Xiangshao Granules Ameliorate Post-Stroke Depression by Inhibiting Activation of Microglia and IDO1 Expression in Hippocampus and Prefrontal Cortex.

OBJECTIVE: To investigate the therapeutic effect of Xiangshao Granules (XSG) on post-stroke depression (PSD) and explore the underlying mechanisms. METHODS: Forty-three C57BL/6J mice were divided into 3 groups: sham (n=15), PSD+vehicle (n=14), and PSD+XSG (n=14) groups according to a random number table. The PSD models were constructed using chronic unpredictable mild stress (CUMS) after middle cerebral artery occlusion (MCAO). The sham group only experienced the same surgical operation, but without MACO and CUMS stimulation. The XSG group received XSG (60 mg/kg per day) by gavage for 4 weeks. The mice in the sham and vehicle groups were given the same volume of 0.9% saline at the same time. The body weight and behavior tests including open field test, sucrose preference test, tail suspension test, and elevated plus-maze test, were used to validate the PSD mouse model. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining were used to evaluate the anti-inflammatory effects of XSG. The potential molecular mechanisms were explored and verified through network pharmacology analysis, Nissl staining, Western blot, ELISA, and RT-qPCR, respectively. RESULTS: The body weight and behavior tests showed that MCAO combined with CUMS successfully established the PSD models. XSG alleviated neuronal damage, reduced the expressions of pro-apoptotic proteins Caspase-3 and B-cell lymphoma-2 (BCL-2)-associated X (BAX), and increased the expression of anti-apoptotic protein BCL-2 in PSD mice (P<0.05 or P<0.01). XSG inhibited microglial activation and the expressions of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin (IL)-1 ß, and IL-6 via the toll-like receptor 4/nuclear factor kappa-B signaling pathway in PSD mice (P<0.05 or P<0.01). Furthermore, XSG decreased the expression of indoleamine 2,3-dioxygenase1 (IDO1) and increased the concentration of 5-hydroxytryptamine in PSD mice (P<0.05 or P<0.01). CONCLUSION: XSG could reverse the anxiety/depressionlike behaviors and reduce the neuronal injury in the hippocampus and prefrontal cortex of PSD mice, which may be a potential therapeutic agent for PSD.

The effect of SGLT2 inhibition on brain-related phenotypes and aging: a drug target Mendelian randomization study.

INTRODUCTION: Observational study suggested SGLT2 inhibitors might promote healthy aging. However, whether brain-related phenotypes mediate this association. We applied Mendelian randomization (MR) to investigate the effect of SGLT2 inhibition on chronological, biological age and cognition and explore the mediation effects of brain imaging-derived phenotypes (IDPs). METHODS: We selected genetic variants associated with both expression levels of SLC5A2 (GTEx and eQTLGen data; N=129 to 31,684) and HbA1c levels (UK Biobank; N=344,182) and used them to proxy the effect of SGLT2 inhibition. Aging related outcomes, including parental longevity (N=389,166) and epigenetic clocks (N=34,710), and cognitive phenotypes, including cognitive function (N=300,486) and intelligence (N= 269,867) were derived from genome-wide association studies. Two-step MR were conducted to explore the associations between SGLT2 inhibition, IDPs, and aging outcomes, cognition. RESULTS: SGLT2 inhibition was associated with longer father's attained age (years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95%CI 1.95 to 11.15), better cognitive function (beta = 0.17, 95%CI 0.03 to 0.31) and higher intelligence (beta = 0.47, 95%CI 0.19 to 0.75). Two-step MR identified two IDPs as mediators linking SGLT2 inhibition with chronological age (total proportion of mediation = 22.6%), where four and five IDPs were mediators for SGLT2 inhibition on cognitive function and intelligence respectively (total proportion of mediation = 61.6% and 68.6% respectively). CONCLUSIONS: Our study supported that SGLT2 inhibition increases father's attained age, cognitive function and intelligence, which was mediated through brain images of different brain regions. Future studies are needed to investigate whether similar effect could be observed for users of SGLT2 inhibitors.

Discovery of SILA-123 as a Highly Potent FLT3 Inhibitor for the Treatment of Acute Myeloid Leukemia with Various FLT3 Mutations.

The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 inhibitor, SILA-123. This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC50 = 2.1 nM) and FLT3-ITD (IC50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC50 = 0.98 nM) and MV4-11 (IC50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

Antithetical impacts of deleterious LRP1B mutations in non-squamous and squamous NSCLCs on predicting benefits from immune checkpoint inhibitor alone or with chemotherapy over chemotherapy alone: retrospective analyses of the POPLAR/OAK and CHOICE-01 trials.

In non-small cell lung cancers, the non-squamous and squamous subtypes (nsqNSCLC and sqNSCLC) exhibit disparities in pathophysiology, tumor immunology, and potential genomic correlates affecting responses to immune checkpoint inhibitor (ICI)-based treatments. In our in-house training cohort (n=85), the presence of the LRP1B deleterious mutation (LRP1B-del) was associated with longer and shorter progression-free survival (PFS) on ICIs alone in nsqNSCLCs and sqNSCLCs, respectively (Pinteraction=0.008). These results were validated using a larger public ICI cohort (n=208, Pinteraction<0.001). Multiplex immunofluorescence staining revealed an association between LRP1B-del and increased and decreased numbers of tumor-infiltrating CD8+ T cells in nsqNSCLCs (P=0.040) and sqNSCLCs (P=0.014), respectively. In the POPLAR/OAK cohort, nsqNSCLCs with LRP1B-del demonstrated improved PFS benefits from atezolizumab over docetaxel (hazard ratio (HR) =0.70, P=0.046), whereas this benefit was negligible in those without LRP1B-del (HR=1.05, P=0.64). Conversely, sqNSCLCs without LRP1B-del benefited more from atezolizumab (HR=0.60, P=0.002) than those with LRP1B-del (HR=1.30, P=0.31). Consistent results were observed in the in-house CHOICE-01 cohort, in which nsqNSCLCs with LRP1B-del and sqNSCLCs without LRP1B-del benefited more from toripalimab plus chemotherapy than from chemotherapy alone (Pinteraction=0.008). This multi-cohort study delineates the antithetical impacts of LRP1B-del in nsqNSCLCs and sqNSCLCs on predicting the benefits from ICI alone or with chemotherapy over chemotherapy alone. Our findings highlight the distinct clinical utility of LRP1B-del in guiding treatment choices for nsqNSCLCs and sqNSCLCs, emphasizing the necessity for a detailed analysis based on pathological subtypes when investigating biomarkers for cancer therapeutics.

Conditional ablation of DIS3L2 ribonuclease in pre-meiotic germ cells causes defective spermatogenesis and infertility in male mice.

Rationale: Spermatogenesis is a highly organized cell differentiation process in mammals, involving mitosis, meiosis, and spermiogenesis. DIS3L2, which is primarily expressed in the cytoplasm, is an RNA exosome-independent ribonuclease. In female mice, Dis3l2-deficient oocytes fail to resume meiosis, resulting in arrest at the germinal vesicle stage and complete infertility. However, the role of DIS3L2 in germ cell development in males has remained largely unexplored. Methods: We established a pre-meiotic germ cell conditional knockout mouse model and investigated the biological function of DIS3L2 in spermatogenesis and male fertility through bulk RNA-seq and scRNA-seq analyses. Results: This study unveils that conditional ablation of Dis3l2 in pre-meiotic germ cells with Stra8-Cre mice impairs spermatogonial differentiation and hinders spermatocyte meiotic progression coupled with cell apoptosis. Such conditional ablation leads to defective spermatogenesis and sterility in adults. Bulk RNA-seq analysis revealed that Dis3l2 deficiency significantly disrupted the transcriptional expression pattern of genes related to the cell cycle, spermatogonial differentiation, and meiosis in Dis3l2 conditional knockout testes. Additionally, scRNA-seq analysis indicated that absence of DIS3L2 in pre-meiotic germ cells causes disrupted RNA metabolism, downregulated expression of cell cycle genes, and aberrant expression of spermatogonial differentiation genes, impeding spermatogonial differentiation. In meiotic spermatocytes, loss of DIS3L2 results in disturbed RNA metabolism, abnormal translation, and disrupted meiotic genes that perturb meiotic progression and induce cell apoptosis, leading to subsequent failure of spermatogenesis and male infertility. Conclusions: Collectively, these findings highlight the critical role of DIS3L2 ribonuclease-mediated RNA degradation in safeguarding the correct transcriptome during spermatogonial differentiation and spermatocyte meiotic progression, thus ensuring normal spermatogenesis and male fertility.

Rosmarinic acid suppresses the progression of COPD via Syk by modulating airway inflammation and epithelial apoptosis in vivo and in vitro.

Rosmarinic acid (RosA), a hydrophilic phenolic compound found in various plants, has several biological effects such as anti-inflammatory and anti-apoptosis activities. However, its potential impact on chronic obstructive pulmonary disease (COPD) and its underlying mechanism has not been investigated. In this study, we explored the potential therapeutic effects and mechanism of RosA on COPD airway inflammation and alveolar epithelial apoptosis in vivo and in vitro. Our data suggested that RosA may be a therapeutic candidate for COPD with low toxicity. The corresponding mechanism lies in its anti-inflammatory effect on macrophage and bronchial epithelial cells, as well as protective effect on lung epithelial apoptosis via the jointly cross-target spleen tyrosine kinase (Syk).

Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis.

Adipose tissue senescence is a precursor to organismal aging and understanding adipose remodelling contributes to discovering novel anti-aging targets. Glutathione peroxidase 3 (GPx3), a critical endogenous antioxidant enzyme, is diminished in the subcutaneous adipose tissue (sWAT) with white adipose expansion. Based on the active role of the antioxidant system in counteracting aging, we investigated the involvement of GPx3 in adipose senescence. We determined that knockdown of GPx3 in adipose tissue by adeno-associated viruses impaired mitochondrial function in mice, increased susceptibility to obesity, and exacerbated adipose tissue senescence. Impairment of GPx3 may cause mitochondrial dysfunction through inner mitochondrial membrane disruption. Adipose reshaping management (cold stimulation and intermittent diet) counteracted the aging of tissues, with an increase in GPx3 expression. Overall metabolic improvement induced by cold stimulation was partially attenuated when GPx3 was depleted. GPx3 may be involved in adipose browning by interacting with UCP1, and GPx3 may be a limiting factor for intracellular reactive oxygen species (ROS) accumulation during stem cell browning. Collectively, these findings emphasise the importance of restoring the imbalanced redox state in adipose tissue to counteract aging and that GPx3 may be a potential target for maintaining mitochondrial homeostasis and longevity.

Dual-layer probiotic encapsulation using metal phenolic network with gellan gum-tamarind gum coating for colitis treatment.

Probiotic oral therapy has been recognised as an effective treatment for inflammatory bowel disease (IBD). However, the efficacy of probiotics is often diminished due to their limited resistance to harsh gastrointestinal conditions. Therefore, the importance of designing innovative strategies for oral probiotic delivery for the effective treatment of IBD is increasingly recognised. In this study, we present a novel encapsulation strategy of Lactobacillus plantarum (L.P) using the dual-layer system consisting of a tannic acid­calcium network and polysaccharide coating (gellan gum-tamarind gum) named L.P-C/T-G/T. This double-layer encapsulation system not only does not affect the normal proliferation of probiotics and provide protection, but also endows probiotics with more functions. More specifically, the acid resistance ability of the encapsulated probiotics is increased by 10 times, the free radical scavenging rate is enhanced by 5 times, and the intestinal retention time can be prolonged by 6-12 h. In the DSS-induced murine colitis model, it significantly alleviated colon shortening, inhibited ROS overexpression, and promoted the repair and regeneration of the mucus layer. This dual-layer encapsulation approach for a single probiotic demonstrates a significant advancement in probiotic delivery technology, offering hope for a comprehensive approach to the treatment of colitis and potentially other gastrointestinal disorders.

The role of radiotherapy in extensive-stage small cell lung cancer after durvalumab-based immunochemotherapy: A retrospective study.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy (RT) following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed. Inverse probability of treatment weighting (IPTW) analysis was performed to address potential confounding factors. The primary focus of our evaluation was to assess the impact of RT on progression-free survival (PFS) and overall survival (OS). RESULTS: After IPTW analysis, 49 patients received durvalumab plus platinum-etoposide(EP) chemotherapy followed by RT (Durva + EP + RT) and 72 patients received immunochemotherapy (Durva + EP). The median OS was 17.2 months vs. 12.3 months (hazard ratio [HR]: 0.38, 95% CI: 0.17-0.85, P = 0.020), and the median PFS was 8.9 months vs. 5.9 months (HR: 0.56, 95% CI: 0.32-0.97, P = 0.030) in Durva + EP + RT and Durva + EP groups, respectively. Thoracic radiation therapy (TRT) resulted in longer OS (17.2 months vs. 14.7 months) and PFS (9.1 months vs. 7.2 months) compared to RT directed to other metastatic sites. Among patients with oligo-metastasis, RT also showed significant benefits, with a median OS of 17.4 months vs. 13.7 months and median PFS of 9.8 months vs. 5.9 months compared to no RT. Continuous durvalumab treatment beyond progression (TBP) prolonged OS compared to patients without TBP, in both the Durva + EP + RT (NA vs. 15.8 months, HR: 0.48, 95% CI: 0.14-1.63, P = 0.238) and Durva + EP groups (12.3 months vs. 4.3 months, HR: 0.29, 95% CI: 0.10-0.81, P = 0.018). Grade 3 or 4 adverse events occurred in 13 (26.5%) and 13 (18.1%) patients, respectively, in the two groups; pneumonitis was mostly low-grade. CONCLUSION: Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.

Sex difference and socioeconomic inequity in hypertension: a national survey study of 98,658 adults from 162 study sites.

BACKGROUND: Sex differences in blood pressure (BP) levels and hypertension are important and the role of socioeconomic status (SES) in sex differences of hypertension remains unclear. OBJECTIVE: We aimed to evaluate the impact of SES on sex differences of hypertension in a nationally representative survey study. METHODS: A total of 98,658 participants aged ≥18 years who have lived in their current residence for ≥6 months were recruited from 162 study sites across mainland China. Sex was self-reported. Individual-level SES included the highest level of education and annual household income. Area-level SES included economic development status, urban/rural residency, and north/south location. Outcomes included levels of systolic and diastolic BP, and hypertension. Linear and Cox regression models were used to examine the associations between sex (women vs. men) and BP characteristics stratified by individual or combined SES indicators. RESULTS: Systolic and diastolic BP levels and prevalence of hypertension were higher in men than women. This sex difference was found across categories of SES with widened sex disparities in participants having more favorable SES. Significant multiplicative interaction effects of SES on the association of sex with BP characteristics were found. Women with improving SES were associated with lower BP and hypertension prevalence compared with men. For combined SES, a 9% (prevalence ratio (PR)=0.91, 95% confidence interval (CI)=0.83, 0.98) and a 30% lower probability (PR=0.70, 95% CI=0.63, 0.78) of having hypertension were found in women with an overall intermediate SES and high SES, respectively compare with low SES while no significant reduction was found in men. CONCLUSIONS: There are significant sex differences in BP characteristics and SES has a potent impact on the disparities. Sex-specific public health policies to alleviate socioeconomic inequalities, especially in women are important for the prevention of hypertension.

Anemia, blood cell indices, genetic correlations, and brain structures: A comprehensive analysis of roles in Parkinson's disease risk.

INTRODUCTION: Anemia may contribute significantly to the onset of Parkinson's disease (PD). Current research on the association between anemia and PD risk is inconclusive, and the relationships between anemia-related blood cell indices and PD incidence require further clarification. This study aims to investigate the relationships between anemia, blood cell indicators, and PD risk using a thorough prospective cohort study. METHODS: We used data from the UK Biobank, a prospective cohort study of 502,649 participants, and ultimately, 365,982 participants were included in the analysis. Cox proportional hazards models were utilized to adjust for confounding factors, aiming to thoroughly explore the associations between anemia and blood cell indices with the risk of incident PD. The interaction between anemia and Polygenic Risk Score (PRS) for PD was also examined. Linear regression and mediation analyses assessed potential mechanisms driven by brain structures, including grey matter volume. RESULTS: During a median follow-up of 14.24 years, 2513 participants were diagnosed with PD. Anemia considerably increased PD risk (hazard ratio [HR] 1.98, 95 % confidence interval [CI]: 1.81-2.18, P < 0.001) after adjustments. Those with high PRS for anemia had an 83 % higher PD incidence compared to low PRS participants. Sensitivity analyses confirmed result robustness. Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. Furthermore, mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD risk. CONCLUSION: In summary, we consider there to be a substantial correlation between anemia and increased PD risk.

Identification of a FOXO gene and its roles in anti-WSSV infection through regulation of Dicers and Argos in Macrobrachium nipponense.

Forkhead box O (FOXO) proteins are a subgroup of the forkhead family of transcription factors that play important roles in the immune response. In this study, we cloned and identified a FOXO gene named MnFOXO from Macrobrachium nipponense. The full-length cDNA of MnFOXO is 2086 bp and contains a 1302 bp open reading frame, which encodes 433 amino acids. MnFOXO consists of five low-complexity regions and a conserved DNA-binding domain (forkhead domain). Evolutionary analyses indicate that MnFOXO proteins cluster with FOXO proteins from crustaceans. Tissue distribution analysis showed that MnFOXO was expressed in all detected tissues, with relatively higher expression levels in the intestine, eyestalks, stomach, and hemocytes than in the hepatopancreas, gills, and heart. The expression levels of MnFOXO in the hepatopancreas and intestine were significantly up-regulated in M. nipponense infected with white spot syndrome virus (WSSV) at 24 and 48 h. Furthermore, knockdown of MnFOXO increased the expression of WSSV envelope protein VP28 during WSSV infection. Further studies showed that knockdown of the MnFOXO gene in M. nipponense inhibited the synthesis of Dicers (MnDicer1, MnDicer2) and Argonautes (MnArgo1, MnArgo2) during WSSV invasion. These findings suggest that MnFOXO positively regulates the expression of Dicers and Argos, and inhibits the expression of VP28. This study provides new evidence for understanding the role of FOXO in antiviral innate immunity in crustaceans.

Identification of immune-related endoplasmic reticulum stress genes in proliferative diabetic retinopathy using bioinformatics analysis.

Background: Proliferative diabetic retinopathy (PDR) is a severe complication of diabetes, and understanding its molecular mechanisms is crucial. Endoplasmic reticulum (ER) stress has been implicated in various diseases, including diabetic complications. This study aims to elucidate ER stress-related biomarkers in PDR, providing insights into the underlying molecular pathways. Methods: We analyzed two independent PDR datasets, GSE102485 and GSE60436. The GSE102485 dataset (22 PDR and 3 normal samples) was the primary dataset for comprehensive analyses, including differential expression, functional enrichment, PPI network construction, immune cell infiltration, and drug prediction. The GSE60436 dataset (6 PDR and 3 normal samples) was used for validation. In vitro experiments using human umbilical vein endothelial cells (HUVECs) in a high-glucose environment were conducted to validate key bioinformatics outcomes. Western blotting assessed protein levels of ER stress markers (TRAM1 and TXNIP). Results: Differential expression analysis identified 2451 genes, including 328 ER stress-related genes. Functional analysis revealed enrichment in ER stress-related processes and pathways. Hub genes (BCL2, CCL2, IL-1ß, TLR4, TNF, TP53) were identified, and immune infiltration analysis showed altered immune cell proportions. Validation in GSE60436 and in vitro confirmed ER stress gene dysregulation. Drug prediction suggested potential small molecules targeting ER stress markers. Conclusion: This study provides a comprehensive molecular characterization of ER stress in PDR, highlighting altered biological processes, immune changes, and potential therapeutic targets. The identified hub genes and small molecules offer avenues for further investigation and therapy development, enhancing understanding of PDR pathogenesis and aiding targeted intervention creation.

Factors associated with moral sensitivity among nurses in adult intensive care units: A cross-sectional study in China.

BACKGROUND: Moral sensitivity may play a role in dealing with ethical issues in ICUs. However, the moral sensitivity of adult ICU nurses in China and its predictors have not been well investigated. AIMS: To analyse the moral sensitivity of intensive care unit (ICU) nurses and its predictors. STUDY DESIGN: A cross-sectional study through convenience sampling was conducted in the ICUs of five hospitals in China between November and December 2022. A total of 331 ICU nurses were recruited. Data were obtained using a self-developed socio-demographic characteristic questionnaire, the Moral Sensitivity Questionnaire, the Jefferson Scale of Empathy-Health Professionals and the Organizational Climate Scale for Nursing. The participating institutions received a link to the tools used for online data collection, which they then forwarded to nursing staff. RESULTS: The valid response rate was 96.98% (n = 321). The total mean moral sensitivity score of nurses was 43.04 ± 5.95. The mean scores for empathic ability and organizational climate for nursing were 91.97 ± 17.88 and 101.28 ± 14.77, respectively. Regression analyses revealed that the primary factors associated with moral sensitivity among critical care nurses included work tenure (p < .05), empathic ability (p < .001) and organizational climate (p < .001). CONCLUSIONS: High levels of moral sensitivity were found in critical care nurses in China. Work tenure, empathic ability and organizational climate were significant predictors of moral sensitivity in critical care nurses. RELEVANCE TO CLINICAL PRACTICE: To enhance the ethical sensitivity of ICU nurses, we suggest to strengthen the training of novice nurses so that they can better face the moral dilemma in clinical practice. In addition, organizational managers should also take measures to create a positive and harmonious working atmosphere, promote the application of moral knowledge in nursing practice and enhance their moral sensitivity.

Dual isotope analysis reveals the COVID-19 lockdown impact on nitrate aerosol sources and formation pathways in Shanghai.

Nitrate (NO3-) is an important contributor to PM2.5 which can adversely affect the environment and human health. A noticeable decrease in NOx concentrations has been reported due to the lockdown measures implemented to curb the spread of Corona Virus Disease 2019 (COVID-19). However, questions remain, regarding the nonlinear relationship between NOx and NO3-. Here, we collected PM2.5 samples in two periods, before and during the lockdown of COVID-19 in Shanghai. Dual isotopes (δ18O-NO3- and δ15N-NO3-) of NO3- were measured to investigate the formation pathways and potential sources of NO3-. The results showed that the concentration of NO3- decreased significantly during the lockdown period compared to the period before the lockdown. Additionally, the hydroxyl pathway was the dominant contributor to NO3- production during the lockdown period, while N2O5 hydrolyses dominated the formation of NO3- before the lockdown. This change is largely attributable to alterations in the oxidative potential of the environment. In comparison to the period preceding the lockdown, the relative contributions of each NOx source remained largely unchanged throughout the lockdown periods. Nevertheless, the concentration of NO3- contributed by each NOx source exhibited a notable decline, particularly the mobile sources and coal combustion. Furthermore, the reduction extent of NO3- due to the lockdown period was also greater than the reduction during the Clean Air Actions (2013-2017). Our findings provide evidence that the COVID-19 lockdown led to a decrease in NO3- concentration due to changes in the formation pathway and reductions in NOx emissions from various sources.

Associations of socioeconomic status and healthy lifestyle with incident dementia and cognitive decline: two prospective cohort studies.

Background: Little is known about the complex associations of socioeconomic status (SES) and healthy lifestyle with cognitive dysfunction. Methods: Using data from the Health and Retirement Study (HRS) [2008-2020] and the English Longitudinal Study of Ageing (ELSA) [2004-2018], SES was constructed by latent class analysis using education level, total household income and wealth. Overall healthy lifestyle was derived using information on never smoking, low to moderate alcohol consumption (drinks/day: (0, 1] for women and (0, 2] for men), top tertile of physical activity, and active social contact. Findings: A total of 12,437 and 6565 participants from the HRS and ELSA were included (40.8% and 46.0% men and mean age 69.3 years and 65.1 years, respectively). Compared with participants of high SES, those of low SES had higher risk of incident dementia (hazard ratio 3.17, 95% confidence interval 2.72-3.69 in the HRS; 1.43, 1.09-1.86 in the ELSA), and the proportions mediated by overall lifestyle were 10.4% (7.3%-14.6%) and 2.7% (0.5%-14.0%), respectively. Compared with participants of high SES and favorable lifestyle, those with low SES and unfavorable lifestyle had a higher risk of incident dementia (4.27, 3.40-5.38 in the HRS; 2.02, 1.25-3.27 in the ELSA) and accelerated rate of global cognitive decline (ß = -0.058 SD/year; 95% CI: -0.073, -0.043 in the HRS; ß = -0.049 SD/year; 95% CI: -0.063, -0.035 in the ELSA). Interpretation: Unhealthy lifestyle only mediated a small proportion of the socioeconomic inequality in dementia risk in both US and UK older adults. Funding: This work was supported by grants from the National Natural Science Foundation of China (82088102 and 82370819), the National Key R&D Program of China (2023YFC2506700), the Shanghai Municipal Government (22Y31900300), the Shanghai Clinical Research Center for Metabolic Diseases (19MC1910100), the Innovative Research Team of High-Level Local Universities in Shanghai, the Special Project for Clinical Research in Health Industry of Shanghai Municipal Health Commission (202340084), and Ruijin Hospital Youth Incubation Project (KY20240805). Y.X. is supported by the National Top Young Talents program.

Increased plasma AACT level as an indicator of poor prognosis in patients hospitalised with community-acquired pneumonia: a multicentre prospective cohort study.

BACKGROUND AND OBJECTIVE: Community-acquired pneumonia (CAP) is a common respiratory disease that frequently requires hospitalisation, and is a significant cause of death worldwide. This study aimed to evaluate the usefulness of alpha-1-antichymotrypsin (AACT) as a diagnostic and prognostic biomarker of CAP. METHODS: We conducted a multicentre prospective cohort study in patients hospitalised with CAP. Plasma AACT levels were measured using a quantitative enzyme-linked immunosorbent assay. Receiver-operating characteristic (ROC) curves and Cox proportional hazards regression were used to assess the association between plasma AACT levels and CAP diagnosis and prognosis. RESULTS: A total of 274 patients with CAP were enrolled in the study. AACT levels were elevated in patients with CAP, especially those with severe CAP and non-survivors. The area under the curve (AUC) of AACT and CRP for diagnosing CAP was 0.755 and 0.843. Cox regression showed that CURB-65 and AACT levels were independent predictors of 30-day mortality. ROC curves showed that plasma AACT levels had the highest accuracy for predicting acute respiratory distress syndrome (ARDS), with an AUC of 0.862. Combining AACT with Pneumonia Severity Index and CURB-65 significantly improved their predictive accuracy for predicting 30-day mortality. CONCLUSION: Plasma AACT levels are elevated in patients with CAP, but plasma AACT level is inferior to the C-reactive protein level for diagnosing CAP. The AACT level can reliably predict the occurrence of ARDS and 30-day mortality in patients with CAP.

The Role of CDCA2 in tumor genesis, prognosis and future treatments.

The Cell Division Cycle Associated 2 (CDCA2) gene is responsible for encoding a targeting subunit of cell-cycle associated protein. CDCA2 plays a crucial role in various cellular processes, including chromosome segregation and decondensation, nuclear envelope reassembly, microtubule assembly, and DNA damage response. Additionally, CDCA2 is involved in multiple signaling pathways such as the PI3K/Akt pathway and p53 pathway. Undoubtedly, there exists a strong association between CDCA2 and cancer. Numerous studies have reported that elevated levels of CDCA2 are correlated with poor prognosis and several clinicopathological characteristics like tumor size and TNM stage across different types of cancer. Therefore, CDCA2 holds great potential as both a biomarker for diagnosis and a therapeutic target for interventions such as targeted therapies or immunotherapy. Given its promising prospects in scientific research and clinical applications, it is imperative for researchers to delve into the underlying mechanisms of CDCA2 and explore its utilization.

The role of left atrium posterior wall isolation in patients undergoing catheter ablation for atrial fibrillation.

The posterior left atrium (LAPW) is an important substrate for initiation and maintenance of atrial fibrillation (AF). While it has been proposed as a potential target for preventing recurrence of atrial tachyarrhythmias, it remains unclear whether electrical silence of LAPW offers additional benefits over pulmonary vein isolation (PVI) alone. We conducted a systematic review of PubMed, Medline, Embase, and Cochrane databases and identified 21 eligible studies, encompassing 1,514 patients assigned to PVI + posterior wall isolation (PWI) group and 1,629 patients assigned to PVI group. Over a median follow-up of 12 months, adjunctive PWI significantly improved the atrial tachyarrhythmia-free survival by 14% in comparison to PVI alone [relative risk (RR): 1.14, 95% confidence interval (CI): 1.04 to 1.25, p=0.004]. This improvement was mainly attributed to a pronounced benefit for patients with persistent AF. In addition, patients undergoing PVI+PWI had a longer procedure time [weighted mean difference (WMD): 23.85, 95% CI: 12.68 to 35.01, p<0.001], ablation time (WMD: 9.27, 95% CI: 5.19 to 13.54, p<0.001), and a nearly negligible increase in fluoroscopic exposure (WMD: 2.69, 95% CI: -0.23 to 5.62, p=0.071). There was no increased risk of procedure-related complications between these approaches (RR: 1.06, 95% CI: 0.71 to 1.57, p=0.787). Compared with PVI alone, PWI adjunctive to PVI exhibited a higher procedure success of sinus rhythm maintenance in persistent AF during an index catheter ablation. Meanwhile, elongated procedure time and ablation time did not compromise the safety of extensive ablation strategy with additional PWI.

MSIsensor-RNA: Microsatellite Instability Detection for Bulk and Single-cell Gene Expression Data.

Microsatellite instability (MSI) is an indispensable biomarker in cancer immunotherapy. Currently, MSI scoring methods by high-throughput omics methods have gained popularity and demonstrated better performance than the gold standard method for MSI detection. However, the MSI detection method on expression data, especially single-cell expression data, is still lacking, limiting the scope of clinical application and prohibiting the investigation of MSI at a single-cell level. Herein, we developed MSIsensor-RNA, an accurate, robust, adaptable, and standalone software to detect MSI status based on expression values of MSI-associated genes. We demonstrated the favorable performance and promise of MSIsensor-RNA in both bulk and single-cell gene expression data in multiplatform technologies including RNA sequencing (RNA-seq), microarray, and single-cell RNA-seq. MSIsensor-RNA is a versatile, efficient, and robust method for MSI status detection from both bulk and single-cell gene expression data in clinical studies and applications. MSIsensor-RNA is available at https://github.com/xjtu-omics/msisensor-rna.