitors, and 57.6% for cytotoxic T lymphocyte-associated antigen-4-Ig (CTLA4-Ig). The initial use of b/tsDMARDs and the use of IL-6 inhibitors in comparison to CTLA4-Ig emerged as a significant factor associated with the improvement of knee joint symptoms. Among 141 patients who underwent knee radiography at baseline and two years later, the deterioration in knee joint radiographs was 7.7% for IL-6 inhibitors, 6.3% for JAK inhibitors, 21.9% for TNF inhibitors, and 25.9% for CTLA4-Ig. The use of IL-6 inhibitors was a significant factor associated with the improvement of knee joint symptoms and the inhibition of joint destruction compared to CTLA4-Ig.
Topics: Humans; Arthritis, Rheumatoid; Female; Male; Interleukin-6; Middle Aged; Abatacept; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Aged; Knee Joint; Adult; Janus Kinase Inhibitors; Treatment Outcome; Tumor Necrosis Factor-alpha
PubMed: 38956271
DOI: 10.1038/s41598-024-66064-3 -
Scientific Reports Jul 2024The relationship between bone mineral density and type 2 diabetes is still controversial. The aim of this study is to investigate the relationship between type 2...
The relationship between bone mineral density and type 2 diabetes is still controversial. The aim of this study is to investigate the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) in elderly men and postmenopausal women. The participants in this study included 692 postmenopausal women and older men aged ≥ 50 years, who were divided into the T2DM group and non-T2DM control group according to whether or not they had T2DM. The data of participants in the two groups were collected from the inpatient medical record system and physical examination center systems, respectively, of the Tertiary Class A Hospital. All data analysis is performed in SPSS Software. Compared with all T2DM group, the BMD and T scores of lumbar spines 1-4 (L1-L4), left femoral neck (LFN) and all left hip joints (LHJ) in the non-T2DM group were significantly lower than those in the T2DM group (P < 0.05), and the probability of major osteoporotic fracture in the next 10 years (PMOF) was significantly higher than that in T2DM group (P < 0.001). However, with the prolongation of the course of T2DM, the BMD significantly decreased, while fracture risk and the prevalence of osteoporosis significantly increased (P < 0.05). We also found that the BMD of L1-4, LFN and LHJ were negatively correlated with homeostatic model assessment-insulin resistance (HOMA-IR) (P = 0.028, P = 0.01 and P = 0.047, respectively). The results also showed that the BMD of LHJ was positively correlated with indirect bilirubin (IBIL) (P = 0.018). Although the BMD was lower in the non-T2DM group than in the T2DM group, the prolongation of the course of T2DM associated with the lower BMD. And the higher prevalence of osteoporosis and fracture risk significantly associated with the prolongation of the course of T2DM. In addition, BMD was significantly associated with insulin resistance (IR) and bilirubin levels in T2DM patients.Registration number: China Clinical Trials Registry: MR-51-23-051741; https://www.medicalresearch.org.cn/search/research/researchView?id=c0e5f868-eca9-4c68-af58-d73460c34028 .
Topics: Humans; Diabetes Mellitus, Type 2; Bone Density; Female; Male; Aged; Middle Aged; Postmenopause; Lumbar Vertebrae; Osteoporosis; Femur Neck; Risk Factors; Osteoporotic Fractures; Prevalence
PubMed: 38956260
DOI: 10.1038/s41598-024-65571-7 -
Scientific Reports Jul 2024To address the problems of the conventional composite supporting structures (CCSSs) such as insufficient anti-dislocation performance and deformation capacity, this...
To address the problems of the conventional composite supporting structures (CCSSs) such as insufficient anti-dislocation performance and deformation capacity, this study used Engineered Cementitious Composite (ECC) lining sections instead of the traditional lining sections and optimized support design parameters, resulting in the development of novel ECC-RC composite supporting structures (ECSSs) of tunnels passing through active fault. The dislocation response characteristics and their parameter sensitivity of the ECSS was revealed by way of 1/25-scale fault dislocation model tests and finite element analysis. The test results show that the mechanical response characteristics and the failure modes of the CCSS and the ECSS are similar under reverse fault dislocation. Compared with the CCSS, the anti-dislocation performance of the ECSS is significantly improved by introducing of the ECC lining and optimizing the design parameters. The vertical deformation of the ECSS and the range of influence under the same dislocation are significantly decreased, and the strain are reduced to different degrees. This phenomenon shows that by improving the material properties, shortening the spacing of aseismatic joints and optimising the thickness of the shock absorption layer, the stress conditions and applicability under deformation of the structure are improved. The ECSS benefits from the crack resistance and toughening effect of fibres, the degree and scope of cracking of the ECSS are significantly reduced compared with those of the CCSS, and internal and external through cracks and local spalling are absent. The results of finite element analysis show that the overall damage degree of the ECSS is decreased and the damage range is increased by decreasing the strength of the surrounding rock in the fault zone. The fault dislocation response pattern of the ECSS varies depending on the fault type. The damage degree caused by different fault types follows the order of normal fault, strike-slip fault, and reverse fault from large to small. However, the damage range caused by the strike-slip fault is significantly larger compared to normal fault and reverse fault. In the design of fault resistance, the surrounding rock conditions of the fault zone and the form of fault dislocation should be considered.
PubMed: 38956190
DOI: 10.1038/s41598-024-65523-1 -
Nature Communications Jul 2024Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential...
Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying immune responses at the cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics and technical variations. Here, to address this, we develop the multimodal generative model mvTCR to fuse modality-specific information across transcriptome and TCR into a shared representation. Our analysis demonstrates the added value of multimodal over unimodal approaches to capture antigen specificity. Notably, we use mvTCR to distinguish T cell subpopulations binding to SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, mvTCR can map newly generated datasets to extensive T cell references, facilitating knowledge transfer. In summary, we envision mvTCR to enable a scalable analysis of multimodal immune profiling data and advance our understanding of immune responses.
Topics: Receptors, Antigen, T-Cell; Single-Cell Analysis; Humans; SARS-CoV-2; COVID-19; Transcriptome; T-Lymphocytes; Gene Expression Profiling; Antigens, Viral
PubMed: 38956082
DOI: 10.1038/s41467-024-49806-9