Experimental localization of metal-binding sites reveals the role of metal ions in type II DNA topoisomerases.

Metal ions have important roles in supporting the catalytic activity of DNA-regulating enzymes such as topoisomerases (topos). Bacterial type II topos, gyrases and topo IV, are primary drug targets for fluoroquinolones, a class of clinically relevant antibacterials requiring metal ions for efficient drug binding. While the presence of metal ions in topos has been elucidated in biochemical studies, accurate location and assignment of metal ions in structural studies have historically posed significant challenges. Recent advances in X-ray crystallography address these limitations by extending the experimental capabilities into the long-wavelength range, exploiting the anomalous contrast from light elements of biological relevance. This breakthrough enables us to confirm experimentally the locations of Mg2+ in the fluoroquinolone-stabilized Streptococcus pneumoniae topo IV complex. Moreover, we can unambiguously identify the presence of K+ and Cl- ions in the complex with one pair of K+ ions functioning as an additional intersubunit bridge. Overall, our data extend current knowledge on the functional and structural roles of metal ions in type II topos.

Development and validation of the patient-reported outcome for older people living with HIV/AIDS in China (PROHIV-OLD).

BACKGROUND: The involvement of quality of life as the UNAIDS fourth 90 target to monitor the global HIV response highlighted the development of patient-reported outcome (PRO) measures to help address the holistic needs of people living with HIV/AIDS (PLWHA) beyond viral suppression. This study developed and tested preliminary measurement properties of a new patient-reported outcome (PROHIV-OLD) measure designed specifically to capture influences of HIV on patients aged 50 and older in China. METHODS: Ninety-three older people living with HIV/AIDS (PLWHA) were interviewed to solicit items and two rounds of patient cognitive interviews were conducted to modify the content and wording of the initial items. A validation study was then conducted to refine the initial instrument and evaluate measurement properties. Patients were recruited between February 2021 and November 2021, and followed six months later after the first investigation. Classical test theory (CTT) and item response theory (IRT) were used to select items using the baseline data. The follow-up data were used to evaluate the measurement properties of the final instrument. RESULTS: A total of 600 patients were recruited at the baseline. Of the 485 patients who completed the follow-up investigation, 483 were included in the validation sample. The final scale of PROHIV-OLD contained 25 items describing five dimensions (physical symptoms, mental status, illness perception, family relationship, and treatment). All the PROHIV-OLD dimensions had satisfactory reliability with Cronbach's alpha coefficient, McDonald's ω, and composite reliability of each dimension being all higher than 0.85. Most dimensions met the test-retest reliability standard except for the physical symptoms dimension (ICC = 0.64). Confirmatory factor analysis supported the structural validity of the final scale, and the model fit index satisfied the criterion. The correlations between dimensions of PROHIV-OLD and MOS-HIV met hypotheses in general. Significant differences on scores of the PROHIV-OLD were found between demographic and clinical subgroups, supporting known-groups validity. CONCLUSIONS: The PROHIV-OLD was found to have good feasibility, reliability and validity for evaluating health outcome of Chinese older PLWHA. Other measurement properties such as responsiveness and interpretability will be further examined.

Factors affecting balance ability among middle-aged and elderly peoplewith depressive symptoms / 预防医学

Objective@#To explore the factors affecting balance ability among middle-aged and elderly people with depressive symptoms, so as to provide the evidence for improving balance ability and prevention of falls.@*Methods@#Based on the 2015 database of China Health and Retirement Longitudinal Study (CHARLS), demographic information, lifestyle and health status were collected from people aged 45 years and older who scored 10 and more on the Self-rating Depression Scale or took antidepressants. The balance ability was assessed by semi-tandem and full-tandem stand tests, which was defined as meeting the standard when both tests were completed. Factors affecting the balance ability among middle-aged and elderly people with depressive symptoms were identified using a multivariable logistic regression model.@*Results@#Data were collected from 4 263 participants with an mean age of (60.73±8.53) years, including 1 748 males (41.00%) and 2 515 females (59.00%). There were 1 241 people failed to meet the standard of balance ability test, accounting for 29.11%. Multivariable logistic regression analysis showed that participants who were at ages of 65 years and older (OR=1.234, 95%CI: 1.071-1.421), were female (OR=1.422, 95%CI: 1.161-1.741), were physically disabled (OR=1.309, 95%CI: 1.127-1.521) and had physical pain (OR=1.170, 95%CI: 1.023-1.340) had higher risks of failing to meet the standard of balance ability test, while participants who took naps (OR=0.856, 95%CI: 0.748-0.980), never smoked (OR=0.641, 95%CI: 0.517-0.793) and had social activities (OR=0.864, 95%CI: 0.755-0.988) had lower risks of failing to meet the standard of balance ability test.@*Conclusion@#The balance ability among middle-aged and elderly people with depressive symptoms was associated with age, gender, napping, smoking, social activities, physical disability and physical pain.

Integrative analysis of transcriptome and proteome in primary Sjögren syndrome.

OBJECTIVE: Primary Sjögren's syndrome (pSS) is a intricate autoimmune disease mainly characterized of immune-mediated destruction of exocrine tissues, such as salivary and lacrimal glands, occurring dry mouth and eyes. Although some breakthroughs in understanding pSS have been uncovered, many questions remain about its pathogenesis, especially the internal relations between exocrine glands and secretions. METHOD: Transcriptomic and proteomic analyses were conducted on salivary tissues and saliva in experimental Sjögren syndrome (ESS). The ESS model was established by immunization with salivary gland protein. The expression of mRNAs and proteins in salivary tissues and saliva were determined by high-throughput sequencing transcriptomic analysis and LC-MS/MS-based proteome, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to recognize dysregulated genes and proteins. The association between RNA and protein abundance was investigated to provides a comprehensive understanding of RNA-protein correlations in the pathogenesis of pSS. RESULTS: As a result, we successfully established the ESS model. We recognized 3221 differentially expressed genes (DEGs) and 253 differentially expressed proteins (DEPs). The sample analysis showed that 61 proteins overlapped through the integrative analysis of transcriptomics and proteomics data. The enrichment pathway analysis of DEGs and DEPs in samples showed alterations in renin-angiotensin-system (RAS), lysosome, and apoptosis. Notably, we found that some genes, such as AGT, FN1, Klk1b26, Klk1, Klk1b5, Klk1b3 had a consistent trend in the regulation at the RNA and protein levels and might be potential diagnostic biomarkers of pSS. CONCLUSION: Herein, we found critical processes and potential biomakers that may contribute to pSS pathogenesis by analyzing dysregulated genes and pathways. Additionally, the integrative multi-omics datasets provided additional insight into understanding complicated disease mechanisms.

Effects of pharmacist-led interventions on glycaemic control, adherence, disease management and health-related quality of life in patients with type 2 diabetes: a protocol for a network meta-analysis.

INTRODUCTION: The increase in the number of patients with uncontrolled type 2 diabetes mellitus (T2DM) is in need of effective management interventions. However, research to date has been limited to the evaluation of the outcomes of community pharmacists alone. Therefore, the aim of the study protocol is to compare the effects of clinical pharmacist-led intervention strategies for the management of T2DM in the outpatient settings. METHOD AND ANALYSIS: The study will collect and analyse data applying standard Cochrane methodological procedures. A search for eligible studies and ongoing trials will be conducted using PubMed, Embase, Medline (via Ovid), EBSCO (via Ovid), Lippincott Williams & Wilkins (LWW) Journals (via Ovid), ProQuest Health and Medical Complete, and ClinicalTrials.gov (clinicaltrials.gov) from database inception to December 2023. Clinical and health outcomes will be measured using both glycaemic control related indicators (eg, glycated haemoglobin, fasting blood glucose, postprandial glucose) and general indicators (eg, adherence, disease management and health-related quality of life). The meta-analysis will conduct pairwise meta-analysis using random effects models and network meta-analysis (NMA) employing the Bayesian hierarchical model. The visualisation and statistical analysis will be carried out using RevMan, R Studio and ADDIS. Additionally, we will evaluate the certainty of the evidence by using Grading of Recommendations Assessment, Development and Evaluation system. ETHICS AND DISSEMINATION: There will be no primary data collection from NMA participants, and there is no requirement for formal ethical review. Our aim is to present the results of this NMA in a peer-reviewed scientific journal, at conferences, and in the mainstream media. PROSPERO REGISTRATION NUMBER: CRD42022355368.

Immune infiltration analysis reveals immune cell signatures in salivary gland tissue of primary Sjögren's syndrome.

Introduction: Mouse models are the basis for primary Sjögren's syndrome (pSS) research. However, the depth of comparisons between mice and humans in salivary gland (SG) immune cells remains limited. Methods: The gene expression profiles of SGs from normal subjects and pSS patients were downloaded from the Gene Expression Comprehensive Database. The proportion of infiltrating immune cell subsets was then assessed by cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT). An experimental Sjögren's syndrome (ESS) mouse model was successfully constructed using SG protein. Based on mouse SG tissue RNA-Seq data, the seq-ImmuCC model was used to quantitatively analyze the compositional ratios of 10 immune cells in pSS patients and mouse model SG tissues. Results: Computed and obtained 31 human data samples using the CIBERSORT deconvolution method. The immune cell infiltration results showed that, compared to normal human SG tissue, the content of gamma delta T cells was significantly different from naive CD4+ T cells and significantly increased, while the plasma cell content decreased. Principal component analysis indicated differences in immune cell infiltration between pSS patients and normal subjects. Meanwhile, for ESS model mouse data analysis, we found that the proportion of macrophages increased, while the proportion of CD4+ T cells, B cells, and monocytes decreased. Furthermore, we found that the proportion of monocytes was decreased, while the proportion of macrophages was increased in the SG tissues of pSS patients and model mice. The infiltration of CD4+ T, CD8+ T, and B cells also showed some differences. Discussion: We comprehensively analyzed SG immune infiltration in pSS patients and model mice. We demonstrated conserved and nonconserved aspects of the immune system in mice and humans at the level of immune cells to help explain the primary regulation of immune mechanisms during the development of Sjögren's syndrome.

Meta-analysis of neonicotinoid insecticides in global surface waters.

Neonicotinoids (NEOs) are a class of insecticides that have high insecticidal activity and are extensively used worldwide. However, increasing evidence suggests their long-term residues in the environment and toxic effects on nontarget organisms. NEO residues are frequently detected in water and consequently have created increasing levels of pollution and pose significant risks to humans. Many studies have focused on NEO concentrations in water; however, few studies have focused on global systematic reviews or meta-analyses of NEO concentrations in water. The purpose of this review is to conduct a meta-analysis on the concentration of NEOs in global waters based on published detections from several countries to extend knowledge on the application of NEOs. In the present study, 43 published papers from 10 countries were indexed for a meta-analysis of the global NEO distribution in water. Most of these studies focus on the intensive agricultural area, such as eastern Asia and North America. The order of mean concentrations is identified as imidacloprid (119.542 ± 15.656 ng L-1) > nitenpyram (88.076 ± 27.144 ng L-1) > thiamethoxam (59.752 ± 9.068 ng L-1) > dinotefuran (31.086 ± 9.275 ng L-1) > imidaclothiz (24.542 ± 2.906 ng L-1) > acetamiprid (23.360 ± 4.015 ng L-1) > thiacloprid (11.493 ± 5.095 ng L-1). Moreover, the relationships between NEO concentrations and some environmental factors are analyzed. NEO concentrations increase with temperature, oxidation-reduction potential, and the percentage of cultivated crops but decrease with stream discharge, pH, dissolved oxygen, and precipitation. NEO concentrations show no significant relations to turbidity and conductivity.

Biotransformation of bisphenol F by white-rot fungus Phanerochaete sordida YK-624 under non-ligninolytic condition.

Environmental bisphenol F (BPF) has a cyclic endocrine disruption effect, seriously threatening animal and human health. It is frequently detected in environmental samples worldwide. For BPF remediation, biological methods are more environmentally friendly than physicochemical methods. White-rot fungi have been increasingly studied due to their potential capability to degrade environmental pollutants. Phanerochaete sordida YK-624 has been shown to degrade BPF by ligninolytic enzymes under ligninolytic conditions. In the present study, degradation of BPF under non-ligninolytic conditions (no production of ligninolytic enzymes) was investigated. Our results showed that BPF could be completely removed after 7-d incubation. A metabolite of BPF, 4,4'-dihydroxybenzophenone (DHBP) was identified by mass spectrometry and nuclear magnetic resonance, and DHBP was further degraded by this fungus to form 4-hydroxyphenyl 4-hydroxybenzoate (HPHB). DHBP and HPHB were the intermediate metabolites of BPF and would be further degraded by P. sordida YK-624. We also found that cytochrome P450s played an important role in BPF degradation. Additionally, transcriptomic analysis further supported the involvement of these enzymes in the action of BPF degradation. Therefore, BPF is transformed to DHBP and then to HPHB likely oxidized by cytochrome P450s in P. sordida YK-624. Furthermore, the toxicological studies demonstrated that the order of endocrine-disrupting activity for BPF and its metabolites was HPHB > BPF > DHBP. KEY POINTS: • White-rot fungus Phanerochaete sordida YK-624 could degrade BPF. • Cytochrome P450s were involved in the BPF degradation. • The order of endocrine disrupting activity was: HPHB > BPF > DHBP.

RNA-sequencing analysis of bisphenol A biodegradation by white-rot fungus Phanerochaete sordida YK-624.

Bisphenol A (BPA) is a representative example of an endocrine-disrupting chemical. It is one of the most produced chemical substances in the world, but it causes harmful effects in organisms, such that the effective degradation of BPA is critical. The white-rot fungus Phanerochaete sordida YK-624 has been shown to effectively degrade BPA under ligninolytic and non-ligninolytic conditions. However, it is still unclear what kinds of enzymes are involved in BPA degradation. To explore the mechanism of BPA degradation, the present study analysed the functional genes of P. sordida YK-624 using RNA-sequencing (RNA-Seq). Oxidation-reduction process and metabolic pathway were enriched under ligninolytic and non-ligninolytic conditions by Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. It is suggested that BPA might be used as a carbon source by P. sordida YK-624. Lignin peroxidase and cytochrome P450 were detected in upregulated differentially expressed genes (DEGs). The lignin-degrading enzyme lignin peroxidase and the intracellular cytochrome P450 system were involved in BPA degradation by P. sordida YK-624, respectively. Furthermore, quantitative real-time PCR (qPCR) was used to validate the reliability of the RNA-Seq results. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03298-w.