ABSTRACT
Understanding the relationship between protein structural dynamics and function is crucial for both basic research and biotechnology. However, methods for studying the fast dynamics of structural changes are limited. Here, we introduce fluorescent nanoantennas as a spectroscopic technique to sense and report protein conformational changes through noncovalent dye-protein interactions. Using experiments and molecular simulations, we detect and characterize five distinct conformational states of intestinal alkaline phosphatase, including the transient enzyme-substrate complex. We also explored the universality of the nanoantenna strategy with another model protein, Protein G and its interaction with antibodies, and demonstrated a rapid screening strategy to identify efficient nanoantennas. These versatile nanoantennas can be used with diverse dyes to monitor small and large conformational changes, suggesting that they could be used to characterize diverse protein movements or in high-throughput screening applications.
Subject(s)
Fluorescent Dyes/chemistry , Proteins/chemistry , Alkaline Phosphatase/chemistry , Alkaline Phosphatase/metabolism , Aniline Compounds/chemistry , Biotin/chemistry , DNA, Single-Stranded/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , Nanostructures/chemistry , Organophosphorus Compounds/chemistry , Protein Conformation , Spectrophotometry, UltravioletABSTRACT
BACKGROUND: Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. RESULTS: The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. CONCLUSIONS: In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.
Subject(s)
Adenosine , Adipogenesis , AlkB Homolog 5, RNA Demethylase , Chickens , Phosphatidylcholine-Sterol O-Acyltransferase , RNA Stability , Animals , Adipogenesis/genetics , Chickens/genetics , Chickens/metabolism , Phosphatidylcholine-Sterol O-Acyltransferase/genetics , Phosphatidylcholine-Sterol O-Acyltransferase/metabolism , AlkB Homolog 5, RNA Demethylase/metabolism , AlkB Homolog 5, RNA Demethylase/genetics , Female , Adenosine/analogs & derivatives , Adenosine/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , MethylationABSTRACT
Increasing evidences suggest that mitochondrial dysfunction is implicated in diseases and aging, and whole-genome sequencing (WGS) is the most unbiased method in analyzing the mitochondrial genome (mtDNA). However, the genetic landscape of mtDNA in the Chinese population has not been fully examined. Here, we described the genetic landscape of mtDNA using WGS data from Chinese individuals (n = 3241). We identified 3892 mtDNA variants, of which 3349 (86%) were rare variants. Interestingly, we observed a trend toward extreme heterogeneity of mtDNA variants. Our study observed a distinct purifying selection on mtDNA, which inhibits the accumulation of harmful heteroplasmies at the individual level: (1) mitochondrial dN/dS ratios were much <1; (2) the dN/dS ratio of heteroplasmies was higher than homoplasmies; (3) heteroplasmies had more indels and predicted deleterious variants than homoplasmies. Furthermore, we found that haplogroup M (20.27%) and D (20.15%) had the highest frequencies in the Chinese population, followed by B (18.51%) and F (16.45%). The number of variants per individual differed across haplogroup groups, with a higher number of homoplasmies for the M lineage. Meanwhile, mtDNA copy number was negatively correlated with age but positively correlated with the female sex. Finally, we developed an mtDNA variation database of Chinese populations called MTCards (http://genemed.tech/mtcards/) to facilitate the query of mtDNA variants in this study. In summary, these findings contribute to different aspects of understanding mtDNA, providing a better understanding of the genetic basis of mitochondrial-related diseases.
Subject(s)
Genome, Mitochondrial , DNA, Mitochondrial/genetics , Female , Genome, Human/genetics , Genome, Mitochondrial/genetics , Humans , Mitochondria/genetics , Whole Genome SequencingABSTRACT
BACKGROUND: Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis. METHODS: We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis. RESULTS: Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE-/- mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK. CONCLUSION: Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis.
Subject(s)
Atherosclerosis , Cell Movement , Foam Cells , Mice, Inbred C57BL , Paxillin , Animals , Paxillin/metabolism , Foam Cells/metabolism , Foam Cells/pathology , Mice , Atherosclerosis/metabolism , Atherosclerosis/pathology , Signal Transduction , Lipoproteins, LDL/metabolism , Male , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , cdc42 GTP-Binding Protein/metabolism , Macrophages/metabolism , Focal Adhesion Kinase 1/metabolism , Focal Adhesion Kinase 1/genetics , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , Disease Models, Animal , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Mice, Knockout , Membrane Glycoproteins , Intracellular Signaling Peptides and ProteinsABSTRACT
BACKGROUND: The obesity paradox has been reported among older adults. However, whether the favorable effect of obesity is dependent on metabolic status remains largely unknown. We aimed to explore the association of metabolic obesity phenotypes and their changes with all-cause mortality among the Chinese oldest-old population. METHODS: This prospective cohort study included 1207 Chinese oldest old (mean age: 91.8 years). Metabolic obesity phenotypes were determined by central obesity and metabolic status, and participants were classified into metabolically healthy obesity (MHO), metabolically unhealthy obesity (MUO), metabolically healthy non-obesity (MHN), and metabolically unhealthy non-obesity (MUN). The hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated by Cox regression models. RESULTS: During 5.3 years of follow-up, 640 deaths were documented. Compared with non-obesity, obesity was associated with a decreased mortality risk among participants with metabolically healthy (HR, 0.75; 95% CI, 0.63-0.91) while this association was insignificant among metabolically unhealthy. Compared to MHO, MHN (HR, 1.27; 95% CI, 1.06-1.53) and MUN (HR, 1.49; 95% CI, 1.10-2.02) were significantly associated with an increased mortality risk. Compared to those with stable MHO, those transited from MHO to MUO demonstrated a higher mortality risk (HR, 1.81; 95% CI, 1.06-3.11). CONCLUSIONS: MHO predicts better survival among the Chinese oldest-old population. These findings suggest that ensuring optimal management of metabolic health is beneficial and taking caution in weight loss based on the individual body weight for the metabolically healthy oldest-old adults.
ABSTRACT
MOTIVATION: Whole-genome sequencing (WGS) is increasingly used to aid the understanding of Mycobacterium tuberculosis (MTB) transmission. The epidemiological analysis of tuberculosis based on the WGS technique requires a diverse collection of bioinformatics tools. Effectively using these analysis tools in a scalable and reproducible way can be challenging, especially for non-experts. RESULTS: Here, we present TransFlow (Transmission Workflow), a user-friendly, fast, efficient and comprehensive WGS-based transmission analysis pipeline. TransFlow combines some state-of-the-art tools to take transmission analysis from raw sequencing data, through quality control, sequence alignment and variant calling, into downstream transmission clustering, transmission network reconstruction and transmission risk factor inference, together with summary statistics and data visualization in a summary report. TransFlow relies on Snakemake and Conda to resolve dependencies among consecutive processing steps and can be easily adapted to any computation environment. AVAILABILITY AND IMPLEMENTATION: TransFlow is free available at https://github.com/cvn001/transflow. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Humans , Mycobacterium tuberculosis/genetics , Software , Workflow , Whole Genome SequencingABSTRACT
BACKGROUND: Atherogenic index of plasma (AIP), a marker of atherosclerosis and cardiovascular disease (CVD). However, few studies have investigated association between AIP and all-cause mortality and specific-mortality in the general population. METHODS: This study included data from 14,063 American adults. The exposure variable was the AIP, which was defined as log10 (triglycerides/high-density lipoprotein cholesterol). The outcome variables included all-cause mortality and specific-mortality. Survey-weighted cox regressions were performed to evaluate the relation between AIP and all-cause mortality and specific-mortality. Weighted restricted cubic spline was conducted to examin the non-linear relationship. RESULTS: During 10 years of follow-up, we documented 2,077, 262, 854, and 476 cases of all-cause mortality, diabetes mortality, CVD mortality and cancer mortality, respectively. After adjustment for potential confounders, we found that atherogenic index of plasma (AIP) was significantly associated with an increased risk of diabetes mortality when comparing the highest to the lowest quantile of AIP in female (p for trend = 0.001) or participants older than 65 years (p for trend = 0.002). AIP was not significantly associated with all-cause mortality, CVD mortality and cancer mortality (p > 0.05). Moreover, a non-linear association was observed between AIP and all-cause mortality in a U-shape (p for non-linear = 0.0011), while a linear relationship was observed with diabetes mortality and non-diabetes mortality (p for linear < 0.0001). CONCLUSIONS: In this study, there is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. Besides, a higher AIP was significantly associated with an increased risk of diabetes mortality, which only found in women older than 65 years. AIP was associated with all-cause mortality in a U-shape. This association could be explained by the finding that higher AIP predicted a higher risk of death from diabetes, and that lower AIP predicted a higher risk of death from non-diabetes causes.
We used a large national database and a prospective cohort study with a long follow-up period. Higher AIP was significantly associated with an increased risk of diabetes mortality, only in women older than 65 years. There is a no significant association between high AIP levels and a high risk of all-cause and cardiovascular mortality. AIP was associated with all-cause mortality in a U-shape. This finding suggest that controlling AIP levels may have a positive effect on reducing diabetes mortality.
Subject(s)
Atherosclerosis , Biomarkers , Cause of Death , Cholesterol, HDL , Diabetes Mellitus , Triglycerides , Humans , Female , Male , Middle Aged , Aged , Risk Assessment , Biomarkers/blood , Atherosclerosis/mortality , Atherosclerosis/blood , Atherosclerosis/diagnosis , Risk Factors , Time Factors , Adult , Diabetes Mellitus/mortality , Diabetes Mellitus/blood , Diabetes Mellitus/diagnosis , Diabetes Mellitus/epidemiology , Cholesterol, HDL/blood , United States/epidemiology , Triglycerides/blood , Prognosis , Neoplasms/mortality , Neoplasms/blood , Neoplasms/diagnosis , Cardiovascular Diseases/mortality , Cardiovascular Diseases/blood , Cardiovascular Diseases/diagnosisABSTRACT
Background: There has been an increased interest in using antegrade cannulation techniques during surgery for type A aortic dissection. While the utilization of central artery cannulation has been on the rise in recent times, its effectiveness and safety still require thorough examination. This study aimed to explore both the efficiency and safety of central arterial cannulation. Methods: A meta-analysis was conducted on studies that evaluated surgical outcomes when using central artery cannulation (CAC) in comparison to axillary artery cannulation (AXC) or femoral artery cannulation (FAC). Results: 10 retrospective observational studies were included, enrolling 3022 patients (CAC = 1208 vs. FAC = 606; CAC = 1051 vs. AXC = 1119). Among these, 4 articles involved axillary artery cannulation, femoral artery cannulation, and central artery cannulation. Central cannulation was linked to decreased short-term mortality [odds ratio, 0.66, 95% confidence interval (CI) (0.48, 0.89), χ 2 = 3.27, p = 0.007; I 2 = 0; p = 0.86] compared to femoral cannulation. Additionally, central cannulation was associated with a lower occurrence of temporary neurological dysfunction (TND) [odds ratio, 0.57, 95% CI (0.38, 0.85), χ 2 = 0.88, p = 0.006; I 2 = 0%, p = 0.83] when compared with femoral cannulation. However, there was no statistical significance in mortality and TND between the central cannulation and axillary cannulation groups. Conclusions: This meta-analysis reveals that central cannulation surpasses femoral cannulation in lowering short-term mortality and the occurrence of TND among patients undergoing surgery for type A acute aortic dissection. However, central cannulation does not exhibit a higher mortality and TND compared to axillary cannulation.
ABSTRACT
BACKGROUND: GEFT is a key regulator of tumorigenesis in rhabdomyosarcoma (RMS), and overexpression of GEFT is significantly correlated with distant metastasis, lymph node metastasis, and a poor prognosis, yet the underlying molecular mechanism is still poorly understood. This study aimed to investigate and validate the molecular mechanism of GEFT-activated lncRNAs in regulating mTOR expression to promote the progression of RMS. METHODS: GEFT-regulated lncRNAs were identified through microarray analysis. The effects of GEFT-regulated lncRNAs on the proliferation, apoptosis, invasion, and migration of RMS cells were confirmed through cell functional experiments. The target miRNAs of GEFT-activated lncRNAs in the regulation of mTOR expression were predicted by bioinformatics analysis combined with quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The expression of lnc-PSMA8-1, miR-144-3p, and mTOR was measured by qRT-PCR in RMS tissue samples and cell lines. The regulatory mechanisms of the lnc-PSMA8-1-miR-144-3p-mTOR signaling axis were verified by RNA-binding protein immunoprecipitation (RIP), a luciferase reporter assay, qRT-PCR analysis, Western blot analysis, and cell functional experiments. RESULTS: The microarray-based analysis identified 31 differentially expressed lncRNAs (fold change > 2.0, P < 0.05). Silencing the 4 upregulated lncRNAs (lnc-CEACAM19-1, lnc-VWCE-2, lnc-GPX7-1, and lnc-PSMA8-1) and overexpressing the downregulated lnc-FAM59A-1 inhibited the proliferation, invasion, and migration and induced the apoptosis of RMS cells. Among the factors analyzed, the expression of lnc-PSMA8-1, miR-144-3p, and mTOR in RMS tissue samples and cells was consistent with the correlations among their expression indicated by the lncRNA-miRNA-mRNA regulatory network based on the ceRNA hypothesis. lnc-PSMA8-1 promoted RMS progression by competitively binding to miR-144-3p to regulate mTOR expression. CONCLUSION: Our research demonstrated that lnc-PSMA8-1 was activated by GEFT and that the former positively regulated mTOR expression by sponging miR-144-3p to promote the progression of RMS. Therefore, targeting this network may constitute a potential therapeutic approach for the management of RMS.
Subject(s)
MicroRNAs , RNA, Long Noncoding , Rhabdomyosarcoma , TOR Serine-Threonine Kinases , Humans , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , MicroRNAs/metabolism , Rhabdomyosarcoma/genetics , Rhabdomyosarcoma/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Up-RegulationABSTRACT
Vascular dementia (VaD) is the most common cause of dementia in older adults. Due to the lack of effective treatment options, there is an urgent need to find an effective pharmaceutical compound to combat VaD. Piracetam has been reported to improve impaired cognitive function in a variety of conditions in both human and animal models. However, the role and mechanism of Piracetam in VaD remain unclear. Therefore this study aimed to elucidate the effect of Piracetam on a cellular model of VaD in vitro. We found that Piracetam enhanced the growth of OGD-stimulated SH-SY5Y cells. In addition, Piracetam inhibited the oxidative stress of OGD-stimulated SH-SY5Y cells. Further, Piracetam improved mitochondrial function of OGD-stimulated SH-SY5Y cells. Mechanistically, Piracetam inhibited the PI3K/Akt/mTOR pathway in OGD-stimulated SH-SY5Y cells. Collectively, Piracetam improved oxidative stress and mitochondrial dysfunction of OGD-stimulated SH-SY5Y cells through PI3K/Akt/mTOR axis. Hence, Piracetam has the potential to serve as a promising drug of VaD.
Subject(s)
Dementia, Vascular , Mitochondria , Oxidative Stress , Piracetam , Oxidative Stress/drug effects , Oxidative Stress/physiology , Humans , Dementia, Vascular/drug therapy , Dementia, Vascular/metabolism , Piracetam/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Cell Line, Tumor , Neuroprotective Agents/pharmacology , Glucose/metabolism , Dose-Response Relationship, DrugABSTRACT
OBJECTIVE: This study aims to investigate the clinical manifestations, operative techniques, and outcomes of patients who undergo open repair after thoracic endovascular aortic repair (TEVAR). METHODS: From January 2010 to June 2022, 113 consecutive type A aortic dissection (TAAD) patients underwent secondary open operation after TEVAR at our institution, and the median interval from primary intervention to open surgery was 12 (1.9-48.0) months. We divided the patients into two groups (RTAD (retrograde type A dissection) group, N = 56; PNAD (proximal new aortic dissection) group, N = 57) according to their anatomical features. Survival analysis during the follow-up was evaluated using a Kaplan-Meier survival curve and a log-rank test. RESULTS: The 30-day mortality was 6.2% (7/113), the median follow-up period was 31.7 (IQR 14.7-65.6) months, and the overall survival at 1 year, 5 years, and 10 years was 88.5%, 88.5%, and 87.6%, respectively. Fourteen deaths occurred during the follow-up, but there were no late aorta-related deaths. Three patients underwent total thoracoabdominal aortic replacement 1 year after a second open operation. The RTAD group had a smaller ascending aorta size (42.5 ± 7.7 mm vs 48.4 ± 11.4 mm; P < .01) and a closer proximal landing zone (P < .01) compared to the PNAD group. However, there were no differences in survival between the two groups. CONCLUSIONS: TAAD can present as an early or a late complication after TEVAR due to stent-grafting-related issues or disease progression. Open operation can be performed to treat TAAD, and this has acceptable early and mid-term outcomes. Follow-up should become mandatory for patients after TEVAR because these patients are at increased risk for TAAD.
ABSTRACT
Preeclampsia (PE) is a common complication of pregnancy, usually accompanied by symptoms such as hypertension and proteinuria. It can induce severe conditions that may result in maternal and fetal morbidity and fatality. In this study, we use bioinformatics analysis to compare microRNA microassay in decidual stromal cells from PE patients and healthy donors. Our result indicated that placentas from PE patients had a higher CCL1/CXCL2 expression, compared with those from healthy donors. Bioinformatics analysis confirmed that decidual stromal cells derived from PE patients expressed significantly lower miR-455-3p than those derived from healthy donors. Transfection of miR-455-3p inhibitors enhanced the CCL2/CXCL8 expression in decidual stromal cells, and luciferase activity assay confirmed that nuclear factor of activated T cells 5 (NFAT5) mRNA was the direct target of miR-455-3p; NFAT5 also promoted cytokine secretion. In the flow cytometry study, higher M1 macrophage infiltration was observed in placentas from PE patients than in those from healthy donors. We also observed that condition medium (CM) derived from decidual stromal cells could significantly promote M1 polarization of macrophages after transfection with miR-455-3p inhibitor; further, transwell invasion assay confirmed that decidual stromal cells-CM educated macrophages suppressed trophoblast invasion. Taken together, our result demonstrates that downregulation of miR-455-3p in decidual stromal cells can promote macrophage polarization and suppress trophoblasts invasion.
Subject(s)
MicroRNAs , Pre-Eclampsia , Pregnancy , Female , Humans , Trophoblasts/metabolism , Down-Regulation/genetics , Placenta/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Pre-Eclampsia/genetics , Pre-Eclampsia/metabolism , Macrophages/metabolism , Cell Movement/genetics , Cell Proliferation/geneticsABSTRACT
BACKGROUND: Dietary diversity has been suggested as a potential preventive measure against frailty in older adults, but the effect of changes in dietary diversity on frailty is unclear. This study was conducted to examine the association between the dietary diversity score (DDS) and frailty among older Chinese adults. METHODS: A total of 12,457 adults aged 65 years or older were enrolled from three consecutive and nonoverlapping cohorts from the Chinese Longitudinal Healthy Longevity Survey (the 2002 cohort, the 2005 cohort, and the 2008 cohort). DDS was calculated based on nine predefined food groups, and DDS changes were assessed by comparing scores at baseline and the first follow-up survey. We used 39 self-reported health items to assess frailty. Cox proportional hazard models were performed to examine the association between DDS change patterns and frailty. RESULTS: Participants with low-to-low DDS had the highest frailty incidence (111.1/1000 person-years), while high-to-high DDS had the lowest (41.1/1000 person-years). Compared to the high-to-high group of overall DDS pattern, participants in other DDS change patterns had a higher risk of frailty (HRs ranged from 1.25 to 2.15). Similar associations were observed for plant-based and animal-based DDS. Compared to stable DDS changes, participants with an extreme decline in DDS had an increased risk of frailty, with HRs of 1.38 (1.24, 1.53), 1.31 (1.19, 1.44), and 1.29 (1.16, 1.43) for overall, plant-based, and animal-based DDS, respectively. CONCLUSIONS: Maintaining a lower DDS or having a large reduction in DDS was associated with a higher risk of frailty among Chinese older adults. These findings highlight the importance of improving a diverse diet across old age for preventing frailty in later life.
Subject(s)
Diet , Frailty , Humans , Aged , Female , Male , Frailty/epidemiology , China/epidemiology , Diet/statistics & numerical data , Diet/methods , Cohort Studies , Frail Elderly/statistics & numerical data , Longitudinal Studies , Aged, 80 and over , Asian People/statistics & numerical data , Proportional Hazards Models , Geriatric Assessment/methods , Geriatric Assessment/statistics & numerical data , East Asian PeopleABSTRACT
BACKGROUND: The association of changes in waist circumference (WC), waist-to-height ratio (WHtR) and weight-adjusted-waist index (WWI) with subsequent risk of multimorbidity remains unclear among older Chinese adults. Therefore, we aimed to assess this association by utilizing data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). METHODS: Our study was based on the 2011/2012 wave of the CLHLS whose follow-up surveys were conducted in 2014 and 2017/2018. A total of 2900 participants aged 65 and above at baseline were enrolled. WC, WHtR, and WWI were calculated from measured height, weight, and waist circumference. Multimorbidity refers to the coexistence of two or more of 18 chronic diseases. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) to evaluate the effect of three-year changes in WC, WHtR, and WWI on the risk of multimorbidity. RESULTS: During a mean follow-up time of 4.2 (2.0) years, 906 multimorbidity cases were identified. Compared to participants in the persistently low WC group, those in the WC gain group and the persistently high WC group had a higher multimorbidity risk with adjusted HRs (95%CI) of 1.23 (1.01-1.50) and 1.34(1.14-1.58), respectively. Participants in the WHtR gain group and the persistently high WHtR group also had higher risks of multimorbidity with HRs (95%CI) of 1.35 (1.08-1.67) and 1.27 (1.05-1.53), respectively, relative to the persistently low WHtR group. Compared to the persistently low WWI group, those in the WWI loss group had a lower risk of multimorbidity with HRs (95%CI) of 0.80 (0.66-0.98). For every standard deviation increase in WC, WHtR, and WWI over three years, the risk of multimorbidity was higher by 12% (95%CI: 1.05-1.19), 13% (95%CI: 1.06-1.20), and 12% (95%CI: 1.05-1.20), respectively. CONCLUSIONS: Associations of changes in WC, WHtR and WWI with multimorbidity are significant among older Chinese adults. The findings highlight the importance of evaluating changes in WC, WHtR, and WWI in screening and prevention of multimorbidity in older adults.
Subject(s)
Multimorbidity , Obesity , Humans , Middle Aged , Aged , Waist Circumference , Risk Factors , China/epidemiology , Body Mass Index , Waist-Height RatioABSTRACT
Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/ß-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/ß-tubulin-GB1 complex.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bacterial Proteins/chemical synthesis , Biological Products/chemical synthesis , Depsipeptides/chemical synthesis , Microtubules/drug effects , Tubulin Modulators/chemical synthesis , Tubulin/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Bacterial Proteins/isolation & purification , Bacterial Proteins/pharmacology , Binding Sites , Biological Products/isolation & purification , Biological Products/pharmacology , Cell Line, Tumor , Colchicine/chemistry , Colchicine/pharmacology , Crystallography, X-Ray , Cyanobacteria/chemistry , Depsipeptides/isolation & purification , Depsipeptides/pharmacology , Drug Discovery , HCT116 Cells , Humans , Maytansine/chemistry , Maytansine/pharmacology , Microtubules/metabolism , Microtubules/ultrastructure , Models, Molecular , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Pyrones/chemistry , Pyrones/pharmacology , Taxoids/chemistry , Taxoids/pharmacology , Tubulin/genetics , Tubulin/metabolism , Tubulin Modulators/isolation & purification , Tubulin Modulators/pharmacology , Vinca Alkaloids/chemistry , Vinca Alkaloids/pharmacologyABSTRACT
Ambient air pollution is a major global health concern. Yet, no study has thoroughly assessed its link to respiratory mortality. Our research evaluated the combined and individual effects of air pollutants on respiratory mortality risks based on the UK Biobank. A total of 366,478 participants were studied. A Cox proportional hazards model was used to estimate the respiratory mortality risk from combined long-term exposure to five pollutants, summarized as a weighted air pollution score. During a median of 13.6 years of follow-up, 6113 deaths due to respiratory diseases were recorded. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of respiratory diseases were 2.64 (2.05-3.39), 1.62 (1.23-2.12), 2.06 (1.73-2.45), 1.20 (1.16-1.25), and 1.07 (1.05-1.08) per 10⯵g/m3 increase in PM2.5, PM2.5-10, PM10, NO2, and NOx, respectively. The air pollution score showed a dose-response association with an elevated respiratory mortality risk. The highest versus lowest quartile air pollution score was linked to a 44% increase in respiratory mortality risk (HR 1.44, 95% CI: 1.33-1.57), with consistent findings in subgroup and sensitivity analyses. Long-term individual and joint air-pollutant exposure showed a dose-response association with an increased respiratory mortality risk, highlighting the importance of a comprehensive air-pollutant assessment to protect public health.
Subject(s)
Air Pollutants , Air Pollution , Respiratory Tract Diseases , Humans , Air Pollutants/adverse effects , Air Pollutants/analysis , Particulate Matter/toxicity , Particulate Matter/analysis , Prospective Studies , Environmental Exposure/adverse effects , Environmental Exposure/analysis , Air Pollution/adverse effects , Air Pollution/analysis , Respiratory Tract Diseases/epidemiology , Nitrogen DioxideABSTRACT
Understanding the emergence and evolution of drug resistance can inform public health intervention to combat tuberculosis (TB). In this prospective molecular epidemiological surveillance study from 2015 to 2021 in eastern China, we prospectively collected whole-genome sequencing and epidemiological data on TB patients. We dissect the ordering of drug resistance mutation acquisition for nine commonly used anti-TB drugs, and we found that the katG S315T mutation first appeared around 1959, followed by rpoB S450L (1969), rpsL L43A (1972), embB M306V (1978), rrs 1401 (1981), fabG1 (1982), pncA (1985) and folC (1988) mutations. GyrA gene mutations appeared after the year of 2000. We observed that the first expansion of Mycobacterium tuberculosis (M.tb) resistance population among eastern China appeared after the introduction of isoniazid, streptomycin and para-amino salicylic acid, and the second expansion after the ethambutol, rifampicin, pyrazinamide, ethionamide and aminoglycosides. We speculate these two expansions are linked with population shift historically. By geospatial analysis, we found drug-resistant isolates migrated within eastern China. With epidemiological data of clonal strains, we observed some strains can evolve continuously in individuals and transmit readily in a population. In conclusion, this study mirrored the emergence and evolution of drug-resistant M.tb in eastern China were linked to the sequence and timing of introduction of anti-TB drugs, and multiple factors may contribute to the resistant population enlarged. To resolve the epidemic of drug-resistant TB, it requires applying anti-TB drugs carefully and/or identifying resistant patients timely to prevent them from developing high-level resistance and transmitting to others.
Subject(s)
Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Humans , Mycobacterium tuberculosis/genetics , Prospective Studies , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/epidemiology , Tuberculosis, Multidrug-Resistant/microbiology , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , China , Mutation , Drug Resistance, Multiple, Bacterial/genetics , Bacterial Proteins/geneticsABSTRACT
BACKGROUND: The accurate identification and evaluation of lymph nodes by CT images is of great significance for disease diagnosis, treatment, and prognosis. PURPOSE: To assess the lymph nodes' segmentation, size, and station by artificial intelligence (AI) for unenhanced chest CT images and evaluate its value in clinical scenarios. MATERIAL AND METHODS: This retrospective study proposed an end-to-end Lymph Nodes Analysis System (LNAS) consisting of three models: the Lymph Node Segmentation model (LNS), the Mediastinal Organ Segmentation model (MOS), and the Lymph Node Station Registration model (LNR). We selected a healthy chest CT image as the template image and annotated 14 lymph node station masks according to the IASLC to build the lymph node station mapping template. The exact contours and stations of the lymph nodes were annotated by two junior radiologists and reviewed by a senior radiologist. Patients aged 18 and above, who had undergone unenhanced chest CT and had at least one suspicious enlarged mediastinal lymph node in imaging reports, were included. Exclusions were patients who had thoracic surgeries in the past 2 weeks or artifacts on CT images affecting lymph node observation by radiologists. The system was trained on 6725 consecutive chest CTs that from Tianjin Medical University General Hospital, among which 6249 patients had suspicious enlarged mediastinal lymph nodes. A total of 519 consecutive chest CTs from Qilu Hospital of Shandong University (Qingdao) were used for external validation. The gold standard for each CT was determined by two radiologists and reviewed by one senior radiologist. RESULTS: The patient-level sensitivity of the LNAS system reached of 93.94% and 92.89% in internal and external test dataset, respectively. And the lesion-level sensitivity (recall) reached 89.48% and 85.97% in internal and external test dataset. For man-machine comparison, AI significantly apparently shortened the average reading time (p < 0.001) and had better lesion-level and patient-level sensitivities. CONCLUSION: AI improved the sensitivity lymph node segmentation by radiologists with an advantage in reading time.
Subject(s)
Artificial Intelligence , Deep Learning , Humans , Retrospective Studies , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Tomography, X-Ray Computed/methodsABSTRACT
The quality control of Chinese medicinal decoction pieces is one of the key tasks in the traditional Chinese medicine industry. In this study, multi-source information fusion was employed to fuse the data from near-infrared spectroscopy, electronic tongues, and other tests and establish an overall quality consistency evaluation method for Atractylodis Macrocephalae Rhizoma, which provided methodological support for the overall quality evaluation of Atractylodis Macrocephalae Rhizoma. The near-infrared spectroscopy information was measured in both static and dynamic states for 23 batches of Atractylodis Macrocephalae Rhizoma samples from different sources, and the electronic tongue sensory information, moisture content, and leachate content were measured. The overall quality of Atractylodis Macrocephalae Rhizoma was evaluated by multi-source information fusion. The results showed that the near-infrared spectroscopy information of 16122103, 801000509, 801000352, 701003656, HX21L01, and 160956 was different from that of other batches of Atractylodis Macrocephalae Rhizoma powder in the static state, and 701003298, 16122103, 701003656, 701003107, 801000229, and 18090404 were the different batches in the dynamic state. The moisture content showed no significant difference between batches. The leachate content in the batch 801000509 was different from that in other batches. The electronic tongue sensory information of 150721004, 151237, 160703004, HX21M01, HX21K04, HX21K01, and 601003516 was different from that of other batches. Furthermore, data layer fusion was employed to analyze the overall quality of Atractylodis Macrocephalae Rhizoma. Four batches, 150721004, HX21M01, HX21K04, and HX21K01, showed the parameters exceeding the 95% control limits and differed from the other samples in terms of the overall quality. This study integrated the information of moisture, near-infrared spectroscopy, and other sources to evaluate the quality consistency among 23 batches of Atractylodis Macrocephalae Rhizoma samples, which provides a reference for the quality consistency evaluation of Chinese medicinal decoction pieces.
Subject(s)
Atractylodes , Drugs, Chinese Herbal , Quality Control , Rhizome , Spectroscopy, Near-Infrared , Rhizome/chemistry , Atractylodes/chemistry , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/analysis , Drugs, Chinese Herbal/standards , Spectroscopy, Near-Infrared/methodsABSTRACT
BACKGROUND: To examine the association of serum 25-hydroxyvitamin D (25[OH]D) with colorectal cancer (CRC) risk in adults with type 2 diabetes (T2D). METHODS: Using UK Biobank data, this study included 18,453 adults with T2D. Serum 25(OH)D concentrations were determined by the chemiluminescent immunoassay method. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC outcomes. RESULTS: During a median follow-up of 8.8 years, there were 284 incident CRC cases. Compared with adults with serum 25(OH)D concentrations <25.0 nmol/L, the adjusted HRs (95% CIs) for lower to higher serum 25(OH)D concentrations (25.0 to <50.0, 50.0 to <75.0, and ≥75.0 nmol/L) were 0.61 (0.46-0.82), 0.50 (0.34-0.74), and 0.53 (0.30-0.94), respectively (Ptrend = 0.001). The risk of CRC decreased by 19.0% for per 1-SD increment in serum 25(OH)D concentrations. A nonlinear association of serum 25(OH)D concentrations with CRC risk was observed using a restricted cubic spline analysis (P nonlinearity = 0.002). CONCLUSIONS: Higher serum 25(OH)D concentrations were significantly and nonlinearly associated with a lower risk of CRC. These findings highlight the potential benefits of maintaining adequate vitamin D levels in CRC prevention among adults with T2D.