Microglia mediate memory dysfunction via excitatory synaptic elimination in a fracture surgery mouse model.

Cognitive impairment is a common issue among human patients undergoing surgery, yet the neural mechanism causing this impairment remains unidentified. Surgical procedures often lead to glial cell activation and neuronal hypoexcitability, both of which are known to contribute to postoperative cognitive dysfunction (POCD). However, the role of neuron-glia crosstalk in the pathology of POCD is still unclear. Through integrated transcriptomics and proteomics analyses, we found that the complement cascades and microglial phagocytotic signaling pathways are activated in a mouse model of POCD. Following surgery, there is a significant increase in the presence of complement C3, but not C1q, in conjunction with presynaptic elements. This triggers a reduction in excitatory synapses, a decline in excitatory synaptic transmission, and subsequent memory deficits in the mouse model. By genetically knockout out C3ar1 or inhibiting p-STAT3 signaling, we successfully prevented neuronal hypoexcitability and alleviated cognitive impairment in the mouse model. Therefore, targeting the C3aR and downstream p-STAT3 signaling pathways could serve as potential therapeutic approaches for mitigating POCD.

Development and validation of deep learning models for identifying the brand of pedicle screws on plain spine radiographs.

Background: In spinal revision surgery, previous pedicle screws (PS) may need to be replaced with new implants. Failure to accurately identify the brand of PS-based instrumentation preoperatively may increase the risk of perioperative complications. This study aimed to develop and validate an optimal deep learning (DL) model to identify the brand of PS-based instrumentation on plain radiographs of spine (PRS) using anteroposterior (AP) and lateral images. Methods: A total of 529 patients who received PS-based instrumentation from seven manufacturers were enrolled in this retrospective study. The postoperative PRS were gathered as ground truths. The training, validation, and testing datasets contained 338, 85, and 106 patients, respectively. YOLOv5 was used to crop out the screws' trajectory, and the EfficientNet-b0 model was used to develop single models (AP, Lateral, Merge, and Concatenated) based on the different PRS images. The ensemble models were different combinations of the single models. Primary outcomes were the models' performance in accuracy, sensitivity, precision, F1-score, kappa value, and area under the curve (AUC). Secondary outcomes were the relative performance of models versus human readers and external validation of the DL models. Results: The Lateral model had the most stable performance among single models. The discriminative performance was improved by the ensemble method. The AP + Lateral ensemble model had the most stable performance, with an accuracy of 0.9434, F1 score of 0.9388, and AUC of 0.9834. The performance of the ensemble models was comparable to that of experienced orthopedic surgeons and superior to that of inexperienced orthopedic surgeons. External validation revealed that the Lat + Concat ensemble model had the best accuracy (0.9412). Conclusion: The DL models demonstrated stable performance in identifying the brand of PS-based instrumentation based on AP and/or lateral images of PRS, which may assist orthopedic spine surgeons in preoperative revision planning in clinical practice.

Metabolic variation and oxidative stress responses of clams (Ruditapes philippinarum) perturbed by ofloxacin exposure.

Ofloxacin (OFL), one of the most widely used fluoroquinolone antibiotics, has been frequently detected in marine environments. Nonetheless, researchers are yet to focus on the effects of OFL on the benthos. In the present study, marine clams (Ruditapes philippinarum) were exposed to OFL (0.5, 50, and 500 µg/L) for 14 d, followed by a 7 d depuration period. The accumulation of OFL, antioxidative defense responses, neurotoxicity, burrowing behavior, and metabolomic changes in clams were evaluated. The results indicated that OFL could accumulate in clams, albeit with a low bioaccumulation capacity. The intermediate (50 µg/L) and high (500 µg/L) levels of OFL induced significant antioxidative responses in the gills and digestive glands of clams, mainly manifesting as the inhibition of catalase activities and the induction of superoxide dismutase and glutathione S-transferase activities, which ultimately elevated the content of malondialdehyde, causing oxidative damage. Furthermore, the significant induction of acetylcholinesterase activities was observed, coinciding with a significant increase in burrowing rates of clams. The high level of OFL affected glycerophospholipid, arachidonic acid, steroid hormone biosynthesis, unsaturated fatty acids biosynthesis, and glycolysis/glycogenesis metabolism. In conclusion, this study has contributed to the understanding of the physiological and biochemical effects and molecular toxicity mechanisms of OFL to marine bivalves.

Effects of LDPE and PBAT plastics on soil organic carbon and carbon-enzymes: A mesocosm experiment under field conditions.

Although the effects of plastic residues on soil organic carbon (SOC) have been studied, variations in SOC and soil carbon-enzyme activities at different plant growth stages have been largely overlooked. There remains a knowledge gap on how various varieties of plastics affect SOC and carbon-enzyme activity dynamics during the different growing stages of plants. In this study, we conducted a mesocosm experiment under field conditions using low-density polyethylene and poly (butylene adipate-co-terephthalate) debris (LDPE-D and PBAT-D, 500-2000 µm (pieces), 0%, 0.05%, 0.1%, 0.2%, 0.5%, 1%, 2%), and low-density polyethylene microplastics (LDPE-M, 500-1000 µm (powder), 0%, 0.05%, 0.1%, 0.5%) to investigate SOC and C-enzyme activities (ß-xylosidase, cellobiohydrolase, ß-glucosidase) at the sowing, seedling, flowering and harvesting stages of soybean (Glycine Max). The results showed that SOC in the LDPE-D treatments significantly increased from the flowering to harvesting stage, by 12.69%-13.26% (p < 0.05), but significantly decreased in the 0.05% and 0.1% LDPE-M treatments from the sowing to seedling stage (p < 0.05). However, PBAT-D had no significant effect on SOC during the whole growing period. For C-enzyme activities, only LDPE-D treatments inhibited GH (17.22-38.56%), BG (46.7-66.53%) and CBH (13.19-23.16%), compared to treatment without plastic addition, from the flowering stage to harvesting stage. Meanwhile, C-enzyme activities and SOC responded nonmonotonically to plastic abundance and the impacts significantly varied among the growing stages, especially in treatments with PBAT-D (p < 0.05). These risks to soil organic carbon cycling are likely mediated by the effects of plastic contamination and degradation soil microbe. These effects are sensitive to plastic characteristics such as type, size, and shape, which, in turn, affect the biogeochemical and mechanical interactions involving plastic particles. Therefore, further research on the interactions between plastic degradation processes and the soil microbial community may provide better mechanistic understanding the effect of plastic contamination on soil organic carbon cycling.

Investigation of the effects of polyethylene microplastics at environmentally relevant concentrations on the plant-soil-microbiota system: A two-year field trial.

Microplastics are a potential threat to agricultural sustainability. However, the effects of microplastics at environmentally relevant concentrations on the plant-soil-microbiota system in realistic field conditions are largely unknown. Herein, we conducted a two-year field trial to study the effects of polyethylene (PE) microplastics at 0, 100, and 600 mg/kg on crop growth, soil properties, and the composition and function of microbial communities in a farmland with rice-wheat rotation. PE did not affect wheat growth but it increased the rice grain weight by 42.5 % at 600 mg/kg, and enhanced rice height by 35.4 % and 30.2 % at 100 and 600 mg/kg, respectively. The presence of PE significantly decreased soil available phosphorus during the wheat season, while it reduced soil total nitrogen, NH4+-N and available phosphorus during the rice season. There were five and sixteen bacterial orders identified changed by PE in wheat and rice soils, respectively. Specifically, PE at different concentrations differentially altered the abundances of sulfate-reducing bacteria Thermodesulfovibrionia, Thermoactinomycetales and Syntrophobacterales, and further modified soil sulfate respiration in wheat soils. During the rice season, PE (100 mg/kg) increased the abundance of Xanthomonadales by 98.0 % and enriched the functional groups of intracellular parasites, while PE (600 mg/kg) inhibited twelve cluster of orthologous group function classes and disturbed bacterial metabolism. This study suggests that PE exhibits a greater impact on the plant-soil-microbiota system during the rice season compared to the previous year's wheat season, highlighting the importance of crop type and cultivation practices in determining the environmental risks of microplastics in agroecosystems.

SARS-CoV-2 Nsp15 antagonizes the cGAS-STING-mediated antiviral innate immune responses.

Coronavirus (CoV) Nsp15 is a viral endoribonuclease (EndoU) with a preference for uridine residues. CoV Nsp15 is an innate immune antagonist which prevents dsRNA sensor recognition and stress granule formation by targeting viral and host RNAs. SARS-CoV-2 restricts and delays the host antiviral innate immune responses through multiple viral proteins, but the role of SARS-CoV-2 Nsp15 in innate immune evasion is not completely understood. Here, we generate an EndoU activity knockout rSARS-CoV-2Nsp15-H234A to elucidate the biological functions of Nsp15. Relative to wild-type rSARS-CoV-2, replication of rSARS-CoV-2Nsp15-H234A was significantly decreased in IFN-responsive A549-ACE2 cells but not in its STAT1 knockout counterpart. Transcriptomic analysis revealed upregulation of innate immune response genes in cells infected with rSARS-CoV-2Nsp15-H234A relative to wild-type virus, including cGAS-STING, cytosolic DNA sensors activated by both DNA and RNA viruses. Treatment with STING inhibitors H-151 and SN-011 rescued the attenuated phenotype of rSARS-CoV-2Nsp15-H234A. SARS-CoV-2 Nsp15 inhibited cGAS-STING-mediated IFN-ß promoter and NF-κB reporter activity, as well as facilitated the replication of EV-D68 and NDV by diminishing cGAS and STING expression and downstream innate immune responses. Notably, the decline in cGAS and STING was also apparent during SARS-CoV-2 infection. The EndoU activity was essential for SARS-CoV-2 Nsp15-mediated cGAS and STING downregulation, but not all HCoV Nsp15 share the consistent substrate selectivity. In the hamster model, rSARS-CoV-2Nsp15-H234A replicated to lower titers in the nasal turbinates and lungs and induced higher innate immune responses. Collectively, our findings exhibit that SARS-CoV-2 Nsp15 serves as a host innate immune antagonist by targeting host cGAS and STING.

Relieving effect of jiao-tune of 5-element music on negative emotions in patients with decompensated hepatitis B virus cirrhosis: A randomized and controlled experiment study.

BACKGROUND: Depression and anxiety are common in patients with decompensated hepatitis B virus (HBV) cirrhosis. This study aimed to evaluate the relieving effects of the jiao-tune of 5-element music on negative emotions in patients with decompensated HBV cirrhosis. METHODS: The patients were randomly allocated into the control group (standard nursing care) and the jiao-tune group (standard nursing care plus a 2-month course of music therapy with the jiao-tune of 5-element music). The negative emotions of patients were assessed before intervention treatment and at the end of the 2-month follow-up using the Zung Self-Rating Depression Scale (SDS) and Zung Self-Rating Anxiety Scale (SAS). RESULTS: The analysis included 209 patients, with 102 in the control group and 107 in the jiao-tune group, all of whom returned their completed questionnaires. Baseline clinical characteristics and length of hospital stay were comparable between 2 groups. Before intervention treatment, there were no significant differences in SAS score (55.78 ±â€…5.64 vs 56.47 ±â€…3.28) and SDS score (65.13 ±â€…3.12 vs 64.48 ±â€…4.47) between the jiao-tune group and control group. After 2-month follow-up, the jiao-tune group had a significantly lower SAS score (53.17 ±â€…5.61) and SDS score (61.28 ±â€…1.52) compared with the control group (55.49 ±â€…3.37 and 63.08 ±â€…2.76), there were significant differences between 2 groups (P < .001). CONCLUSIONS: The jiao-tune of 5-element music can relieve the negative emotions in patients with decompensated HBV cirrhosis.

Predictor of Surgical Failure Following Transvaginal Mesh Repair Using Minimally Invasive Prolapse System Device (MIPS).

Background: The Minimally Invasive Prolapse System (MIPS) device, a novel single-incision transvaginal mesh, represents recent advancements in mesh technology, providing lightweight, biocompatible support for pelvic organ prolapse while reducing erosion, allowing for customization and improving surgical outcomes. This study aimed to identify factors associated with pelvic organ prolapse (POP) recurrence after transvaginal mesh (TVM) repair using the Minimally Invasive Prolapse System device. Methods: Two hundred and eighteen women with symptomatic stage II to IV POP underwent TVM. Preoperative and postoperative assessments included urinalyses and pelvic examinations using the POP quantification (POP-Q) staging system. Results: During a follow-up period of 12-46 months, 7 of 218 (3.2%) women experienced POP recurrence. Univariate analysis was conducted to identify predictors of surgical failure, revealing no significant differences in body mass index, POP stage, or preoperative urinary symptoms between the recurrence and success groups (p > 0.05). However, functional urethral length <20 mm based on urodynamics (p = 0.011), ICI-Q scores ≥7 (p = 0.012), and the first 60 surgical cases (p = 0.018) were significant predictors of surgical failure. Multivariate logistic regression confirmed these findings. Conclusions: Functional urethral length <20 mm, ICI-Q scores ≥7, and limited surgical experience were significant predictors of TVM failure using the Minimally Invasive Prolapse System kit. POP recurrence after mesh repair is less likely beyond the learning curve.

Anoikis-Related Long Non-Coding RNA Signatures to Predict Prognosis and Immune Infiltration of Gastric Cancer.

Anoikis is a distinct type of programmed cell death and a unique mechanism for tumor progress. However, its exact function in gastric cancer (GC) remains unknown. This study aims to investigate the function of anoikis-related lncRNA (ar-lncRNA) in the prognosis of GC and its immunological infiltration. The ar-lncRNAs were derived from RNA sequencing data and associated clinical information obtained from The Cancer Genome Atlas. Pearson correlation analysis, differential screening, LASSO and Cox regression were utilized to identify the typical ar-lncRNAs with prognostic significance, and the corresponding risk model was constructed, respectively. Comprehensive methods were employed to assess the clinical characteristics of the prediction model, ensuring the accuracy of the prediction results. Further analysis was conducted on the relationship between immune microenvironment and risk features, and sensitivity predictions were made about anticancer medicines. A risk model was built according to seven selected ar-lncRNAs. The model was validated and the calibration plots were highly consistent in validating nomogram predictions. Further analyses revealed the great accuracy of the model and its ability to serve as a stand-alone GC prognostic factor. We subsequently disclosed that high-risk groups display significant enrichment in pathways related to tumors and the immune system. Additionally, in tumor immunoassays, notable variations in immune infiltrates and checkpoints were noted between different risk groups. This study proposes, for the first time, that prognostic signatures of ar-lncRNA can be established in GC. These signatures accurately predict the prognosis of GC and offer potential biomarkers, suggesting new avenues for basic research, prognosis prediction and personalized diagnosis and treatment of GC.

Hydrogelation of peptides and carnosic acid as regulators of adaptive immunity against postoperative recurrence of cutaneous melanoma.

The in-situ activation of adaptive immunity at the surgical site has demonstrated remarkable efficacy in inhibiting various forms of tumour recurrence and even holds the promise of a potential cure. However, extensive research and bioinformatic analysis conducted in this study have unveiled the formidable challenge posed by melanoma-intrinsic ß-catenin signaling, which hinders the infiltration of cytotoxic T-lymphocytes (CTLs) and their subsequent anti-tumour action. To overcome this obstacle, a ß-catenin antagonist called carnosic acid (CA) was co-assembled with a RADA-rich peptide to create a nanonet-derived hydrogel known as Supra-gelδCA. This injectable hydrogel is designed to be retained at the surgical site while simultaneously promoting hemostasis. Importantly, Supra-gelδCA directly releases CA to the site of residual tumour lesions, thereby enhancing infiltration of CTLs and subsequently activating adaptive immunity. Consequently, it effectively suppresses postoperative recurrence of skin cutaneous melanoma (SKCM) in vivo. Collectively, the presented Supra-gelδCA not only provides an efficacious immunotherapy strategy for regulating adaptive immunity by overcoming the obstacle posed by melanoma-intrinsic ß-catenin signaling-induced absence of CTLs but also offers a clinically translatable hydrogel that revolutionizes post-surgical management of SKCM.

Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation: A multicenter, case-series study in China.

Objective: To provide real-world evidence for the application of first-line dacomitinib treatment for epidermal growth factor receptor (EGFR) 21L858R mutant non-small cell lung cancer (NSCLC) patients in China and to explore the factors influencing the efficacy and safety. Methods: A longitudinal, consecutive case-series, multicenter study with mixed prospective and retrospective data was conducted. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included duration of treatment (DOT), overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety. Results: A total of 155 EGFR 21L858R mutant patients treated with first-line dacomitinib were included. The median follow-up time for these patients was 20.4 months. Among 134 patients with evaluable lesions, the ORR was 70.9% and the DCR was 96.3%. The median PFS was 16.3 [95% confidence interval (95% CI), 13.7-18.9] months. Multivariate Cox regression analysis suggested that the baseline brain metastasis (BM) status [with vs. without BM: hazard ratio (HR), 1.331; 95% CI, 0.720-2.458; P=0.361] and initial doses (45 mg vs. 30 mg: HR, 0.837; 95% CI, 0.427-1.641; P=0.604) did not significantly affect the median PFS. The median DOT was 21.0 (95% CI, 17.5-24.6) months and the median OS was not reached. Genetic tests were performed in 64 patients after progression, among whom 29 (45.3%) patients developed the EGFR 20T790M mutation. In addition, among the 46 patients who discontinued dacomitinib treatment after progression, 31 (67.4%) patients received subsequent third-generation EGFR-tyrosine kinase inhibitors. The most common grade 3-4 adverse events were rash (10.4%), diarrhea (9.1%), stomatitis (7.1%) and paronychia (4.5%). The incidence of grade 3-4 rash was significantly higher in the 45 mg group than that in the 30 mg group (21.9% vs. 7.5%, P=0.042). Conclusions: First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial.

BACKGROUND: There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations. METHODS: In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m2 on day 1 and either plinabulin (30 mg/m2) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed. FINDINGS: Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group. INTERPRETATION: Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population. FUNDING: BeyondSpring Pharmaceuticals.

Branched-chain amino acids supplementation induces insulin resistance and pro-inflammatory macrophage polarization via INFGR1/JAK1/STAT1 signal pathway.

BACKGROUND: Obesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes. METHODS: In vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings. RESULTS: We found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1ß), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization. CONCLUSIONS: The obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients.

Global-local aware Heterogeneous Graph Contrastive Learning for multifaceted association prediction in miRNA-gene-disease networks.

Unraveling the intricate network of associations among microRNAs (miRNAs), genes, and diseases is pivotal for deciphering molecular mechanisms, refining disease diagnosis, and crafting targeted therapies. Computational strategies, leveraging link prediction within biological graphs, present a cost-efficient alternative to high-cost empirical assays. However, while plenty of methods excel at predicting specific associations, such as miRNA-disease associations (MDAs), miRNA-target interactions (MTIs), and disease-gene associations (DGAs), a holistic approach harnessing diverse data sources for multifaceted association prediction remains largely unexplored. The limited availability of high-quality data, as vitro experiments to comprehensively confirm associations are often expensive and time-consuming, results in a sparse and noisy heterogeneous graph, hindering an accurate prediction of these complex associations. To address this challenge, we propose a novel framework called Global-local aware Heterogeneous Graph Contrastive Learning (GlaHGCL). GlaHGCL combines global and local contrastive learning to improve node embeddings in the heterogeneous graph. In particular, global contrastive learning enhances the robustness of node embeddings against noise by aligning global representations of the original graph and its augmented counterpart. Local contrastive learning enforces representation consistency between functionally similar or connected nodes across diverse data sources, effectively leveraging data heterogeneity and mitigating the issue of data scarcity. The refined node representations are applied to downstream tasks, such as MDA, MTI, and DGA prediction. Experiments show GlaHGCL outperforming state-of-the-art methods, and case studies further demonstrate its ability to accurately uncover new associations among miRNAs, genes, and diseases. We have made the datasets and source code publicly available at https://github.com/Sue-syx/GlaHGCL.

The clinicopathological significance and prognostic impact of 14-3-3σ/stratifin expression on patients with surgically resectable intrahepatic cholangiocarcinoma.

INTRODUCTION: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer after hepatocellular carcinoma. Through data mining of publicly available iCCA transcriptomic datasets from the Gene Expression Omnibus, we identified SFN as the most significantly up-regulated gene in iCCA compared to normal tissue, focusing on the Gene Ontology term "cell proliferation" (GO:0008283). SFN encodes the 14-3-3σ protein, also known as stratifin, which plays crucial roles in various cellular processes. MATERIALS AND METHODS: Immunohistochemistry was used to assess stratifin expression in 182 patients with localized iCCAs undergoing surgical resection. Patients were divided into low and high expression groups, and the association between stratifin expression and clinicopathological features was analyzed. Univariate and multivariate survival analyses were performed to assess overall survival (OS), disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MeFS). RESULTS: Elevated stratifin expression in iCCAs was significantly associated with the absence of hepatitis, positive surgical margins, advanced primary tumor stages, and higher histological grades (all p ≤ 0.011). Survival analyses demonstrated a significant negative association between stratifin expression and all prognostic indicators, including OS, DSS, LRFS, and MeFS (all p ≤ 0.0004). Multivariate analysis revealed that stratifin overexpression was significantly correlated with poorer outcomes in terms of DSS, LRFS, and MeFS (all p < 0.001). CONCLUSIONS: These findings suggest that stratifin may play a crucial role in iCCA oncogenesis and tumor progression, serving as a potential novel prognostic biomarker.

Base-mediated synthesis of aryl enol ethers from α-aryl allylic alcohols and arylsulfonium salts.

A concise synthesis of aryl enol ethers from allylic alcohols and arylsulfonium salts by simply using an inorganic base as a mediator is described. The reaction enabled the facile conversion of various α-aryl allylic alcohols into the corresponding aryl enol ethers in good yields with excellent selectivity. The results demonstrated that both symmetric triarylsulfonium triflate and 10-methyl-5-aryl-5,10-dihydrophenothiazin-5-ium salts were effective arylation reagents for the base-initiated selective O-arylation and isomerization of α-aryl allylic alcohols. This reaction represents the first use of arylsulfonium salts as arylation reagents to access aryl enol ethers directly from allylic alcohols.

Sini san regulates intestinal flora and short-chain fatty acids to ameliorate hepatocyte apoptosis and relieve CCl4-induced liver fibrosis in mice.

Introduction: Si-Ni-San (SNS), a traditional Chinese medicine, is effective in treating liver fibrosis with an unclear mechanism. Although disturbance of intestinal flora and the subsequent secretion of short-chain fatty acids (SCFAs) is suggested to be involved in the progression of liver fibrosis, whether SNS produces the anti-fibrosis effect through the regulation of intestinal flora and SCFAs remains unclear. Methods: In the current study, carbon tetrachloride (CCl4)-treated mice were dosed with SNS to examine the anti-fibrotic effects and the involved mechanism. Biochemical parameters, histological staining, and analyses of fibrotic gene expression were used to evaluate the anti-fibrotic effect of SNS, while intestinal flora and SCFA content were determined by 16S rRNA and LC-MS to evaluate the mechanism. Results: In vivo results showed that SNS improved liver function, reduced hepatocyte apoptosis and FFAR2/3 expression, and restored intestinal dysbiosis and reduced PA, BA, and IsA levels. In vitro experiments showed that PA, BA, and IsA exacerbated TNF-α-induced HepG2 apoptosis. Notably, the protective effects of SNS were compromised in pseudo-sterile mice. Discussion: In conclusion, our experimental results suggest that the disturbance in intestinal flora results in elevated SCFA levels, which further exacerbates hepatocyte apoptosis in liver fibrosis, while SNS suppresses CCl4-induced liver fibrosis at least partially by reinstating intestinal flora homeostasis and reducing SCFA levels.

Graph Fourier transform for spatial omics representation and analyses of complex organs.

Spatial omics technologies decipher functional components of complex organs at cellular and subcellular resolutions. We introduce Spatial Graph Fourier Transform (SpaGFT) and apply graph signal processing to a wide range of spatial omics profiling platforms to generate their interpretable representations. This representation supports spatially variable gene identification and improves gene expression imputation, outperforming existing tools in analyzing human and mouse spatial transcriptomics data. SpaGFT can identify immunological regions for B cell maturation in human lymph nodes Visium data and characterize variations in secondary follicles using in-house human tonsil CODEX data. Furthermore, it can be integrated seamlessly into other machine learning frameworks, enhancing accuracy in spatial domain identification, cell type annotation, and subcellular feature inference by up to 40%. Notably, SpaGFT detects rare subcellular organelles, such as Cajal bodies and Set1/COMPASS complexes, in high-resolution spatial proteomics data. This approach provides an explainable graph representation method for exploring tissue biology and function.

Polyphenol (-)-Epigallocatechin Gallate (EGCG) mitigated kidney injury by regulating metabolic homeostasis and mitochondrial dynamics involvement with Drp1-mediated mitochondrial fission in mice.

The study aimed to examine effects of (-)-epigallocatechin-3-gallate (EGCG) on energy metabolism and mitochondrial dynamics in mouse model of renal injury caused by doxorubicin (DOX). Here, mice were divided into Control group, EGCG-only treated group, DOX group, and three doses of EGCG plus DOX groups. Our results showed that EGCG behaved beneficial effects against kidney injury via attenuation of pathological changes in kidney tissue, which was confirmed by reducing serum creatinine (SCr), blood urea nitrogen (BUN), and apoptosis. Subsequently, changes in reactive oxygen species generation, malondialdehyde content, and activities of antioxidant enzymes were considerably ameliorated in EGCG + DOX groups when compared to DOX group. Furthermore, EGCG-evoked renal protection was associated with increases of mitochondrial membrane potential and decreases of mitochondrial fission protein Dynamin-related protein 1 (Drp1). Moreover, changing glycolysis into mitochondrial oxidative phosphorylation was observed, evidenced by controlling activities of malate dehydrogenase (MDH) and hexokinase (HK) in EGCG + DOX groups when compared to DOX group, indicating that reprogramming energy metabolism was linked to EGCG-induced renal protection in mice. Therefore, EGCG was demonstrated to have a protective effect against kidney injury by reducing oxidative damage, metabolic disorders, and mitochondrial dysfunction, suggesting that EGCG has potential as a feasible strategy to prevent kidney injury.

Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34+ cell therapy to induce fetal hemoglobin for sickle cell disease.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here, we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34+ hematopoietic stem progenitor cells (HSPCs) from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies toward clinical trials for treating SCD and other blood disorders.