Analysis of Co-localized Biosynthetic Gene Clusters Identifies a Membrane-Permeabilizing Natural Product.

Combination therapy is an effective strategy to combat antibiotic resistance. Multiple synergistic antimicrobial combinations are produced by enzymes encoded in biosynthetic gene clusters (BGCs) that co-localize on the bacterial genome. This phenomenon led to the hypothesis that mining co-localized BGCs will reveal new synergistic combinations of natural products. Here, we bioinformatically identified 38 pairs of co-localized BGCs, which we predict to produce natural products that are related to known compounds, including polycyclic tetramate macrolactams (PoTeMs). We further showed that ikarugamycin, a PoTeM, increases the membrane permeability of Acinetobacter baumannii and Staphylococcus aureus, which suggests that ikarugamycin might be an adjuvant that facilitates the entry of other natural products. Our work outlines a promising avenue to discover synergistic combinations of natural products by mining bacterial genomes.

Serum lipid metabolism characteristics and potential biomarkers in patients with unilateral sudden sensorineural hearing loss.

BACKGROUND: Glycerophospholipids (GPLs) are essential for cell membrane structure and function. Sphingomyelin and its metabolites regulate cell growth, apoptosis, and stress responses. This study aimed to investigate lipid metabolism in patients experiencing sudden sensorineural hearing loss across all frequencies (AF-SSNHL). METHODS: The study included 60 patients diagnosed with unilateral AF-SSNHL, among whom 30 patients had a level of hearing improvement ≥ 15 dB after 6 months of follow-up. A propensity score-matched (2:1) control group was used. Liquid chromatography‒mass spectrometry based untargeted lipidomics analysis combined with multivariate statistics was performed to investigate the lipids change. The "lipidome" R package and weighted gene co-expression network analysis (WGCNA) were utilised to assess the lipids' structural features and the association between lipids and hearing. RESULTS: Lipidomics successfully differentiated the AF-SSNHL group from the control group, identifying 17 risk factors, mainly including phosphatidylcholine (PC), phosphatidylethanolamine (PE), and related metabolites. The ratios of lysophosphatidylcholine/PC, lysophosphatidylethanolamine/PE, and lysodimethylphosphatidylethanolamine/PE were upregulated, while some glycerophospholipid (GPL)-plasmalogens were downregulated in the AF-SSNHL group, indicating abnormal metabolism of GPLs. Trihexosylceramide (d34:1), PE (18:1e_22:5), and sphingomyelin (d40:3) were significantly different between responders and nonresponders, and positively correlated with hearing improvement. Additionally, the results of the WGCNA also suggested that partial GPL-plasmalogens were positively associated with hearing improvement. CONCLUSION: AF-SSNHL patients exhibited abnormally high blood lipids and pronounced GPLs metabolic abnormalities. Sphingolipids and GPL-plasmalogens had an association with the level of hearing improvement. By understanding the lipid changes, clinicians may be able to predict the prognosis of hearing recovery and personalize treatment approaches.

Sarcopenic obesity and falls in older adults: A validation study of ESPEN/EASO criteria and modifications in Western China communities.

OBJECTIVES: The ESPEN and the EASO recently developed consensus criteria for sarcopenic obesity (SO), employing the skeletal muscle mass to weight (SMM/W) ratio. Emerging evidence suggests that adjusting skeletal muscle mass for body mass index (SMM/BMI) could enhance the predictive accuracy for health outcomes. We aimed to validate the ESPEN/EASO criteria and explore the potential benefits of the SMM/BMI adjustment in predicting falls among older adults in Western China. METHODS: We conducted a multicenter, cross-sectional study and included community-dwelling older adults. The diagnosis of SO was determined using the standard ESPEN/EASO consensus criteria (SOESPEN) and a modified version adjusting SMM/BMI (SOESPEN-M). The associations of SOESPEN, SOESPEN-M, and their components with falls were analyzed. RESULTS: Among the 1353 participants, the prevalence of SO was 13.2 % (SOESPEN) and 11.4 % (SOESPEN-M), which increased with age and higher BMI levels. Within participants with a normal BMI, 4.2 % and 6.2 % were found to have SOESPEN and SOESPEN-M, respectively. SMM/W and SMM/BMI negatively correlated with fall risk (p=0.042 and p=0.021, respectively). Upon adjusting for confounders, only SOESPEN was significantly associated with falls (odds ratios [OR] 1.61, 95 % confidence interval [CI] 1.08 to 2.40), whereas the association for SOESPEN-M did not achieve significance (OR 1.55, 95 % CI 0.99 to 2.43). CONCLUSIONS: This research validated the ESPEN/EASO criteria (SOESPEN) and their modified version (SOESPEN-M) among community-dwelling older adults in Western China. The SMM/BMI adjustment appears to offer a lower estimate of SO prevalence, with only SOESPEN showing a significant association with falls.

Associations of parity and cognitive decline, depression, and chronic comorbidity in West China: Results from WCHAT study.

OBJECTIVE: To investigate the associations between parity (the number of offspring a female has borne) and cognitive function, depression, and chronic comorbidity in Western China. METHODS: A total of 846 women aged 50-55 years were included in the current analysis. Cognitive status was measured using a 10-item short portable mental status questionnaire (SPMSQ). Depressive symptoms were assessed using the 15-item geriatric depression scale (GDS-15). Other characteristics were self-reported. The associations between parity and cognitive decline, depression, and chronic comorbidity were analyzed using univariable and multivariable models. Multivariable models were adjusted for age, ethnic group, occupation, marital status, educational level, lifestyle factors, and sleeping time. RESULTS: Among the enrolled women, 26.71% were either childless or had one child, 47.40% had two children, 18.32% had three children, and 7.57% had ≥4 children. Compared to women with low parity, women with two or more children exhibited a higher risk of cognitive decline. Moreover, having four or more children was significantly associated with depression and chronic comorbidity. After adjusting covariates, women with three or more children exhibited a higher risk of cognitive decline than those with low parity. However, high parity was not significantly associated with depression or chronic comorbidity after adjustment for covariates. CONCLUSION: Our study showed that ≥3 children was associated with cognitive decline in women. Longitudinal studies are needed to evaluate this conclusion and to investigate the mechanisms involved. More importantly, families and societies should pay more attention to women's long-term health outcomes related to fertility.

Psychological Status and Warfarin Therapy in Patients after Valve Replacement during the COVID-19 Pandemic: A Cross-sectional Study.

OBJECTIVE: The standardization of warfarin anticoagulant therapy is the key to lifelong treatment for patients after heart valve replacement. The present study explored the possible risk factors for anxiety and depression during the coronavirus disease 2019 (COVID-19) pandemic and analyzed the influence of psychological state on medication safety. METHODS: Eligible patients received a web-based questionnaire survey via the Wenjuanxing platform during outpatient visits. Depression was evaluated by the Self-Rating Depression Scale (SDS). Anxiety was evaluated by the Self-Rating Anxiety Scale (SAS). Medication adherence was evaluated by the Morisky scale. RESULTS: A total of 309 patients (aged 52.2±11.4 years) were included in the present study. The SDS score of all included patients was 36.9±9.4 points, of which 11 (3.6%) patients were diagnosed as having depression. The SAS score of all included patients was 43.1±9.3 points, of which 71 (23%) patients were diagnosed as having anxiety. Seven patients (2.3%) had both anxiety and depression. Logistic regression analysis revealed that only monthly income was an independent influencing factor for depression. Regarding anxiety, patients who underwent repeated operations had a 2.264-fold greater risk, and patients who received combination medication had a 2.140-fold greater risk. More bleeding events and coagulation disorders could be observed in patients with anxiety, depression or both. When anxiety occurred, patients showed worse medication adherence. However, depression had no significant effect on medication adherence. CONCLUSION: During the COVID-19 pandemic, the detection rate of mental illnesses such as anxiety and depression was high, which seriously affected the medication safety of warfarin. Analysis of its influencing factors will provide a reference for further standardized regulation of warfarin anticoagulant therapy after valve replacement.

Genetic characteristics and phylogenetic analysis of coxsackievirus A6 isolated in Linyi, China, 2022-2023.

Hand, foot and mouth disease (HFMD) was one of the most common infectious disease in the past few decades. After 2013, coxsackievirus A6 (CVA6) has replaced enterovirus 71 (EV-A71) and coxsackievirus A16 (CVA16), becoming the predominant pathogen responsible for HFMD in many areas in China. The objective of this study is to investigate the genetic characteristics and molecular epidemiology of CVA6 in Linyi from 2022 to 2023. A total of 965 HFMD cases were enrolled in this study and analyses based on VP1 nucleotide sequences were performed to determine the evolutionary trajectory of CVA6. In 2022, 281 (281/386, 72.8%) were positive for enterovirus (EVs), and 217 (217/281, 77.2%) were CVA6 positive. In 2023, 398 (398/579, 68.7%) samples were positive for EVs, and 243 (243/398, 61.1%) were CVA6 positive. Six sequences were selected from each year for the homology analysis. The results showed that 12 strains isolated in Linyi were far from the prototype strain (AY421764) and the first CVA6 strain reported in China (JQ364886). Phylogenetic analysis showed that the CVA6 strains isolated in Linyi all belonged to D3 subgenotype. CVA6 is emerging as a common pathogen causing HFMD in Linyi, and continuous surveillance of HFMD etiological agents is necessary.

Association of Renal Impairment with Clinical Outcomes Following Endovascular Therapy in Acute Basilar Artery Occlusion.

Purpose: Renal impairment (RI) is associated with unfavourable outcome after acute ischaemic stroke with anterior circulation large vessel occlusion. We assessed the association of RI with clinical outcomes in patients with acute basilar artery occlusion (ABAO), and the impact of RI on the effects of endovascular therapy (EVT) versus standard medical treatment (SMT). Patients and Methods: We used data from the BASILAR registry, an observational, prospective, nationwide study of patients with ABAO in routine clinical practice in China. Baseline estimated glomerular filtration rate (eGFR) was recorded at admission. The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Secondary outcomes included favourable outcome (mRS score 0-3), mortality, and symptomatic intracranial haemorrhage (sICH). Multivariate logistic regression was used to assess the association of RI with mortality and functional improvement at 90 days. Results: Among 829 patients enrolled, 747 patients were analysed. The median baseline eGFR was 89 mL/min/1.73m2 (IQR, 71-100), and 350 (46.8%), 297 (39.8%), and 100 (13.4%) patients had baseline eGFR values of ≥90, 60-89, and <60 mL/min/1.73m2, respectively. RI was associated with increased mortality (adjusted odds ratio [aOR], 1.97; 95% CI, 1.15-3.67) at 90 days and decreased survival probability (aOR 1.74; 95% CI, 1.30-2.33) within 1 year. EVT was associated with better functional improvement (common aOR, 2.50; 95% CI, 1.43-4.35), favourable outcome (aOR 5.42; 95% CI, 1.92-15.29) and lower mortality (aOR 0.47; 95% CI, 0.25-0.88) in ABAO patients with eGFR ≥90 mL/min/1.73m2. However, RI was not modified the relationship of EVT with functional improvement (common aOR, 3.03; 95% CI, 0.81-11.11), favourable outcome (aOR 2.10; 95% CI, 0.45-9.79), and mortality (aOR 0.56; 95% CI, 0.15-2.06) by eGFR categories. Conclusion: RI is associated with reduced efficacy of EVT and worse functional outcome and higher mortality at 3 months and lower survival probability at 1 year in patients with ABAO.

Vaginal flora in HPV infection: a cross­sectional analysis.

OBJECTIVE: The vaginal flora has been reported to be associated with human papillomavirus (HPV) infection. The purpose of this study was to investigate the characteristics of the cervical microbiota in patients with HPV infection and to analyse the changes in the vaginal flora and enzyme profiles in females with HPV infection. METHODS: We conducted a cross-sectional study involving 206 participants who underwent HPV genotyping, sexually transmitted diseases pathogen testing, cytology examination, and microbiome analysis. Additionally, we collected 115 HPV-negative samples and 48 HPV-positive samples for 16S rRNA amplicon sequencing. The vaginal microbial communities of both groups were analysed for diversity and differences to explore their association with HPV infection. RESULTS: The abundance of Lactobacillus was found to be reduced, while Gardnerella vaginalis was significantly more prevalent in the HPV + group. In terms of alpha diversity indices, the Shannon index (P = .0036) and Simpson index (P = .02) were higher in the HPV + group compared to the HPV - group, indicating greater community diversity in the HPV + group. Among the 10 sexually transmitted diseases pathogens analysed, Uup3 and Uup6 were significantly associated with HPV infection. Statistically significant differences were observed in Nugent scores and bacterial vaginosis between the two groups (P < .05). In functional analysis, 11 proteins and 13 enzymes were found to be significantly altered in the HPV + group. CONCLUSION: Our study demonstrates that disruptions in the vaginal flora are associated with HPV infection. Reduced levels of Lactobacillus, increased prevalence of Gardnerella, and abnormal enzyme profiles are closely linked to HPV infection.

The purpose of this study was to investigate the characteristics of the cervical microbiota in patients with human papillomavirus infection and to analyse the changes in the vaginal flora and enzyme profiles in females with human papillomavirus infection. We conducted a cross-sectional study involving 206 participants who underwent human papillomavirus genotyping, sexually transmitted diseases pathogen testing, cytology examination, and microbiome analysis. Additionally, we collected 115 HPV-negative samples and 48 HPV-positive samples for 16S rRNA amplicon sequencing. The abundance of Lactobacillus was found to be reduced, while Gardnerella vaginalis was significantly more prevalent in the HPV + group. In functional analysis, 11 proteins and 13 enzymes were found to be significantly altered in the HPV + group. Our study demonstrates that disruptions in the vaginal flora are associated with HPV infection. Reduced levels of Lactobacillus, increased prevalence of Gardnerella, and abnormal enzyme profiles are closely linked to HPV infection.

Applicability of wheat brewer's spent grain in steamed bread-making based on physicochemical and visual profiles assessment of doughs and breads.

Brewer's spent grain (BSG), one of the main byproducts of brewing, has been widely used in the food industry due to its high nutritional components of dietary fiber, proteins, polysaccharides, and polyphenols. This study investigated the influence of wheat brewer's spent grain (WBSG) on the physicochemical properties of dough and steamed bread-making performance. The incorporation of WBSG in wheat flour significantly increased water absorption, development time, and degree of softening while decreasing the stability time of blending dough. Excessive WBSG up to 20% restricted the dough formation. WBSG contributed to the remarkable increase of pasting viscosities, pasting temperature, and immobilized water proportion in doughs. For all doughs, storage moduli (G') were higher than viscous moduli (G″). WBSG addition resulted in higher moduli values and the formation of highly networked gluten structure, finally leading to the lower specific volume, spread ratio, and elasticity of bread. Lightness (L*) of bread decreased with increasing WBSG while redness (a*) and total color difference (ΔE) augmented. Low WBSG addition (≤5%) could endow steamed bread with the appearance of a chocolate-like color and pleasant malt flavor, which is acceptable for most consumers. Nevertheless, the improvement of nutritional and functional characteristics of steamed bread incorporated with WBSG should be more focused in the future.

The levels of women's awareness, experience, acceptability and preference for Vaginal Human Papillomavirus (HPV) self-sampling in three provinces of China: a cross-sectional study.

BACKGROUND: The primary screening technique for precancerous lesions and cervical cancer is human papillomavirus (HPV) testing, and HPV self-sampling has been shown to be consistent with clinician sampling in terms of the accuracy of the results and may improve cervical cancer screening rates. The aim of this study was to understand the level of awareness, experience, acceptability, and preference for vaginal HPV self-sampling among women in Jiangsu, Zhejiang, and Shanghai, China, and to analyze the possible influencing factors to determine the feasibility of implementing self-sampling. METHODS: Overall, 1793 women were included in the data analysis. A self-administered questionnaire was utilized. In addition to descriptive analysis, univariate and multivariate analyses were used to explore the associations between sociodemographic features, history of cervical cancer screening, and the level of awareness, experience, acceptability, and preference for HPV self-samples. RESULTS: The participants' level of awareness of and experience with HPV self-sampling were moderate. A total of 88.8% of participants rated the acceptability as "high", and self-sampling was preferred by 64.2% of them for cervical cancer screening. People aged 45 to 54 years showed a preference for both clinician sampling(OR = 1.762 (1.116-2.163)) and self-sampling (OR = 1.823 (1.233-2.697)). Those who had graduated from high school or above (OR = 2.305 (1.517-3.503), OR = 2.432 (1.570-3.768), OR = 3.258 (2.024-5.244)) preferred clinician-sampling, and those with a bachelor's degree or above (OR = 1.664 (1.042-2.657)) preferred self-sampling. Middle- and high-income individuals showed no preference for either sampling method (OR < 1). CONCLUSIONS: HPV self-sampling is widely accepted, but awareness, experience and preferences need to be improved. These results may help to adjust public health strategies for the early inclusion of HPV self-sampling as a screening method in national initiatives to prevent cervical cancer.

Comparative Study on the Mechanism of Macrophage Activation Induced by Polysaccharides from Fresh and Dried Longan.

Longan (Dimcarpus longan Lour.) is a kind of traditional fruit used as a medicine and a food. Fresh longan is primarily consumed as a fruit, whereas dried longan is commonly employed for medicinal purposes. The differences in the immunomodulatory activities and mechanisms of polysaccharides between dried and fresh longan remain unclear. The present study comparatively analyzed the mechanisms of macrophage activation induced by polysaccharides from dried (LPG) and fresh longan (LPX). The results revealed that LPG and LPX differentially promoted macrophage phagocytosis and the secretion of NO, TNF-α, and IL-6. RNA-seq analysis revealed that LPG and LPX differentially affected gene expression in macrophages. The LPG treatment identified Tnf and chemokine-related genes as core genes, while myd88 and interferon-related genes were the core genes affected by LPX. A comprehensive analysis of the differentially expressed genes showed that LPG initiated macrophage activation primarily through the TLR2/4-mediated TRAM/TRAF6 and CLR-mediated Src/Raf1 NF-κB signaling pathways. LPX initiated macrophage activation predominantly via the CLR-mediated Bcl10/MALT1 and NLR-mediated Rip2/TAK1 MAPK and NF-κB signaling pathways. Interestingly, the non-classical NF-κB signaling pathway was activated by polysaccharides in both dried and fresh longan to elicit a slow, mild immune response. LPG tends to promote immune cell migration to engage in the immune response, while LPX facilitates antigen presentation to promote T cell activation. These findings contribute insights into the mechanisms underlying the differences in bioactivity between dried and fresh longan and their potential applications in immune-enhancing strategies and functional-food development.

Serum Prealbumin as a Potential Predictive Factor for Age-Related Hearing Loss: A Retrospective Study.

Objectives: Age-related hearing loss (ARHL) is a complex disease associated with the interaction of multiple factors. Furthermore, indicators of liver function represent the body's metabolic, immune, and repair abilities. This study investigated correlations between liver function and ARHL. Methods: A total of 107 patients with ARHL and 107 age- and sex-matched healthy volunteers were included. Linear correlations, logistic regression, and receiving operator characteristic curves were used to assess the associations between liver function and ARHL. Results: Serum prealbumin (PAB) levels were significantly lower in the ARHL group compared to the control group. Logistic regression analysis indicated that low PAB levels may be an independent risk factor for ARHL. The ARHL was divided into 2 groups according to the degree of hearing loss (moderately severe-to-profound and mild-to-moderate); the median ages in the 2 groups were 70.48 and 66.85 years, respectively, with the difference being significant. Age was an independent risk factor for moderately severe-to-profound ARHL, as shown by the logistic regression analysis. Conclusions: Lower PAB levels in patients with ARHL suggested that PAB may be a risk factor for ARHL. Furthermore, higher age in patients with ARHL was associated with a greater degree of hearing loss.

The relationship between asymmetrical grip strength criteria and fall incidence among middle-aged and older Chinese adults.

PURPOSE: Current handgrip strength (HGS) protocols employ a variety of criteria, affecting the assessment of asymmetric HGS. The impact of these different criteria on fall prediction is understudied. This study was devised to compare the relative performance of average and maximum HGS asymmetry criteria as tools to predict fall incidence among middle-aged or older adults in China. METHODS: 9627 Chinese adults 50 + years of age who were participants in the China Health and Retirement Longitudinal Study (2013-2015 waves) were evaluated. The measurement of HGS was achieved based on either the maximum recorded value (HGSmax) or the average (HGSave), and these values were employed for the calculation of HGS asymmetry. Fall incidence over a 2-year period was evaluated based on self-reported data. Logistic regression analyses were utilized to determine the predictive performance of HGSmax asymmetry or HGSave asymmetry when gaging 2-year fall risk. RESULTS: Significant differences in overall rates of HGS asymmetry and the rates of subdivisions thereof were observed when comparing the HGSmax and HGSave criteria, with moderate consistency (kappa = 0.599, p < 0.001). Over the 2-year follow-up period, 1743 fall incidents were recorded. Adjusted logistic regression models indicated that only HGSmax asymmetry > 30.0% was significantly related to fall risk (p = 0.034, odds ratio = 1.36, 95% confidence interval: 1.02-1.81). CONCLUSION: These findings highlight the importance of HGS criteria in detecting HGS asymmetry, and suggest that HGSmax is a more robust criterion for predicting fall risk among Chinese adults 50 + years of age.

Post-treatment with Resolvin D1 attenuates pulmonary hypertension by inhibiting endothelial-to-mesenchymal transition.

Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling. Endothelial-to-mesenchymal transition (EndMT) is an important manifestation and mechanism of pulmonary vascular remodeling. Resolvin D1 (RvD1) is an endogenous lipid mediator promoting the resolution of inflammation. However, the role of RvD1 on EndMT in PH remains unknown. Here, we aimed to investigate the effect and mechanisms of RvD1 on the treatment of PH. We showed that RvD1 and its receptor FPR2 expression were markedly decreased in PH patients and both chronic hypoxia-induced PH (CH-PH) and sugen 5416/hypoxia-induced PH (SuHx-PH) mice models. RvD1 treatment decreased right ventricular systolic pressure (RVSP) and alleviated right ventricular function, and reduced pulmonary vascular remodeling and collagen deposition in the perivascular of both two PH mice models. Then, RvD1 inhibited EndMT in both the lungs of PH mice models and primary cultured human umbilical vein endothelial cells (HUVECs) treated with TGF-ß and IL-1ß. Moreover, RvD1 inhibited EndMT by downregulating Smad2/3 phosphorylation in vivo and in vitro via FPR2. In conclusion, our date suggest that RvD1/FPR2 axis prevent experimental PH by inhibiting endothelial-mensenchymal-transition and may be a therapeutic target for PH.

Identification of potential biomarkers and pathways for asthenozoospermia by bioinformatics analysis and experiments.

Background: Asthenozoospermia, a type of male infertility, is primarily caused by dysfunctional sperm mitochondria. Despite previous bioinformatics analysis identifying potential key lncRNAs, miRNAs, hub genes, and pathways associated with asthenospermia, there is still a need to explore additional molecular mechanisms and potential biomarkers for this condition. Methods: We integrated data from Gene Expression Omnibus (GEO) (GSE22331, GSE34514, and GSE160749) and performed bioinformatics analysis to identify differentially expressed genes (DEGs) between normozoospermia and asthenozoospermia. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to gain insights into biological processes and signaling pathways. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules associated with asthenozoospermia. Expression levels of key genes were assessed using datasets and experimental data. Gene Set Enrichment Analysis (GSEA) and correlation analysis identified pathways associated with the hub gene and explore the relationship between the ZNF764 and COQ9 and mitochondrial autophagy-related genes. Competitive endogenous RNA (ceRNA) networks were constructed, and in vitro experiments using exosome samples were conducted to validate this finding. Results: COQ9 was identified as a marker gene in asthenozoospermia, involved in autophagy, ATP-dependent chromatin remodeling, endocytosis, and cell cycle, etc. The ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) was constructed, and PCR demonstrated that LINC00893 and COQ9 were downregulated in asthenozoospermia, while miR-125a-5p and m6A methylation level of LINC00893 were upregulated in asthenozoospermia compared to normozoospermic individuals. Conclusion: The ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) likely plays a crucial role in the mechanism of asthenozoospermia. However, further functional experiments are needed to fully understand its significance.

Activation of nicotinic acetylcholine receptor α7 subunit limits Zika viral infection via promoting autophagy and ferroptosis.

Vagus nerve regulates viral infection and inflammation via the alpha 7 nicotinic acetylcholine receptor (α7 nAChR); however, the role of α7 nAChR in ZIKA virus (ZIKV) infection, which can cause severe neurological diseases such as microcephaly and Guillain-Barré syndrome, remains unknown. Here, we first examined the role of α7 nAChR in ZIKV infection in vitro. A broad effect of α7 nAChR activation was identified in limiting ZIKV infection in multiple cell lines. Combined with transcriptomics analysis, we further demonstrated that α7 nAChR activation promoted autophagy and ferroptosis pathways to limit cellular ZIKV viral loads. Additionally, activation of α7 nAChR prevented ZIKV-induced p62 nucleus accumulation, which mediated an enhanced autophagy pathway. By regulating proteasome complex and an E3 ligase NEDD4, activation of α7 nAChR resulted in increased amount of cellular p62, which further enhanced the ferroptosis pathway to reduce ZIKV infection. Moreover, utilizing in vivo neonatal mouse models, we showed that α7 nAChR is essential in controlling the disease severity of ZIKV infection. Taken together, our findings identify an α7 nAChR-mediated effect that critically contributes to limiting ZIKV infection, and α7 nAChR activation offers a novel strategy for combating ZIKV infection and its complications.

The metal release and transformation mechanisms of V-Ti magnetite tailings: Role of the alternate flooding and drying cycles and organic acids.

V-Ti magnetite tailings (VTMTs) contain various heavy metals, such as Fe, Mn, V, Co, and Ni. The groundwater pollution caused by the tailing metal release has become a local environmental concern. Although studies have demonstrated the influence of alternate flooding and drying cycles (FDCs) on metal form and mobility in minerals, little was known about whether FDCs affect the metal release of VTMTs and the transformation of released metals. This study investigated the metal release kinetics of VTMTs and the metal transformation under FDCs in the absence and presence of acid rain (sulfuric and nitric acids) and bio-secreted organic acids (acetic, oxalic, and citric acids). The results showed that FDCs promoted metal release whether or not acids were present. The maximum released concentrations of V, Mn, Fe, Co, and Ni were as high as 78.63 mg L-1,1.47 mg L-1, 67.96 µg L-1, 1.34 mg L-1, and 0.80 mg L-1, respectively, under FDCs and citric acids. FDCs enhanced the tailing metal release by increasing the metal labile fraction proportion. However, the concentrations of released Fe, Mn, V, Co, and Ni all gradually decreased due to their (co-)precipitation. These precipitates conversely inhibited the subsequent mineral dissolution by covering the tailing surface. FDCs also enhanced the tailings' porosities by 2.94%-9.94%. The mineral dissolution, expansion and shrinkage, and changes in tension destroyed the tailing microstructure during FDCs. This study demonstrated the low metal pollution risk of VTMTs under FDCs, either in acid rain or bio-secreted organic acids. However, the increase in tailing porosity should be seriously considered as it would affect the tailing pond safety.

Developmental pathways from insomnia to suicidality: A resilience perspective.

BACKGROUND: Insomnia has been identified as a potential risk factor for suicidality. However, to date, few studies using the longitudinal-design have examined the underlying mechanism of this relationship. Based on a resilience perspective, this study aimed to investigate the dynamic longitudinal relationships between insomnia, resilience, and suicidality. METHODS: A total of 5785 freshmen were sampled from a large-scale health-related cohort among Chinese college students. This study spanned six waves, covering the period from 2020 to 2022. Data from T1 to T4 were used because resilience was not measured at baseline (T0) and T5. The cross-lagged panel models and the latent growth curve mediation model were used to examine the longitudinal dynamic relationships between insomnia, resilience, and suicidality. RESULTS: The results showed that insomnia symptoms and suicidality mutually predicted each other, and resilience played a longitudinal mediating role in linking insomnia symptoms and suicidality. CONCLUSIONS: Given that resilience served as a mediator in the relation between insomnia symptoms and suicidality, some resilience-oriented prevention and intervention programs will be helpful in reducing the risk of suicide among university students.

The Role of Ubiquitination and the E3 Ligase Nedd4 in Regulating Corneal Epithelial Wound Healing.

Purpose: Ubiquitination serves as a fundamental post-translational modification in numerous cellular events. Yet, its role in regulating corneal epithelial wound healing (CEWH) remains elusive. This study endeavored to determine the function and mechanism of ubiquitination in CEWH. Methods: Western blot and immunoprecipitation were used to discern ubiquitination alterations during CEWH in mice. Interventions, including neuronally expressed developmentally downregulated 4 (Nedd4) siRNA and proteasome/lysosome inhibitor, assessed their impact on CEWH. In vitro analyses, such as the scratch wound assay, MTS assay, and EdU staining, were conducted to gauge cell migration and proliferation in human corneal epithelial cells (HCECs). Moreover, transfection of miR-30/200 coupled with a luciferase activity assay ascertained their regulatory mechanism on Nedd4. Results: Global ubiquitination levels were markedly increased during the mouse CEWH. Importantly, the application of either proteasomal or lysosomal inhibitors notably impeded the healing process both in vivo and in vitro. Furthermore, Nedd4 was identified as an essential E3 ligase for CEWH. Nedd4 expression was significantly upregulated during CEWH. In vivo studies revealed that downregulation of Nedd4 substantially delayed CEWH, whereas further investigations underscored its role in regulating cell proliferation and migration, through the Stat3 pathway by targeting phosphatase and tensin homolog (PTEN). Notably, our findings pinpointed miR-30/200 family members as direct regulators of Nedd4. Conclusions: Ubiquitination holds pivotal significance in orchestrating CEWH. The critical E3 ligase Nedd4, under the regulatory purview of miR-30 and miR-200, facilitates CEWH through PTEN-mediated Stat3 signaling. This revelation sheds light on a prospective therapeutic target within the realm of CEWH.

Increased coexpression of PD-L1 and IDO1 is associated with poor overall survival in patients with NK/T-cell lymphoma.

Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.