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Novel brain clearing methods revolutionize imaging by increasing visualization throughout the brain at high resolution. However, combining the standard tool of immunostaining targets of interest with clearing methods has lagged behind. We integrate whole-mount immunostaining with PEGASOS tissue clearing, referred to as iPEGASOS (immunostaining-compatible PEGASOS), to address the challenge of signal quenching during clearing processes. iPEGASOS effectively enhances molecular-genetically targeted fluorescent signals that are otherwise compromised during conventional clearing procedures. Additionally, we demonstrate the utility of iPEGASOS for visualizing neurochemical markers or viral labels to augment visualization that transgenic mouse lines cannot provide. Our study encompasses three distinct applications, each showcasing the versatility and efficacy of this approach. We employ whole-mount immunostaining to enhance molecular signals in transgenic reporter mouse lines to visualize the whole-brain spatial distribution of specific cellular populations. We also significantly improve the visualization of neural circuit connections by enhancing signals from viral tracers injected into the brain. Last, we show immunostaining without genetic markers to selectively label beta-amyloid deposits in a mouse model of Alzheimers disease, facilitating the comprehensive whole-brain study of pathological features.

Abstract Background Quality assessment of the prevalence and distribution of human papillomavirus (HPV) genotypes could support additional targeted HPV vaccinations. However, the characteristics of HPV infection in Wuhan city are limited in the past decade. We aimed to assess the epidemiology of HPV infection among women and provide a reference for the prevention and treatment of cervical cancer in this region. Methods A retrospective study employing 105,679 women attending Wuhan Medical and Health Center for Women and Children for cervical cancer screening from January 2015 to December 2022 was conducted. The HPV genotype was detected by polymerase chain reaction (PCR) and diversion hybridization. The overall incidence and age-specific type distribution of HPV infection and the relationship between HPV infection and cervical cytology were analyzed. Results The overall HPV infection rate was 16.87% in Wuhan city, and the prevalence rates of high-risk, low-risk and mixed high- and low-risk HPV infections were 13.64%, 1.77% and 1.46%, respectively. The five most prevalent genotypes were HPV52 (4.24%), HPV58 (2.42%), HPV16 (2.34%), HPV53 (1.87%), and HPV39 (1.66%). The prevalence of HPV in women exhibited a “two-peak” pattern, the peaks of which were observed in the

Abstract Background Left ventricular hypertrabeculation (LVHT) is a heterogeneous entity with life-threatening complications and variable prognosis. However, there are limited prediction models available to identify individuals at high risk of adverse outcomes, and the current risk score in LVHT is comparatively complex for clinical practice. This study aimed to develop and validate a simplified risk score to predict major adverse cardiovascular events (MACE) in LVHT. Methods This multicenter longitudinal cohort study consecutively enrolled morphologically diagnosed LVHT patients between January 2009 and December 2020 at Fuwai Hospital (derivation cohort, n = 300; internal validation cohort, n = 129), and between January 2014 and December 2022 at two national-level medical centers (external validation cohort, n = 95). The derivation/internal validation cohorts and the external validation cohort were followed annually until December 2022 and December 2023, respectively. MACE was defined as a composite of all-cause mortality, heart transplantation/left ventricular assist device implantation, cardiac resynchronization therapy, malignant ventricular arrhythmia, and thromboembolism. A simplified risk score, the ABLE-SCORE, was developed based on independent risk factors in the multivariable Cox regression predictive model for MACE, and underwent both internal and external validations to confirm its discrimination, calibration, and clinical applicability. Results A total of 524 LVHT patients (43.5 ± 16.6 years, 65.8% male) were included in the study. The ABLE-SCORE was established using four easily accessible clinical variables: age at diagnosis, N-terminal pro-brain natriuretic peptide levels, left atrium enlargement, and left ventricular ejection fraction ≤ 40% measured by echocardiography. The risk score showed excellent performance in discrimination, with Harrell’s C-index of 0.821 [95% confidence interval (CI), 0.772–0.869], 0.786 (95%CI, 0.703–0.869), and 0.750 (95%CI, 0.644–0.856) in the derivation, internal validation, and external validation cohort, respectively. Calibration plots of the three datasets suggested accurate agreement between the predicted and observed 5-year risk of MACE in LVHT. According to decision curve analysis, the ABLE-SCORE displayed greater net benefits than the existing risk score for LVHT, indicating its strength in clinical applicability. Conclusions A simplified and efficient risk score for MACE was developed and validated using a large LVHT cohort, making it a reliable and convenient tool for the risk stratification and clinical management of patients with LVHT.

Objective To investigate the long-term efficacy of amygdala-hippocampus deep brain stimulation (AH - DBS) in treating refractory medial temporal lobe epilepsy (mTLE) and its impact on cognitive function. Methods Seven patients with refractory mTLE who were treated at The First Medical Center of Chinese PLA General Hospital from January 2014 to December 2018 were enrolled in this study. All 7 patients underwent AH -DBS. Seizure types, seizure frequency, and antiepileptic seizure medicine (ASM) usage were compared before and after surgery. Cognitive function was assessed using Wechsler Adult Intelligence Scale - Revised (WAIS - R). Post - operative stimulation parameters and surgery - related complications were recorded. Results Of the 7 patients, 4 patients received bilateral AH-DBS, 2 patients received left AH - DBS, and one patient received left AH - DBS combined with right anterior temporal lobectomy. There were 6 patients underwent the occipital approach, and one patient underwent the frontal approach. Only one patient experienced poor healing of the scalp incision, which healed after local skin grafting. The mean follow-up period was (73.00 ± 8.98) months. During the follow-up period, there were reductions in complex partial seizure (CPS) frequency [1.00 (0.00, 31.00) times per month vs. 2.00 (1.50, 60.00) times per month; Z = - 2.207, P = 0.027], secondary generalized tonic - clonic seizure (SGTCS) frequency [0.00 (0.00, 1.00) times per month vs. 2.00 (1.00, 3.00) times per month; Z = - 2.428, P = 0.015], and the total seizure frequency [1.00 (0.50, 31.00) times per month vs. 5.00 (2.50, 64.00) times per month; Z = - 2.366, P = 0.018]. However, there were no significant differences in the number of ASM types [1.00 (1.00, 2.00) types vs. 1.00 (1.00, 3.00) types; Z = - 1.633, P = 0.102] or WAIS-R [(85.50 ± 7.09) scores vs. (89.00 ± 9.47) scores; t = - 1.761, P = 0.078] before and after surgery. Conclusions As a novel anti - epileptic treatment method, AH-DBS can reduce the frequency of refractory mTLE without serious adverse events and has no significant impact on cognitive function.

Abstract Background This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH status (pre-existing/new-onset/persistent/regression) using Systolic Blood Pressure Intervention Trial (SPRINT) Electrocardiogram Data. Methods Poisson regression was used to assess new-onset LVH and LVH regression rates. Multivariable-adjusted Cox proportional hazard models determined the risk of adverse cardiovascular events (ACE), a composite of myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure, or cardiovascular death, alongside safety adverse events. Results In 8,016 participants, intensive BP control significantly reduced new-onset LVH (8.27 vs. 14.79 per 1000-person years; adjusted p

Abstract Drug resistance remains a significant challenge in the treatment of pancreatic cancer. The development of drug-resistant cell lines is crucial to understanding the underlying mechanisms of resistance and developing novel drugs to improve clinical outcomes. Here, a novel pancreatic cancer cell line, PDAC-X1, derived from Chinese patients has been established. PDAC-X1 was characterized by the immune phenotype, biology, genetics, molecular characteristics, and tumorigenicity. In vitro analysis revealed that PDAC-X1 cells exhibited epithelial morphology and cell markers (CK7 and CK19), expressed cancer-associated markers (E-cadherin, Vimentin, Ki-67, CEA, CA19-9), and produced pancreatic cancer-like organs in suspension culture. In vivo analysis showed that PDAC-X1 cells maintained tumorigenicity with a 100% tumor formation rate. This cell line exhibited a complex karyotype, dominated by subtriploid karyotypes. In addition, PDAC-X1 cells exhibited intrinsic multidrug resistance to multiple drugs, including gemcitabine, paclitaxel, 5-fluorouracil, and oxaliplatin. In conclusion, the PDAC-X1 cell line has been established and characterized, representing a useful and valuable preclinical model to study the underlying mechanisms of drug resistance and develop novel drug therapeutics to improve patient outcomes.

Background Nonrheumatic valvular heart disease (NRVD) is increasingly becoming a significant public health concern, particularly among older people. In the context of population aging, a detailed report on the epidemiological trends of NRVD is crucial for policymakers to effectively allocate health care resources. This study aimed to explore these trends using data from the GBD (Global Burden of Disease) 2019 study. Methods and Results We assessed the changing trends of the incidence, mortality, and disability‐adjusted life years rates for NRVD by calculating the estimated annual percentage change for each. Additionally, we examined the impact of a region's level of social development on NRVD epidemiological trends and identified key risk factors contributing to NRVD‐related deaths. Between 1990 and 2019, the global incidence of NRVD showed a gradual increase, with an estimated annual percentage change of 0.39 (95% CI, 0.30–0.48). The data revealed that women and older people are more likely to develop NRVD. High‐sociodemographic index countries exhibited higher age‐standardized incidence and mortality rates compared with low‐ and middle‐sociodemographic index countries. The most significant risk factor for NRVD‐related mortality was identified as high systolic blood pressure. Conclusions Over the past 3 decades, the burden of NRVD has intensified, indicating a need for more health care resources to address this issue, which is closely associated with an aging population. Currently, high‐sociodemographic index countries report the highest incidences and deaths due to NRVD. However, low‐ and middle‐sociodemographic index countries should also implement measures to manage the rapidly increasing burden of NRVD.

Nitrate is a significant source of nitrogen in soils and also serves as a critical signal for root development. Previous studies have demonstrated that the local nitrate supply promotes lateral root elongation primarily through local nitrate signals, rather than nutritional effects. In this study, we report that Calcineurin B-like protein 1 (OsCBL1) positively regulates local nitrate signaling, thereby triggering lateral root colonization, as revealed by a comparative analysis of the phenotype and whole transcriptome of the knockdown mutant (OsCBL1-KD) and the wild-type (WT). In the split-root system, the knockdown of OsCBL1 was found to inhibit local nitrate-induced lateral root growth. Transcriptome analyses identified 398 differentially expressed genes (DEGs) that were under the control of OsCBL1 and associated with the phenotype of nitrate-induced lateral root colonization. Further analysis revealed that the nitrate transporter/sensor gene OsNRT1.1B was up-regulated under Sp-NaNO3 conditions compared to Sp-NaCl in WT but not in OsCBL1-KD plants. Pathway mapping of DEGs (i.e., genes exhibiting a significant change in expression in the Sp-NaNO3 condition compared to the Sp-NaCl condition) revealed a preferential upregulation of genes involved in lignin biosynthesis and a downregulation of genes involved in auxin and salicylic acid signaling. This suggests that OsCBL1 might function as a transmitter within the auxin, salicylic acid signaling, lignin biosynthesis, and nitrate sensor (OsNRT1.1B)-mediated pathways in response to local nitrate signaling. We also identified a transcriptional regulatory network downstream of OsCBL1 in nitrate-rich patches that is centered on several core transcription factors. Our study provides new insights into how plants adapt to an inhomogeneous distribution of nitrogen in the soil.

Background Psychological resilience refers to an individual’s ability to cope with and adapt to challenging life circumstances and events.Objective This study aims to explore the association between psychological resilience and all-cause mortality in a national cohort of US older adults by a cross-sectional study.Methods The Health and Retirement Study (2006–2008) included 10 569 participants aged ≥50. Mortality outcomes were determined using records up to May 2021. Multivariable Cox proportional hazards models were used to analyse the associations between psychological resilience and all-cause mortality. Restricted cubic splines were applied to examine the association between psychological resilience and mortality risk.Findings During the follow-up period, 3489 all-cause deaths were recorded. The analysis revealed an almost linear association between psychological resilience and mortality risk. Higher levels of psychological resilience were associated with a reduced risk of all-cause mortality in models adjusting for attained age, sex, race and body mass index (HR=0.750 per 1 SD increase in psychological resilience; 95% CI 0.726, 0.775). This association remained statistically significant after further adjustment for self-reported diabetes, heart disease, stroke, cancer and hypertension (HR=0.786; 95% CI 0.760, 0.813). The relationship persisted even after accounting for smoking and other health-related behaviours (HR=0.813; 95% CI 0.802, 0.860).Conclusions This cohort study highlights the association between psychological resilience and all-cause mortality in older adults in the USA.Clinical implications Psychological resilience emerges as a protective factor against mortality, emphasising its importance in maintaining health and well-being.

Abstract Diabetic heart disease (DHD) is a serious complication in patients with diabetes. Despite numerous studies on the pathogenic mechanisms and therapeutic targets of DHD, effective means of prevention and treatment are still lacking. The pathogenic mechanisms of DHD include cardiac inflammation, insulin resistance, myocardial fibrosis, and oxidative stress. Macrophages, the primary cells of the human innate immune system, contribute significantly to these pathological processes, playing an important role in human disease and health. Therefore, drugs targeting macrophages hold great promise for the treatment of DHD. In this review, we examine how macrophages contribute to the development of DHD and which drugs could potentially be used to target macrophages in the treatment of DHD.

Abstract Background The relationship between lung function and sarcopenia remains ambiguous. The primary aim of this study was to investigate the potential association between lung function and sarcopenia in the older adults, as well as to examine the mediating role of cognitive function in this relationship. Methods The participants were selected from a nationally representative population-based cohort in China. The peak expiratory flow (PEF) measurement was used to evaluate the lung function in older persons. The sarcopenia was diagnosed using the guidelines of the Asian Working Group for Sarcopenia (AWGS) in 2019. The Cox proportional hazard model was utilized to perform primary analyses of the relationship between PEF and sarcopenia. The mediating effect of cognitive function was evaluated using the counterfactual mediation method. Results This cohort study included 4,011 older adults (average age, 66.6 years; 53.3% males). During a follow-up period of 3.86 years, 349 individuals were diagnosed with sarcopenia. After adjusting for potential confounders, each one-standard-deviation increase in PEF was associated with a 28% reduction in the risk of sarcopenia (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.63, 0.80). There was a significant mediation of cognition for the association between PEF and incident sarcopenia, and the proportion mediated was 12.2% (95% CI: 4.5%, 23.1%). Conclusions Older adults with impaired lung function are more likely to develop sarcopenia. Nevertheless, cognition can explain only a small portion of this association. Thus, other potential pathways between lung function and sarcopenia must be elucidated.

The association between serum folate and all-cause mortality in general population remains unclear. The objective of this study was to investigate the potential association between serum folate concentrations and all-cause mortality in a large, prospective, long-term U.S. cohort. Our study included adults from the National Health and Nutrition Examination Survey (NHANES) III, and mortality data was obtained by linking with the National Death Index (NDI) until December 31, 2019. Cox proportional hazard models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to assess the association between serum folate concentrations and all-cause mortality. A total of 12,862 participants were included in this cohort study. After a median follow-up of 26.4 years [interquartile range (IQR), 15.4–28.7 years], a total of 5,299 deaths were recorded. The risk of death was lower by 12% per 1.0 g/L increase in log-transformed serum folate concentrations (HR, 0.88; 95% CI, 0.83–0.94). Compared with the lowest quartiles of serum folate level, the risk of death was lower in the second (HR, 0.84; 95% CI, 0.72–0.97), third (HR, 0.78; 95% CI, 0.68–0.91) and the highest quartiles (HR, 0.78; 95% CI, 0.69–0.88) in multivariable-adjusted model. In subgroup analyses, the inverse association between serum folate and all-cause mortality remained statistically significant for women, men and non-Hispanic White people. Higher serum folate levels were found to be significantly associated with reduced risk of all-cause mortality. However, further studies are needed to verify these findings and explore the underlying mechanism.

Bladder cancer (BC) is the most common malignancy of the urinary system and often recurs after tumor removal and/or is resistant to chemotherapy. In cancer cells, the activity of the signaling pathway changes significantly, affecting a wide range of cell activities from growth and proliferation to apoptosis, invasion and metastasis. Nrf2 is a transcription factor that plays an important role in cellular defense responses to a variety of cellular stresses. There is increasing evidence that Nrf2 acts as a tumor driver and that it is involved in the maintenance of malignant cell phenotypes. Abnormal expression of Nrf2 has been found to be common in a variety of tumors, including bladder cancer. Over-activation of Nrf2 can lead to DNA damage and the development of bladder cancer, and is also associated with various pathological phenomena of bladder cancer, such as metastasis, angiogenesis, and reduced toxicity and efficacy of therapeutic anticancer drugs to provide cell protection for cancer cells. However, the above process can be effectively inhibited or reversed by inhibiting Nrf2. Therefore, Nrf2 signaling may be a potential targeting pathway for bladder cancer. In this review, we will characterize this signaling pathway and summarize the effects of Nrf2 and crosstalk with other signaling pathways on bladder cancer progression. The focus will be on the impact of Nrf2 activation on bladder cancer progression and current therapeutic strategies aimed at blocking the effects of Nrf2. To better determine how to promote new chemotherapy agents, develop new therapeutic agents, and potential therapeutic targets.

【Objective】 In view of the lack of integrated facilities for measuring and controlling flow of Doudou (agricultural) channel in irrigation area, an integrated quantity control building-Measurement and Control Integrated Water Distribution Farm Gate was designed to explore its performance on trapezoidal channel. 【Method】 Using the combination of agricultural gate control disc valve and circular pipe to form an integrated water distribution gate (hereinafter referred to as the water distribution gate), the hydraulic characteristics and flow formulas of the water distribution gate under different flow rates and different opening of the agricultural gate control disc valve are studied by model test. 【Result】 ①The flow formula of Water Distribution Farm Gate was fitted and designed. The average error of the flow calculated by the formula was 4.34% compared with the measured flow, and the measurement error of flow was less than ±5%, which met the water accuracy requirements of irrigation area. ②The “optimal water head” of Water Distribution Farm Gate is between 0.475 and 0.575 L in the overall length of the pipeline.③The water distribution gate mainly produces local head loss and head loss along the distance when the water flow passes through the disc valve, and the range of head loss is 29.54% to 38.89%. 【Conclusion】 When the flow rate is in the range of 30 - 65 m3/h, under different flow conditions and disc valve opening degree, the water metering can be carried out in the final channel of the irrigation area. Therefore, Water Distribution Farm Gate has a high prospect of popularization and practical application value in the future.