SLIDE: Significant Latent Factor Interaction Discovery and Exploration across biological domains.

Modern multiomic technologies can generate deep multiscale profiles. However, differences in data modalities, multicollinearity of the data, and large numbers of irrelevant features make analyses and integration of high-dimensional omic datasets challenging. Here we present Significant Latent Factor Interaction Discovery and Exploration (SLIDE), a first-in-class interpretable machine learning technique for identifying significant interacting latent factors underlying outcomes of interest from high-dimensional omic datasets. SLIDE makes no assumptions regarding data-generating mechanisms, comes with theoretical guarantees regarding identifiability of the latent factors/corresponding inference, and has rigorous false discovery rate control. Using SLIDE on single-cell and spatial omic datasets, we uncovered significant interacting latent factors underlying a range of molecular, cellular and organismal phenotypes. SLIDE outperforms/performs at least as well as a wide range of state-of-the-art approaches, including other latent factor approaches. More importantly, it provides biological inference beyond prediction that other methods do not afford. Thus, SLIDE is a versatile engine for biological discovery from modern multiomic datasets.

Innovative super-resolution in spatial transcriptomics: a transformer model exploiting histology images and spatial gene expression.

Spatial transcriptomics technologies have shed light on the complexities of tissue structures by accurately mapping spatial microenvironments. Nonetheless, a myriad of methods, especially those utilized in platforms like Visium, often relinquish spatial details owing to intrinsic resolution limitations. In response, we introduce TransformerST, an innovative, unsupervised model anchored in the Transformer architecture, which operates independently of references, thereby ensuring cost-efficiency by circumventing the need for single-cell RNA sequencing. TransformerST not only elevates Visium data from a multicellular level to a single-cell granularity but also showcases adaptability across diverse spatial transcriptomics platforms. By employing a vision transformer-based encoder, it discerns latent image-gene expression co-representations and is further enhanced by spatial correlations, derived from an adaptive graph Transformer module. The sophisticated cross-scale graph network, utilized in super-resolution, significantly boosts the model's accuracy, unveiling complex structure-functional relationships within histology images. Empirical evaluations validate its adeptness in revealing tissue subtleties at the single-cell scale. Crucially, TransformerST adeptly navigates through image-gene co-representation, maximizing the synergistic utility of gene expression and histology images, thereby emerging as a pioneering tool in spatial transcriptomics. It not only enhances resolution to a single-cell level but also introduces a novel approach that optimally utilizes histology images alongside gene expression, providing a refined lens for investigating spatial transcriptomics.

Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer's disease.

The associations of synaptic loss with amyloid-ß (Aß) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer's disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [18F]SynVesT-1 PET/MR scans to assess synaptic density and [18F]florbetapir and [18F]MK6240 PET/CT scans to evaluate Aß plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aß42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [18F]SynVesT-1 PET/MRI and [18F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aß and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aß deposition was associated with synaptic loss in the medial (r = -0.431, p < 0.001) and lateral (r = -0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aß deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aß42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = -0.412, p = 0.001/r = -0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aß plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aß plaques, and also can predict longitudinal synaptic loss.

Two-Dimensional Ultrathin Fe3Sn2 Kagome Metal with Defect-Dependent Magnetic Property.

Two-dimensional (2D) Fe3Sn2, which is a room-temperature ferromagnetic kagome metal, has potential applications in spintronic devices. However, the systematic synthesis and magnetic study of 2D Fe3Sn2 single crystals have rarely been reported. Here we have synthesized 2D hexagonal and triangular Fe3Sn2 nanosheets by controlling the amount of FeCl2 precursors in the chemical vapor deposition (CVD) method. It is found that the hexagonal Fe3Sn2 nanosheets exist with Fe vacancy defects and show no obvious coercivity. While the triangular Fe3Sn2 nanosheet has obvious hysteresis loops at room temperature, its coercivity first increases and then remains stable with an increase in temperature, which should result from the competition of the thermal activation mechanism and spin direction rotation mechanism. A first-principles calculation study shows that the Fe vacancy defects in Fe3Sn2 can increase the distances between Fe atoms and weaken the ferromagnetism of Fe3Sn2. The resulting 2D Fe3Sn2 nanosheets provide a new choice for spintronic devices.

Subsidized gestational diabetes mellitus screening and management program in rural China: a pragmatic multicenter, randomized controlled trial.

BACKGROUND: The increasing prevalence of gestational diabetes mellitus (GDM) is a major challenge, particularly in rural areas of China where control rates are suboptimal. This study aimed to evaluate the effectiveness of a GDM subsidy program in promoting GDM screening and management in these underserved regions. METHODS: This multicenter, randomized controlled trial (RCT) was conducted in obstetric clinics of six rural hospitals located in three provinces in China. Eligible participants were pregnant women in 24-28 weeks' gestation, without overt diabetes, with a singleton pregnancy, access to a telephone, and provided informed consent. Participants were randomly assigned in a 1:1 ratio to either the intervention or control groups using an internet-based, computer-generated randomization system. The intervention group received subsidized care for GDM, which included screening, blood glucose retesting, and lifestyle management, with financial assistance provided to health care providers. In contrast, the control group received usual care. The primary outcomes of this study were the combined maternal and neonatal complications associated with GDM, as defined by the occurrence of at least one pre-defined complication in either the mother or newborn. The secondary outcomes included the GDM screening rate, rates of glucose retesting for pregnant women diagnosed with GDM, dietary patterns, physical activity levels, gestational weight gain, and antenatal visit frequency for exploratory purposes. Primary and secondary outcomes were obtained for all participants with and without GDM. Binary outcomes were analyzed by the generalized linear model with a link of logistic, and odds ratios (OR) with 95% confidence intervals (CIs) were reported. Count outcomes were analyzed by Poisson regression, and incidence rate ratios with 95% CIs were reported. RESULTS: A total of 3294 pregnant women were randomly assigned to either the intervention group (n = 1649) or the control group (n = 1645) between 15 September 2018 and 30 September 2019. The proportion of pregnant women in the intervention group who suffered from combined maternal and/or neonatal complications was lower than in the control group with adjusted OR = 0.86 (0.80 to 0.94, P = 0.001), and a more significant difference was observed in the GDM subgroup (adjusted OR = 0.66, 95% CI 0.47 to 0.95, P = 0.025). No predefined safety or adverse events of ketosis or ketoacidosis associated with GDM management were detected in this study. Both the intervention and control groups had high GDM screening rates (intervention: 97.2% [1602/1649]; control: 94.5% [1555/1645], P < 0.001). Moreover, The intervention group showed a healthier lifestyle, with lower energy intake and more walking minutes (P values < 0.05), and more frequent blood glucose testing (1.5 vs. 0.4 visits; P = 0.001) compared to the control group. CONCLUSION: In rural China, a GDM care program that provided incentives for both pregnant women and healthcare providers resulted in improved maternal and neonatal health outcomes. Public health subsidy programs in China should consider incorporating GDM screening and management to further enhance reproductive health. TRIAL REGISTRATION: China Clinical Trials Registry ChiCTR1800017488. https://www.chictr.org.cn/.

Prevalence of, risk factors for, and target organ damage from metabolic syndrome among people living with HIV on ART: A cross-sectional analysis in Chongqing, China.

INTRODUCTION: The incidence of metabolic syndrome (MetS) in people living with HIV is significantly higher than in people without HIV. MetS is not only a major driver of cardiovascular disease (CVD) but is also closely related to the development of chronic kidney disease (CKD). The aim of this study was to investigate the prevalence of and risk factors for MetS and to further understand the degree of damage to target organs. METHODS: This was a cross-sectional descriptive study conducted at Chongqing Public Health Medical Center, China. Information was collected via questionnaire survey, physical examination, and laboratory tests. We used the China Diabetes Society guidelines to define MetS. Pooled cohort equations were calculated to compare CVD risk in the next 10 years in people living with HIV aged ≥40 years with or without MetS. We used Student's t-test, the chi-squared test, Fisher's exact test, binary logistic regression, and multiple linear regression in the statistical analysis. RESULTS: The study included 979 people living with HIV, including 13 who have experienced CVD, receiving antiretroviral therapy (ART). The median age was 43.0 years, 20.9% were female, and the median ART time was 45.0 months. The prevalence of MetS was 33.9%. The components of MetS criteria were hyperglycaemia (50.4%), hypertriglyceridaemia (48.4%), hypertension (46.8%), low concentrations of high-density lipoprotein cholesterol (28.2%), and abdominal obesity (25.0%). Higher body mass index (odds ratio [OR] 1.266; 95% confidence interval [CI] 1.203-1.333), higher total cholesterol (OR 1.267; 95% CI 1.011-1.588), high alcohol consumption (OR 1.973; 95% CI 1.009-3.859), and family history of diabetes (OR 1.726; 95% CI 1.075-2.770) were independent risk factors for MetS. Compared with the non-MetS group, the MetS group had a higher rate of urine albumin (23.8% vs 14.8%, p = 0.001), and the estimated glomerular filtration rate <90 mL/min/1.73 m2 (18.37% vs. 12.8%, p = 0.020) and ß2-microglobin (p = 0.004) increased more markedly in the MetS group. Regarding the risk of developing CVD events in the next 10 years, 38.5% of those in the MetS group were at high or very high risk, which was significantly higher than in the non-MetS group (p < 0.001). In addition, age (p < 0.001) and sex (p = 0.002) are independent risk factors for developing CVD events in the next 10 years. CONCLUSIONS: The prevalence of MetS in people living with HIV on ART is high in Chongqing, China. Risk factors for the development of MetS are high alcohol consumption, family history of diabetes, higher body mass index, and higher total cholesterol levels. In addition, MetS is associated with a risk of CKD and the incidence of 10-year CVD.

Correlation between small-cell lung cancer serum protein/peptides determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and chemotherapy efficacy.

BACKGROUND: Currently, no effective measures are available to predict the curative efficacy of small-cell lung cancer (SCLC) chemotherapy. We expect to develop a method for effectively predicting the SCLC chemotherapy efficacy and prognosis in clinical practice in order to offer more pertinent therapeutic protocols for individual patients. METHODS: We adopted matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinPro Tools system to detect serum samples from 154 SCLC patients with different curative efficacy of standard chemotherapy and analyze the different peptides/proteins of SCLC patients to discover predictive tumor markers related to chemotherapy efficacy. Ten peptide/protein peaks were significantly different in the two groups. RESULTS: A genetic algorithm model consisting of four peptides/proteins was developed from the training group to separate patients with different chemotherapy efficacies. Among them, three peptides/proteins (m/z 3323.35, 6649.03 and 6451.08) showed high expression in the disease progression group, whereas the peptide/protein at m/z 4283.18 was highly expressed in the disease response group. The classifier exhibited an accuracy of 91.4% (53/58) in the validation group. The survival analysis showed that the median progression-free survival (PFS) of 30 SCLC patients in disease response group was 9.0 months; in 28 cases in disease progression group, the median PFS was 3.0 months, a statistically significant difference (χ2 = 46.98, P < 0.001). The median overall survival (OS) of the two groups was 13.0 months and 7.0 months, a statistically significant difference (χ2 = 40.64, P < 0.001). CONCLUSIONS: These peptides/proteins may be used as potential biological markers for prediction of the curative efficacy and prognosis for SCLC patients treated with standard regimen chemotherapy.

Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in initiating ART among HIV-Infected patients in China-risk factors and management.

BACKGROUND: China is a country burdened with a high incidence of both tuberculosis (TB) and HIV, Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important early complication in TB and HIV co-infected patients, but data from China are limited. Additionally, as an integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) regimen becomes the first-line treatment, concerns have arisen regarding the potential increase in the incidence of paradoxical TB-IRIS. Nevertheless, the existing data are inconclusive and contradictory. METHODS: We conducted a retrospective study at Chongqing Public Health Clinical Center from January 2018 to December 2021. We collected demographic and clinical data of HIV/TB co-infected patients who initiated ART. We described the patient characteristics, identified predictors for TB-IRIS, and determined clinical outcomes. The Statistical Package for Social Science (SPSS 25) was used to analyse the data. Continuous variables were compared using Student's t-test or rank sum test. Counting data were compared using the chi-square test or Fisher's exact test. The variables with statistical significance in the univariate analysis were added to the binary logistic regression. A p-value less than 0.05 was considered statistically significant. RESULTS: A total of 384 patients co-infected with naive HIV and pulmonary TB (PTB) who were given ATT and ART combination were included. 72 patients (18.8%) developed paradoxical TB-IRIS with a median of 15 (12, 21) days after initiating ART. Baseline age ≤ 40years, CD4 + T-cell counts ≤ 50cells/µL, HIV viral load ≥ 500,000 copies/mL were found to be significantly associated with development of paradoxical TB-IRIS. Mortality rates were similar in the TB-IRIS (n = 5, 6.9%) group and non-TB-IRIS (n = 13, 4.2%) group. Interestingly, CD4+ T-cell counts recovery post-ART was significant higher in the TB-IRIS group when compared to the non-TB-IRIS group at the end of 24 weeks (P = 0.004), as well as at 48 weeks (P = 0.015). In addition, we consider that INSTI- based ART regimen do not increased the risk of Paradoxical TB-IRIS. CONCLUSION: Paradoxical TB-IRIS, while often leading to clinical deterioration and hospitalization, is generally manageable. It appears to have a positive impact on the recovery of CD4 + T-cell counts over time. Importantly, our data suggest that INSTI-based ART regimens do not elevate the risk of TB-IRIS. Thus, paradoxical TB-IRIS should not be considered an impediment to initiating ART in adults with advanced immunodeficiency, except in the case of tuberculous meningitis (TBM).

Emission of Intermediate Volatile Organic Compounds from Animal Dung and Coal Combustion and Its Contribution to Secondary Organic Aerosol Formation in Qinghai-Tibet Plateau, China.

Intermediate volatility organic compounds (IVOCs) are important precursors to secondary organic aerosols (SOAs), but they are often neglected in studies concerning SOA formation. This study addresses the significant issue of IVOCs emissions in the Qinghai-Tibetan plateau (QTP), where solid fuels are extensively used under incomplete combustion conditions for residential heating and cooking. Our field measurement data revealed an emission factor of the total IVOCs (EFIVOCs) ranging from 1.56 ± 0.03 to 9.97 ± 3.22 g/kg from various combustion scenarios in QTP. The markedly higher EFIVOCs in QTP than in plain regions can be attributed to oxygen-deficient conditions. IVOCs were dominated by gaseous phase emissions, and the primary contributors of gaseous and particulate phase IVOCs are the unresolved complex mixture and alkanes, respectively. Total IVOCs emissions during the heating and nonheating seasons in QTP were estimated to be 31.7 ± 13.8 and 6.87 ± 0.45 Gg, respectively. The estimated SOA production resulting from combined emissions of IVOCs and VOCs is nearly five times higher than that derived from VOCs alone. Results from this study emphasized the pivotal role of IVOCs emissions in air pollution and provided a foundation for compiling emission inventories related to solid fuel combustion and developing pollution prevention strategies.

Effect of Liraglutide combined with Jinlida granules on glycolipid metabolism and islet function of type 2 diabetes mellitus.

To investigate whether Liraglutide combined with Jinlida granules affects glycolipid metabolism and islet function in the treatment of type 2 diabetes mellitus (T2DM), a control group and an observation group were established with 90 T2DM patients. The control group was given Jinlida treatment and the observation group was given liraglutide combined treatment for 12 weeks. The clinical efficacy, glycolipid metabolism, bone metabolism, islet function, and endothelial function. The curative effect of the observation group was better than that of the control group. After treatment, FBG, 2hPG, HbAlc, TC, TG, and LDL-C in the observation group were lower and HDL-C was higher than those in the control group (P < 0.05). After treatment, the observation group showed higher bone mineral density, osteocalcin, FINS, and HOMA-ß and lower HOMA-IR than the control group (P < 0.05). After treatment, endothelin-1 level in the observation group was lower than that in the control group, and the NO level was higher (P < 0.05). No significant difference was found in the incidence of adverse reactions between the two groups (P > 0.05). Liraglutide combined with Jinlida in T2DM can improve glucose, lipid, and bone metabolism, promote the recovery of islet function, and enhance vascular endothelial function.

Dominance by cyanobacteria in the newly formed biofilms on stone monuments under a protective shade at the Beishiku Temple in China.

Following the installation of a protective shade, rapid propagation of microorganisms showing in black and grey colors occurred at Beishiku Temple in Gansu Province of China. This study employed a combination of high-throughput sequencing technology, morphological examinations, and an assessment of the surrounding environmental condition to analyze newly formed microbial disease spots. The investigation unveiled the responsible microorganisms and the instigating factors of the microbial outbreak that subsequently to the erection of the shade. Through comparison of bioinformatics, the ASV method surpasses the OTU method in characterizing community compositional changes by the dominant microbial groups, the phylum Cyanobacteria emerged as the most dominant ones in the microbial community accountable for the post-shade microbial deterioration. The black spot and grey spot are predominantly composed of Mastigocladopsis and Scytonema, respectively. Validation analysis, based on the active RNA-level community results, supported and validated these conclusions. Comparative scrutiny of the microbial community before shade installation and the background environmental data disclosed that the erection of the shade prompted a decrease in temperatures and an increase in humidity within the protected area. Consequently, this spurred the exponential proliferation of indigenous cyanobacteria in the spots observed. The outcomes of this study carry considerable significance in devising preventive conservation strategies for cultural heritage and in managing the process of biodeterioration.

Survival analysis of laparoscopic surgery and open surgery for hilar cholangiocarcinoma: a retrospective cohort study.

BACKGROUND/PURPOSE: This study compared the clinical efficacy and safety of laparoscopic versus open resection for hilar cholangiocarcinoma (HCCA) and analyzed potential prognostic factors. METHODS: The study included patients who underwent HCCA resection at our center from March 2012 to February 2022. Perioperative complications and postoperative prognosis were compared between the laparoscopic surgery (LS) and open surgery (OS) groups. RESULTS: After screening 313 HCCA patients, 68 patients were eligible for the study in the LS group (n = 40) and OS group (n = 28). Kaplan-Meier survival curve analysis revealed that overall survival > 2 years and 3-year disease-free survival (DFS) were more common in the LS than OS group, but the rate of 2-year DFS was lower in the LS group than OS group. Cox multivariate regression analysis revealed age (< 65 years), radical resection, and postoperative adjuvant therapy were associated with reduced risk of death (hazard ratio [HR] = 0.380, 95% confidence interval [CI] = 0.150-0.940, P = 0.036; HR = 0.080, 95% CI = 0.010-0.710, P = 0.024 and HR = 0.380, 95% CI = 0.150-0.960, P = 0.040), whereas preoperative biliary drainage was an independent factor associated with increased risk of death (HR = 2.810, 95% CI = 1.130-6.950, P = 0.026). Perineuronal invasion was identified as an independent risk factor affecting DFS (HR = 5.180, 95% CI = 1.170-22.960, P = 0.030). CONCLUSIONS: Compared with OS, laparoscopic HCCA resection does not significantly differ in terms of clinical efficacy. Age (<65 years), radical resection, and postoperative adjuvant therapy reduce the risk of death, and preoperative biliary drainage increases the risk of death.

Tethered cord syndrome from pediatric and adult perspectives: a comprehensive systematic review of 6135 cases.

OBJECTIVE: This study aimed to investigate the differences in clinical features, diagnostic examination, treatment, and pathological results between adult-onset and pediatric-onset tethered cord syndrome (TCS). METHODS: The authors searched the PubMed, Embase, and Cochrane Library databases through January 2023 for reports on TCS, extracting information on clinical features, imaging data, treatment modalities, prognosis, and pathological research results. A total of 6135 cases from 246 articles were included in the analysis. This review was conducted in accordance with the 2020 PRISMA guidelines and registered on PROSPERO. RESULTS: The most common adult clinical manifestations were pain, urinary symptoms, and numbness; in children, they were urinary symptoms, skin lesions, bowel symptoms, and unspecific motor deficits. Surgical treatment was the primary approach for both adults and children, with a higher clinical improvement rate observed in adults. However, adults also had a higher rate of surgical complications than children. TCS pathological studies have not yet identified the differences between adults and children, and the pathogenesis of adult-onset TCS requires further investigation. CONCLUSIONS: Adult-onset and pediatric-onset TCS exhibit certain differences in clinical characteristics, diagnostic examinations, and treatments. However, significant differences have not been found in current pathological studies between adults and children. Systematic review registration no.: CRD42023479450 (www.crd.york.ac.uk/prospero).

Development and validation of nomograms to evaluate the survival outcome of HCC patients undergoing selective postoperative adjuvant TACE.

PURPOSE: The objective of this study was to develop and validate a novel prognostic nomogram to evaluate the survival benefit of hepatocellular carcinoma (HCC) patients receiving postoperative adjuvant transarterial chemoembolization (PA-TACE). MATERIALS AND METHODS: Clinical data of HCC patients who underwent hepatectomy at four medical centers were retrospectively analyzed, including those who received PA-TACE and those who did not. These two categories of patients were randomly allocated to the development and validation cohorts in a 7:3 ratio. RESULTS: A total of 1505 HCC patients who underwent hepatectomy were included in this study, comprising 723 patients who did not receive PA-TACE and 782 patients who received PA-TACE. Among them, patients who received PA-TACE experienced more adverse events, although these events were mild and manageable (Grade 1-2, all p < 0.05). Nomograms were constructed and validated for patients with and without PA-TACE using independent predictors that influenced disease-free survival (DFS) and overall survival (OS). These two nomograms had C-indices greater than 0.800 in the development cohort and exhibited good calibration and discrimination ability compared to six conventional HCC staging systems. Patients in the intermediate-to-high-risk group in the nomogram who received PA-TACE had higher DFS and OS (all p < 0.05). In addition, tumor recurrence was significantly controlled in the intermediate-to-high-risk group of patients who received PA-TACE, while there was no significant difference in the low-risk group of patients who received PA-TACE. CONCLUSION: The nomograms were developed and validated based on large-scale clinical data and can serve as online decision-making tools to predict survival benefits from PA-TACE in different subgroups of patients.

Asiaticoside enhances the effect of propofol on the invasion, ferroptosis and immune escape of bladder cancer.

Bladder cancer is a highly prevalent malignancy. Asiaticoside (AC), a triterpenoid derivative, exhibits antitumor effect on different tumors. This study aimed to explore the role and mechanism of AC on bladder cancer. J82 and T24 cells were treated with AC and/or propofol, and nude mice were subcutaneously administrated with T24 cells. The effect and mechanism of AC and/or propofol were explored by cell counting kit-8, transwell, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry and western blot assays both in vitro and in vivo. Cell viability of J82 and T24 cells was inhibited by AC with a IC50 value of 2.43 µM and 2.16 µM, and by propofol with a IC50 value of 42.51 µM and 48.37 µM, respectively. AC or propofol alone decreased cell proliferation, invasion, and immune escape with the increased ferroptosis, as well as downregulating the level of the PI3K/AKT pathway in both animal and cell experiments. The effect of propofol on the above-mentioned indicators was further enhanced with the co-treatment of AC in vitro and in vivo. Taken together, AC promoted the ameliorative effect of propofol on bladder cancer involved in PI3K/AKT pathway.

Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment.

INTRODUCTION: Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD). METHODS: Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [18F]SynVesT-1 and [18F]PSS232 positron emission tomography (PET)/magnetic resonance to assess synaptic density and mGluR5 availability. The associations between mGluR5 availability and synaptic density were examined. A mediation analysis was performed to investigate the possible mediating effects of mGluR5 availability and synaptic loss on the relationship between amyloid deposition and cognition. RESULTS: CI patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and cognition. CONCLUSIONS: Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD and are closely linked. HIGHLIGHTS: Cognitively impaired patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and global cognition. With further research, modulating mGluR5 availability might be a potential therapeutic strategy for improving synaptic function in AD.

APOE ε4 is associated with decreased synaptic density in cognitively impaired participants.

INTRODUCTION: We aimed to investigate the effect of apolipoprotein E4 (APOE) ε4 on synaptic density in cognitively impaired (CI) participants. METHODS: One hundred ten CI participants underwent amyloid positron emission tomography (PET) with 18F-florbetapir and synaptic density PET with 18F-SynVesT-1. We evaluated the influence of APOE ε4 allele on synaptic density and investigated the effects of ε4 genotype on the associations of synaptic density with Alzheimer's disease (AD) biomarkers. The mediation effects of AD biomarkers on ε4-associated synaptic density loss were analyzed. RESULTS: Compared with non-carriers, APOE ε4 allele carriers exhibited significant synaptic loss in the medial temporal lobe. Amyloid beta (Aß) and tau pathology mediated the effects of APOE ε4 on synaptic density to different extents. The associations between synaptic density and tau pathology were regulated by the APOE ε4 genotype. DISCUSSION: The APOE ε4 allele was associated with decreased synaptic density in CI individuals and may be driven by AD biomarkers.

Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis and Treatment in the Era of Precision Medicine.

Bile acid diarrhea (BAD) is a multifaceted intestinal disorder involving intricate molecular mechanisms, including farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and Takeda G protein-coupled receptor 5 (TGR5). Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and 75Selenium HomotauroCholic acid test (75SeHCAT). Treatment primarily involves BAS and FXR agonists. However, due to the limited sensitivity and specificity of current diagnostic methods, as well as suboptimal treatment efficacy and the presence of side effects, there is an urgent need to establish new diagnostic and treatment methods. While prior literature has summarized various diagnostic and treatment methods and the pathogenesis of BAD, no previous work has linked the two. This review offers a molecular perspective on the clinical diagnosis and treatment of BAD, with a focus on FXR, FGFR4, and TGR5, emphasizing the potential for identifying additional molecular mechanisms as treatment targets and bridging the gap between diagnostic and treatment methods and molecular mechanisms for a novel approach to the clinical management of BAD.

Exploring Advanced Therapies for Primary Biliary Cholangitis: Insights from the Gut Microbiota-Bile Acid-Immunity Network.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota-bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

Development and Validation of a Nomogram for Predicting Postoperative Early Relapse and Survival in Hepatocellular Carcinoma.

BACKGROUND: Early relapse after hepatectomy presents a significant challenge in the treatment of hepatocellular carcinoma (HCC). The aim of this study was to construct and validate a novel nomogram model for predicting early relapse and survival after hepatectomy for HCC. PATIENTS AND METHODS: We conducted a large-scale, multicenter retrospective analysis of 1,505 patients with surgically treated HCC from 4 medical centers. All patients were randomly divided into either the training cohort (n=1,053) or the validation cohort (n=452) in a 7:3 ratio. A machine learning-based nomogram model for prediction of HCC was established by integrating multiple risk factors that influence early relapse and survival, which were identified from preoperative clinical data and postoperative pathologic characteristics of the patients. RESULTS: The median time to early relapse was 7 months, whereas the median time from early relapse to death was only 19 months. The concordance indexes of the postoperative nomogram for predicting disease-free survival and overall survival were 0.741 and 0.739, respectively, with well-calibrated curves demonstrating good consistency between predicted and observed outcomes. Moreover, the accuracy and predictive performance of the postoperative nomograms were significantly superior to those of the preoperative nomogram and the other 7 HCC staging systems. The patients in the intermediate- and high-risk groups of the model had significantly higher probabilities of early and critical recurrence (P<.001), whereas those in the low-risk group had higher probabilities of late and local recurrence (P<.001). CONCLUSIONS: This postoperative nomogram model can better predict early recurrence and survival and can serve as a useful tool to guide clinical treatment decisions for patients with HCC.