Comprehensive evaluation of digital village development in the context of rural revitalization: A case study from Jiangxi Province of China.

Digital rural construction is a key strategic direction to promote China's rural revitalization and alleviate global climate problems. In order to put forward feasible suggestions for the subsequent development and ensure the smooth development of digital village construction, how to reflect the development level of the digital village through scientific and reasonable comprehensive evaluation has become an urgent problem to be solved. This paper establishes a comprehensive evaluation index system through the Delphi method and principal component analysis method, then assigns weights to the evaluation indicators based on the improved CRITIC-G1 method, and then grades the development level of digital villages according to the extension matter element method. Finally, taking Jiangxi Province in China as an example, the overall development level of digital villages in Jiangxi Province is evaluated from the provincial level according to the proposed method. And put forward the corresponding countermeasures and suggestions. Results: Firstly, the development level of digital villages in Jiangxi Province is good, and there is a trend of excellent development level. Secondly, from different aspects of digital rural development, the digitalization of infrastructure, services, economy, and green production in Jiangxi Province is at a good level, and the digitalization of life has reached an excellent level. Thirdly, from the perspective of development trends, the digitization of infrastructure has a progressive trend towards an excellent level of development, while the digitization of services, economy and green production has signs of development regression. According to the analysis results, the relevant countermeasures and suggestions are put forward from four aspects: talent, capital, governance system and development planning. Other regions can evaluate the development level of the digital village according to the evaluation model proposed in this paper so as to analyze the existing problems and put forward targeted solutions to promote the construction of the digital village.

Assessing the role of programmed cell death signatures and related gene TOP2A in progression and prognostic prediction of clear cell renal cell carcinoma.

Kidney Clear Cell Carcinoma (KIRC), the predominant form of kidney cancer, exhibits a diverse therapeutic response to Immune Checkpoint Inhibitors (ICIs), highlighting the need for predictive models of ICI efficacy. Our study has constructed a prognostic model based on 13 types of Programmed Cell Death (PCD), which are intertwined with tumor progression and the immune microenvironment. Validated by analyses of comprehensive datasets, this model identifies seven key PCD genes that delineate two subtypes with distinct immune profiles and sensitivities to anti-PD-1 therapy. The high-PCD group demonstrates a more immune-suppressive environment, while the low-PCD group shows better responses to PD-1 treatment. In particular, TOP2A emerged as crucial, with its inhibition markedly reducing KIRC cell growth and mobility. These findings underscore the relevance of PCDs in predicting KIRC outcomes and immunotherapy response, with implications for enhancing clinical decision-making.

Decreased Treg cells induced by bisphenol A is associated with up-regulation of PI3K/Akt/mTOR signaling pathway and Foxp3 DNA methylation in spleen of adolescent mice.

The current study aimed to explore whether bisphenol A (BPA) exposure aggravated the decrease in Tregs induced by ovalbumin (OVA) in adolescent female mouse models of asthma, and whether the process was associated with mTOR-mediated signaling pathways and DNA methylation levels. A total of 40 female C57BL/6 mice at the age of four weeks were used and divided into five groups after 1 week of domestication. Each group consisted of eight mice: the control group, OVA group, OVA + BPA (0.1 µg mL-1) group, OVA + BPA (0.2 µg mL-1) group, and OVA + BPA (0.4 µg mL-1) group. Results revealed that Foxp3 protein levels decreased in the spleens of mice exposed to BPA compared to those in the OVA group. After an elevation in BPA dose, the mRNAs of methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) were gradually upregulated. The mechanism was related to the activity of TLR4/NF-κB and PI3K/Akt/mTOR signaling pathways and the enhancement of Foxp3 DNA methylation. Our results, collectively, provided a new view for studying the mechanisms underlying BPA exposure-induced immune dysfunction. Investigation of the regulatory mechanisms of DNA methylation in the abnormal Th immune response caused by BPA exposure could help reveal the causes and molecular mechanisms underlying the high incidence of allergic diseases in children in recent years.

Antimicrobial sensitisers: Gatekeepers to avoid the development of multidrug-resistant bacteria.

The resistance of multidrug-resistant bacteria to existing antibiotics forces the continued development of new antibiotics and antibacterial agents, but the high costs and long timeframe involved in the development of new agents renders the hope that existing antibiotics may again play a part. The "antibiotic adjuvant" is an indirect antibacterial strategy, but its vague concept has, in the past, limited the development speed of related drugs. In this review article, we put forward an accurate concept of a "non-self-antimicrobial sensitisers (NSAS)", to distinguish it from an "antibiotic adjuvant", and then discuss several scientific methods to restore bacterial sensitivity to antibiotics, and the sources and action mechanism of existing NSAS, in order to guide the development and further research of NSAS.

Cerebral Small Vessel Disease Burden in Patients with Transient Global Amnesia and its Relationship with Recurrence.

OBJECTIVE: Cerebral Small Vessel Disease (CSVD) has not been systematically studied in patients with Transient Global Amnesia (TGA). We aimed to investigate the CSVD burden in patients with TGA and its relationship with TGA recurrence. METHODS: We retrospectively examined 69 patients diagnosed with TGA in a single center between January 2015 and November 2023. The overall CSVD burden and single CSVD imaging markers, including enlarged perivascular spaces in the hippocampus (H-EPVS), were measured in each patient and compared with those in 69 age- and sex-matched healthy controls. Multivariate logistic regression was performed to determine independent predictors of recurrence. RESULTS: Of the 69 included patients, 40 (58%) were female, and the median age was 67 years (range 42-83 years). Twenty-one patients (30.4%) showed dot-like hippocampal hyperintensities on diffusion-weighted imaging (DWI). The mean follow-up was 51 months. Sixteen patients (23.2%) experienced TGA recurrence. The burden of overall CSVD, lacunes, WMH, EPVS, and extensive H-EPVS was higher in TGA patients than in controls. TGA patients who experienced recurrence had a heavier overall CSVD burden, lower frequency of hippocampal DWI hyperintensities, and longer follow-up duration than those who had with single episode. In the multivariate analysis, only follow-up duration was an independent predictor of TGA recurrence. CONCLUSION: The overall CSVD burden and extensive H-EPVS burden were higher in patients with TGA than healthy controls. Follow-up duration but not overall CSVD burden may predict TGA recurrence.

The regulatory relationship between NAMPT and PD-L1 in cancer and identification of a dual-targeting inhibitor.

Cancer is a heterogeneous disease. Although both tumor metabolism and tumor immune microenvironment are recognized as driving factors in tumorigenesis, the relationship between them is still not well-known, and potential combined targeting approaches remain to be identified. Here, we demonstrated a negative correlation between the expression of NAMPT, an NAD+ metabolism enzyme, and PD-L1 expression in various cancer cell lines. A clinical study showed that a NAMPTHigh PD-L1Low expression pattern predicts poor prognosis in patients with various cancers. In addition, pharmacological inhibition of NAMPT results in the transcription upregulation of PD-L1 by SIRT-mediated acetylation change of NF-κB p65, and blocking PD-L1 would induce NAMPT expression through a HIF-1-dependent glycolysis pathway. Based on these findings, we designed and synthesized a dual NAMPT/PD-L1 targeting compound, LZFPN-90, which inhibits cell growth in a NAMPT-dependent manner and blocks the cell cycle, subsequently inducing apoptosis. Under co-culture conditions, LZFPN-90 treatment contributes to the proliferation and activation of T cells and blocks the growth of cancer cells. Using mice bearing genetically manipulated tumors, we confirmed that LZFPN-90 exerted target-dependent antitumor activities, affecting metabolic processes and the immune system. In conclusion, our results demonstrate the relevance of NAD+-related metabolic processes in antitumor immunity and suggest that co-targeting NAD+ metabolism and PD-L1 represents a promising therapeutic approach.

Combination of click chemistry and Schiff base reaction: Post-synthesis of covalent organic frameworks as an immobilized metal ion affinity chromatography platform for efficient capture of global phosphopeptides in serum with chronic obstructive pulmonary disease.

Reasonable design and construction of functionalized materials are of great importance for the enrichment of global phosphopeptides. In this work, Ti4+ functionalized hydrophilic covalent organic frameworks by introducing glutathione (GSH) and 2,3,4-trihydroxy benzaldehyde (THBA) via click chemistry and Schiff base reaction (COF-V@GSH-THBA-Ti4+ ) was constructed and applied for selective enrichment of phosphopeptides in serum. Benefit from the high surface area, excellent hydrophilicity as well as regular mesoporous structure, COF-V@GSH-THBA-Ti4+ displayed high selectivity (molar ratio of 2000:1), low limit of detection (0.5 fmol), high load capacity (100.0 mg/g) and excellent size-exclusion effect (1:10000) for enrichment of phosphopeptides. For actual bio-sample analysis, 15 phosphopeptides assigned to 10 phosphoproteins with 16 phosphorylated sites and 33 phosphopeptides assigned to 25 phosphoproteins with 34 phosphorylated sites were detected from the serum of patients with chronic obstructive pulmonary disease (COPD), and normal controls. Biological processes and molecular functions analysis further disclosed the difference of serums with phosphoproteomics between COPD and normal controls.

Human dental pulp stem cell-derived exosomes decorated titanium scaffolds for promoting bone regeneration.

Exosomes, nanoscale extracellular vesicles crucial for intercellular communication, hold great promise as a therapeutic avenue in cell-free tissue regeneration. In this study, we identified and utilized exosomes to adorn anodized titanium scaffolds, inducing osteogenic differentiation in human dental pulp stem cells (hDPSCs). The osteogenesis of hDPSCs was stimulated by exosomes derived from hDPSCs that underwent various periods of osteogenic differentiation. After purification, these exosomes were loaded onto anodized titanium scaffolds. Notably, the scaffolds loaded with exosomes deriving from osteogenic differentiated hDPSCs demonstrated superior bone tissue regeneration compared to those loaded with exosomes deriving from hDPSCs within 10-week. RNA-sequencing analysis shed light on the underlying mechanism, revealing that the osteogenic exosomes carried specific cargo, which is due to upregulated miRNAs (Hsa-miR-29c-5p, Hsa-miR-378a-5p, Hsa-miR-10b-5p and Hsa-miR-9-3p) associated with osteogenesis. And down-regulated anti-osteogenic miRNA (Hsa-miR-31-3p, Hsa-miR-221-3p, Hsa-miR-183-5p and Hsa-miR-503-5p). In conclusion, the identification and utilization of exosomes derived from osteogenic differentiated stem cells offer a novel and promising strategy for achieving cell-free bone regeneration.

DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER.

Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.

Intelligence detection of oil absorption in French fries by surface profiles.

Surface profiles are important evaluation indices for oil absorption behavior of fried foods. This research established two intelligent models of partial least-squares regression (PLSR) and back propagation artificial neural network (BP-ANN) for monitoring the oil absorption behavior of French fries based on the surface characteristics. Surface morphology and texture of French fries by rapeseed oil (RO) and high-oleic peanut oil (HOPO) at different temperatures were investigated. Results showed that oil content of samples increased with frying temperature, accounting for 37.7% and 41.4% of samples fried by RO and HOPO respectively. The increase of crust ratio, roughness and texture parameters (Fm, Nwr, fwr, Wc) and the decrease of uniformity were observed with the frying temperature. Coefficients of prediction set of PLSR and BP-ANN models were more than 0.93, which indicated that surface features combined with chemometrics were rapid and precise methods for determining the oil content of French fries.

Dapagliflozin improves podocytes injury in diabetic nephropathy via regulating cholesterol balance through KLF5 targeting the ABCA1 signalling pathway.

Diabetic nephropathy (DN), one of the more prevalent microvascular complications in patients diagnosed with diabetes mellitus, is attributed as the main cause of end-stage renal disease (ESRD). Lipotoxicity in podocytes caused by hyperglycemia has been recognised as a significant pathology change, resulting in the deterioration of the glomerular filtration barrier. Research has demonstrated how dapagliflozin, a kind of SGLT2i, exhibits a multifaceted and powerful protective effect in DN, entirely independent of the hypoglycemic effect, with the specific mechanism verified. In this present study, we found that dapagliflozin has the potential to alleviate apoptosis and restore cytoskeleton triggered by high glucose (HG) in vivo and in vitro. We also discovered that dapagliflozin could mitigate podocyte cholesterol accumulation by restoring the expression of ABCA1, which is the key pathway for cholesterol outflows. This research also mechanistically demonstrates that the protective effect of dapagliflozin can be mediated by KLF-5, which is the upstream transcription factor of ABCA1. Taken together, our data suggest that dapagliflozin offers significant potential in alleviating podocyte injury and cholesterol accumulation triggered by high glucose. In terms of the mechanism, we herein reveal that dapagliflozin could accelerate cholesterol efflux by restoring the expression of ABCA1, which is directly regulated by KLF-5.

GDF-15 alleviates diabetic nephropathy via inhibiting NEDD4L-mediated IKK/NF-κB signalling pathways.

Podocyte inflammatory injury has been indicated to play a pivotal role in the occurrence and development of diabetic nephropathy (DN). However, the pathogenesis of inflammation remains unclear. Recent researches have shown that GDF-15, a member of the transforming growth factor-ß superfamily, were elevated under pathological conditions, such as myocardial ischemia, cancer, as well as inflammation. Here, we demonstrated that GDF-15 could alleviate podocyte inflammatory injury by modulating the NF-κB pathway. GDF-15 and other pro-inflammatory factors, such as TNF-α, IL-1ß, and IL-6 were upregulated in the serum of HFD/STZ rat models. GDF-15 was also elevated in diabetic glomeruli and hyperglycemic stimuli treated-podocytes. The silence of GDF-15 in HG-stimulated podocytes further augmented inflammation and podocyte injury, while overexpression of GDF-15 significantly reduced the inflammatory response in podocytes. Mechanistically, we demonstrated that GDF-15 could inhibit the nuclear translocation of NF-κB through IKK and IκBα by interaction with ubiquitin ligase NEDD4L. Taken together, our data suggested a protective mechanism of elevated GDF-15 in DN through obstruction of ubiquitin degradation of IKK by inhibiting NEDD4L expression, thus decreasing the activation of NF-κB and relieving the inflammation. GDF-15 could serve as a potential therapeutic target for DN.

Placebo and Nocebo Responses in Pharmacological Trials of Tic Disorders: A Meta-Analysis.

BACKGROUND: Clinical trials of new drugs for tic disorders (TD) often fail to yield positive results. Placebo and nocebo responses play a vital role in interpreting the outcomes of randomized controlled trials (RCTs), yet these responses in RCTs of TD remain unexplored. OBJECTIVE: The aim was to assess the magnitude of placebo and nocebo responses in RCTs of pharmacological interventions for TD and identify influencing factors. METHODS: A systematic search of the Embase, Medline, Cochrane Central Register of Controlled Trials, and PsycINFO databases was conducted. Eligible studies were RCTs that compared active pharmacological agents with placebos. Placebo response was defined as the change from baseline in TD symptom severity in the placebo group, and nocebo response as the proportion experiencing adverse events (AEs) in this group. Subgroup analysis and meta-regression were performed to explore modifying factors. RESULTS: Twenty-four trials involving 2222 participants were included in this study. A substantial placebo response in TD symptom severity was identified, with a pooled effect size of -0.79 (95% confidence interval [CI] -0.99 to -0.59; I2 = 67%). Forty-four percent (95% CI 27% to 63%; I2 = 92%) of patients experienced AEs while taking inert pills. Sample size, study design, and randomization ratio were correlated with changes in placebo and nocebo responses. CONCLUSION: There were considerable placebo and nocebo responses in TD clinical trials. These results are of great relevance for the design of future trials and for clinical practice in TD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration ID CRD42023388397. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cancer pain intensity and perceived social support in palliative care: 1-week prospective study.

OBJECTIVES: Pain is a complex and multidimensional experience affected by psychosocial factors. Perceived social support (PSS) has been considered as a positive psychosocial resource for effective regulation of cancer patients' well-being. Our study examined the relationship between PSS and pain intensity under 1-week palliative care. METHODS: A prospective study was conducted of terminal cancer inpatients (N=84) recruited from the hospice ward. Pain intensity was assessed on admission and 1 week later, and patients completed self-report questionnaires assessing PSS at admission. The repeated designed analysis of variance was used to explore the correlate of PSS with cancer pain. RESULTS: Pain intensity decreased after 1 week (t=2.303, p=0.024), and 47.62% gained pain relief. For pain intensity, there was a significant PSS group×time interaction effect detected (F=4.544, p=0.036). Pain intensity in the high PSS group was significantly reduced 1 week later (p=0.008), while the change of pain intensity was not significant in the low PSS group (p=0.609). CONCLUSIONS: PSS at admission predicted the 1-week development of pain intensity. Identifying PSS of terminal cancer patients leads to early interventions that are more effective in improving pain management of palliative care.

Simultaneously Improved Activity and Stability for Acidic Water Oxidation of IrRu Oxides by a Dual Role of Tungsten Doping.

Acidic oxygen evolution reaction (OER) remains a significant challenge due to the low activity and/or poor stability of the catalysts, even with state-of-the-art catalysts such as IrO2 and RuO2. Herein, we propose a strategy to enhance both the catalytic activity and stability of IrRu oxides for acidic OER by doping non-noble metal W. The W-doped IrRu3Ox (W-IrRu3Ox) undergoes a process of W leaching and reconstruction during the OER, leading to a more uniform distribution of elements, while the electronegative nature of W influences the electronic structures of Ir and Ru in W-IrRu3Ox. The dual role of W in promoting the formation of active site Ir5+ and inhibiting the concentration of soluble Ru>4+ ions results in a synergistic enhancement of both the activity and stability of acidic OER. Remarkably, W-IrRu3Ox exhibits outstanding catalytic activity for the OER in 0.5 M H2SO4, with a high stability of more than 500 h. This work presents a novel and feasible strategy for the development of efficient and stable catalysts for acid OER, shedding light on the design of advanced electrocatalysts for energy conversion and storage applications.

Dual-Signal Feature Spaces Map Protein Subcellular Locations Based on Immunohistochemistry Image and Protein Sequence.

Protein is one of the primary biochemical macromolecular regulators in the compartmental cellular structure, and the subcellular locations of proteins can therefore provide information on the function of subcellular structures and physiological environments. Recently, data-driven systems have been developed to predict the subcellular location of proteins based on protein sequence, immunohistochemistry (IHC) images, or immunofluorescence (IF) images. However, the research on the fusion of multiple protein signals has received little attention. In this study, we developed a dual-signal computational protocol by incorporating IHC images into protein sequences to learn protein subcellular localization. Three major steps can be summarized as follows in this protocol: first, a benchmark database that includes 281 proteins sorted out from 4722 proteins of the Human Protein Atlas (HPA) and Swiss-Prot database, which is involved in the endoplasmic reticulum (ER), Golgi apparatus, cytosol, and nucleoplasm; second, discriminative feature operators were first employed to quantitate protein image-sequence samples that include IHC images and protein sequence; finally, the feature subspace of different protein signals is absorbed to construct multiple sub-classifiers via dimensionality reduction and binary relevance (BR), and multiple confidence derived from multiple sub-classifiers is adopted to decide subcellular location by the centralized voting mechanism at the decision layer. The experimental results indicated that the dual-signal model embedded IHC images and protein sequences outperformed the single-signal models with accuracy, precision, and recall of 75.41%, 80.38%, and 74.38%, respectively. It is enlightening for further research on protein subcellular location prediction under multi-signal fusion of protein.

Endogenous FGF1 Deficiency Aggravates Doxorubicin-Induced Hepatotoxicity.

Doxorubicin (DOX) is a broad-spectrum antineoplastic agent that widely used in clinic. However, its application is largely limited by its toxicity in multiple organs. Fibroblast growth factor 1 (FGF1) showed protective potential in various liver diseases, but the role of endogenous FGF1 in DOX-induced liver damage is currently unknown. Both wild-type (WT) and FGF1 knockout (FGF1-KO) mice were treated with DOX. DOX induced loss of body weight and liver weight and elevation of ALT and AST in WT mice, which were aggravated by FGF1 deletion. FGF1 deletion exacerbated hepatic oxidative stress mirrored by further elevated 3-nitrosative modification of multiple proteins and malondialdehyde content. These were accompanied by blunted compensatively antioxidative responses indicated by impaired upregulation of nuclear factor erythroid 2-related factor 2 and its downstream antioxidant gene expression. The aggravated oxidative stress was coincided with exacerbated cell apoptosis in DOX-treated FGF1-KO mice reflected by further increased TUNEL positive cell staining and BCL-2-associated X expression and caspase 3 cleavage. These detrimental changes in DOX-treated FGF1-KO mice were associated with worsened intestinal fibrosis and increased upregulation fibrotic marker connective tissue growth factor and α-smooth muscle actin expression. However, DOX-induced hepatic inflammatory responses were not further affected by FGF1 deletion. These results demonstrate that endogenous FGF1 deficiency aggravates DOX-induced liver damage and FGF1 is a potential therapeutic target for treatment of DOX-associated hepatoxicity.

HAR_Locator: a novel protein subcellular location prediction model of immunohistochemistry images based on hybrid attention modules and residual units.

Introduction: Proteins located in subcellular compartments have played an indispensable role in the physiological function of eukaryotic organisms. The pattern of protein subcellular localization is conducive to understanding the mechanism and function of proteins, contributing to investigating pathological changes of cells, and providing technical support for targeted drug research on human diseases. Automated systems based on featurization or representation learning and classifier design have attracted interest in predicting the subcellular location of proteins due to a considerable rise in proteins. However, large-scale, fine-grained protein microscopic images are prone to trapping and losing feature information in the general deep learning models, and the shallow features derived from statistical methods have weak supervision abilities. Methods: In this work, a novel model called HAR_Locator was developed to predict the subcellular location of proteins by concatenating multi-view abstract features and shallow features, whose advanced advantages are summarized in the following three protocols. Firstly, to get discriminative abstract feature information on protein subcellular location, an abstract feature extractor called HARnet based on Hybrid Attention modules and Residual units was proposed to relieve gradient dispersion and focus on protein-target regions. Secondly, it not only improves the supervision ability of image information but also enhances the generalization ability of the HAR_Locator through concatenating abstract features and shallow features. Finally, a multi-category multi-classifier decision system based on an Artificial Neural Network (ANN) was introduced to obtain the final output results of samples by fitting the most representative result from five subset predictors. Results: To evaluate the model, a collection of 6,778 immunohistochemistry (IHC) images from the Human Protein Atlas (HPA) database was used to present experimental results, and the accuracy, precision, and recall evaluation indicators were significantly increased to 84.73%, 84.77%, and 84.70%, respectively, compared with baseline predictors.