Precise planning based on 3D-printed dry-laboratory models can reduce perioperative complications of laparoscopic surgery for complex hepatobiliary diseases: a preoperative cohort study.

BACKGROUND & AIMS: Complications after laparoscopic liver resection (LLR) are important factors affecting the prognosis of patients, especially for complex hepatobiliary diseases. The present study aimed to evaluate the value of a three-dimensional (3D) printed dry-laboratory model in the precise planning of LLR for complex hepatobiliary diseases. METHODS: Patients with complex hepatobiliary diseases who underwent LLR were preoperatively enrolled, and divided into two groups according to whether using a 3D-printed dry-laboratory model (3D vs. control group). Clinical variables were assessed and complications were graded by the Clavien-Dindo classification. The Comprehensive Complication Index (CCI) scores were calculated and compared for each patient. Multivariable analysis was performed to determine the risk factors of postoperative complications. RESULTS: Sixty-two patients with complex hepatobiliary diseases underwent the precise planning of LLR. Among them, thirty-one patients acquired the guidance of a 3D-printed dry-laboratory model, and others were only guided by traditional enhanced CT or MRI. The results showed no significant differences between the two groups in baseline characters. However, compared to the control group, the 3D group had a lower incidence of intraoperative blood loss, as well as postoperative 30-day and major complications, especially bile leakage (all P < 0.05). The median score on the CCI was 20.9 (range 8.7-51.8) in the control group and 8.7 (range 8.7-43.4) in the 3D group (mean difference, -12.2, P = 0.004). Multivariable analysis showed the 3D model was an independent protective factor in decreasing postoperative complications. Subgroup analysis also showed that a 3D model could decrease postoperative complications, especially for bile leakage in patients with intrahepatic cholelithiasis. CONCLUSION: The 3D-printed models can help reduce postoperative complications. The 3D-printed models should be recommended for patients with complex hepatobiliary diseases undergoing precise planning LLR.

Mobilizing endogenous neuroprotection: the mechanism of the protective effect of acupuncture on the brain after stroke.

Given its high morbidity, disability, and mortality rates, ischemic stroke (IS) is a severe disease posing a substantial public health threat. Although early thrombolytic therapy is effective in IS treatment, the limited time frame for its administration presents a formidable challenge. Upon occurrence, IS triggers an ischemic cascade response, inducing the brain to generate endogenous protective mechanisms against excitotoxicity and inflammation, among other pathological processes. Stroke patients often experience limited recovery stages. As a result, activating their innate self-protective capacity [endogenous brain protection (EBP)] is essential for neurological function recovery. Acupuncture has exhibited clinical efficacy in cerebral ischemic stroke (CIS) treatment by promoting the human body's self-preservation and "Zheng Qi" (a term in traditional Chinese medicine (TCM) describing positive capabilities such as self-immunity, self-recovery, and disease prevention). According to research, acupuncture can modulate astrocyte activity, decrease oxidative stress (OS), and protect neurons by inhibiting excitotoxicity, inflammation, and apoptosis via activating endogenous protective mechanisms within the brain. Furthermore, acupuncture was found to modulate microglia transformation, thereby reducing inflammation and autoimmune responses, as well as promoting blood flow restoration by regulating the vasculature or the blood-brain barrier (BBB). However, the precise mechanism underlying these processes remains unclear. Consequently, this review aims to shed light on the potential acupuncture-induced endogenous neuroprotective mechanisms by critically examining experimental evidence on the preventive and therapeutic effects exerted by acupuncture on CIS. This review offers a theoretical foundation for acupuncture-based stroke treatment.

Nitrogen migration and transformation during re-suspension and photo-induction in landscape water replenished by reclaimed water.

Sediment re-suspension plays a crucial role in releasing endogenous nitrogen and greenhouse gases in shallow urban waters. However, the impacts of repeated re-suspension and photo-induced processes on migration and transformation from endogenous nitrogen, as well as the emission of greenhouse gases, remain unclear. This study simulated three conditions: re-suspension (Rs), re-suspension combined with ultravioletirradiation (Rs + UV), and ultraviolet irradiation (UV). The findings revealed that both repeated sediment re-suspension and exposure to UV light altered the characteristics of surface sediments. Decrease of convertible nitrogen in sediments, leading to the release of ion-exchangeable nitrogen (IEF-N) into NH4+-N and NO3--N, influenced greenhouse gas production differently under various conditions. The study observed the highest concentration of dissolved N2O in under UV irradiation, positively correlated with NO2--N and NO3--N. Re-suspension increased the turbidity of the overlying water and accelerated nitrification, resulting in the highest NO3--N concentration and the lowest dissolved N2O concentration. Additionally, in the Rs + UV dissolved N2O maintained the higher concentrations than in Rs, with greatest amount of N conversion in surface sediments, and a 59.45% reduction in IEF-N. The production of N2O during re-suspension was mainly positively correlated with NH4+-N in the overlying water. Therefore, this study suggest that repeated re-suspension and light exposure significantly influence nitrogen migration and transformation processes in sediment, providing a theoretical explanation for the eutrophication of water and greenhouse gas emissions.

Predicting Survival Using Whole-Liver MRI Radiomics in Patients with Hepatocellular Carcinoma After TACE Refractoriness.

PURPOSE: To develop a model based on whole-liver radiomics features of pre-treatment enhanced MRI for predicting the prognosis of hepatocellular carcinoma (HCC) patients undergoing continued transarterial chemoembolization (TACE) after TACE-resistance. MATERIALS AND METHODS: Data from 111 TACE-resistant HCC patients between January 2014 and March 2018 were retrospectively collected. At a ratio of 7:3, patients were randomly assigned to developing and validation cohorts. The whole-liver were manually segmented, and the radiomics signature was extracted. The tumor and liver radiomics score (TLrad-score) was calculated. Models were trained by machine learning algorithms and their predictive efficacies were compared. RESULTS: Tumor stage, tumor burden, body mass index, alpha-fetoprotein, and vascular invasion were revealed as independent risk factors for survival. The model trained by Random Forest algorithms based on tumor burden, whole-liver radiomics signature, and clinical features had the highest predictive efficacy, with c-index values of 0.85 and 0.80 and areas under the ROC curve of 0.96 and 0.83 in the developing cohort and validation cohort, respectively. In the high-rad-score group (TLrad-score > - 0.34), the median overall survival (mOS) was significantly shorter than in the low-rad-score group (17 m vs. 37 m, p < 0.001). A shorter mOS was observed in patients with high tumor burden compared to those with low tumor burden (14 m vs. 29 m, p = 0.007). CONCLUSION: The combined radiomics model from whole-liver signatures may effectively predict survival for HCC patients continuing TACE after TACE refractoriness. The TLrad-score and tumor burden are potential prognostic markers for TACE therapy following TACE-resistance.

Improving water quality and mitigating CH4 and N2O production in urban landscape water simultaneously by optimizing calcium peroxide dosage.

Recent studies show that greenhouse gas (GHG) emissions from urban landscape water are significant and cannot be overlooked, underscoring the need to develop effective strategies for mitigating GHG production from global freshwater systems. Calcium peroxide (CaO2) is commonly used as an eco-friendly reagent for controlling eutrophication in water bodies, but whether CaO2 can reduce GHG emissions remains unclear. This study investigated the effects of CaO2 dosage on the production of methane (CH4) and nitrous oxide (N2O) in urban landscape water under anoxic conditions during summer. The findings reveal that CaO2 addition not only improved the physicochemical and organoleptic properties of simulated urban landscape water but also reduced N2O production by inhibiting the activity of denitrifying bacteria across various dosages. Moreover, CaO2 exhibited selective effects on methanogens. Specifically, the abundance of acetoclastic methanogen Methanosaeta and methylotrophic methanogen Candidatus_Methanofastidiosum increased whereas the abundance of the hydrogenotrophic methanogen Methanoregula decreased at low, medium, and high dosages, leading to higher CH4 production at increased CaO2 dosage. A comprehensive multi-objective evaluation indicated that an optimal dosage of 60 g CaO2/m2 achieved 41.21 % and 84.40 % reductions in CH4 and N2O production, respectively, over a 50-day period compared to the control. This paper not only introduces a novel approach for controlling the production of GHGs, such as CH4 and N2O, from urban landscape water but also suggests a methodology for optimizing CaO2 dosage, providing valuable insights for its practical application.

Higher Dietary Quercetin Intake Is Associated with Lower Risk of Adverse Outcomes among Individuals with Inflammatory Bowel Disease in a Prospective Cohort Study.

BACKGROUND: Cumulative preclinical evidence reported quercetin, a major flavonoid, can attenuate the disease activity of inflammatory bowel diseases (IBD). However, there is limited evidence that supports the benefits of quercetin for patients with IBD. OBJECTIVES: To investigate whether dietary quercetin intake is associated with adverse outcomes among individuals with IBD in a prospective cohort study. METHODS: We included 2293 participants with IBD (764 Crohn's disease [CD] and 1529 ulcerative colitis [UC]) from the UK Biobank. Dietary information was collected using validated 24-h dietary assessments, and quercetin intake was estimated based on national nutrient databases. Two outcomes, enterotomy and all-cause mortality, were obtained based on the national data. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: After a mean (standard deviation) follow-up of 9.6 (1.8) y, we documented 193 enterotomy events and 176 deaths. Compared with participants with the lowest quartile intake of quercetin, those in the highest quartiles were associated with lower risk of enterotomy (HR: 0.46; 95% CI: 0.28, 0.76) and all-cause mortality (HR: 0.53; 95% CI: 0.33, 0.83) in IBD. The inverse associations between quercetin and enterotomy were consistent in CD (HR: 0.30; 95% CI: 0.12, 0.78) but not UC (HR: 0.58; 95% CI: 0.32, 1.07), while the inverse associations between quercetin and mortality were consistent both in CD (HR: 0.37; 95% CI: 0.15, 0.92) and UC (HR: 0.55; 95% CI: 0.31, 0.95). CONCLUSIONS: Higher dietary intake of quercetin was associated with lower risk of enterotomy and all-cause mortality in IBD. Our study provides novel evidence that further suggests the benefits of quercetin for patients with IBD, while also calling for further validation in other cohorts and clinical trials.

Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis.

BACKGROUND: The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. METHODS: Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P < 5 × 10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. FINDINGS: Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. INTERPRETATION: The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. FUNDING: Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).

Molecular basis of Gabija anti-phage supramolecular assemblies.

As one of the most prevalent anti-phage defense systems in prokaryotes, Gabija consists of a Gabija protein A (GajA) and a Gabija protein B (GajB). The assembly and function of the Gabija system remain unclear. Here we present cryo-EM structures of Bacillus cereus GajA and GajAB complex, revealing tetrameric and octameric assemblies, respectively. In the center of the complex, GajA assembles into a tetramer, which recruits two sets of GajB dimer at opposite sides of the complex, resulting in a 4:4 GajAB supramolecular complex for anti-phage defense. Further biochemical analysis showed that GajA alone is sufficient to cut double-stranded DNA and plasmid DNA, which can be inhibited by ATP. Unexpectedly, the GajAB displays enhanced activity for plasmid DNA, suggesting a role of substrate selection by GajB. Together, our study defines a framework for understanding anti-phage immune defense by the GajAB complex.

Risk of subsequent gastrointestinal disease assessed by skeletal muscle strength and mass in a prospective cohort study.

Skeletal muscle may mutually interact with gastrointestinal disease through metabolic homeostasis and nutritional status and therefore may be a marker for early risk detection. We conducted a prospective cohort analysis including 393,606 participants (mean age 56.0 years, 53.9% female) from the UK Biobank. The exposures were grip strength and skeletal muscle mass (SMM). The primary outcomes were 24 incident gastrointestinal diseases. During a mean follow-up of 12.1 years, we found that one sex-specific SD increase in grip strength and SMM were associated with reduced risk of 16 and 19 gastrointestinal diseases, respectively. For grip strength, the HRs ranged from 0.94 (for ulcerative colitis) to 0.80 (for liver cancers). For SMM, the HRs ranged from 0.92 (for colorectal cancer) to 0.51 (for non-alcoholic fatty liver disease). Our finding suggested that grip strength and SMM might be significant indicators for gastrointestinal diseases risk screen.

Ultrasound-assisted annealing treatment to improve physicochemical and digestive properties of banana flour.

BACKGROUND: Banana flour can provide a solution to people with gluten intolerance, as it is gluten-free. Native banana flour may have limited functionality in certain applications. In this study, banana flour was modified by ultrasonic (US) and annealing (ANN) treatments at four incubation time spans, namely 12, 24, 36 and 72 h, separately or combined sequentially (US-ANN) to enhance the physicochemical and digestive properties. RESULTS: US led to exposed granular surfaces and damaged non-starch components. Both treatments, at extended incubation time, increased crystallinity, resulting in a narrower starch gelatinization temperature range. The swelling power was significantly lower for ANN and US-ANN compared to US alone, providing a delay of gelatinization temperature. However, none of the treatments affected the gelatinization enthalpy. Furthermore, US increased peak viscosity, breakdown, final viscosity and setback whereas the opposite results were obtained for ANN and US-ANN. Additionally, US prior to ANN significantly increased the resistant starch (RS) content for annealing times over 24 h, especially for the US-ANN treatment for 72 h, which provided the highest RS content (49.3%) compared to ANN treatment for 72 h (44.0%) and native flour (36.3%). CONCLUSIONS: US prior to ANN treatment offers an alternative method to improve the functional and digestive properties of banana flour, extending the range of applications. © 2024 Society of Chemical Industry.

Effect of early peri-operative arterial lactate concentration level ratios on post-hepatectomy liver failure.

BACKGROUND: Post-hepatectomy liver failure (PHLF) is a serious complication after hepatectomy and a major cause of death. The current criteria for PHLF diagnosis (ISGLS consensus) require laboratory data of elevated INR level and hyperbilirubinemia on or after postoperative day 5. This study aims to propose a new indicator for the early clinical prediction of PHLF. METHODS: The peri-operative arterial lactate concentration level ratios were derived from time points within the 3 days before surgery and within POD1, the patients were divided into two groups: high lactate ratio group (≥ 1) and low lactate ratio group (< 1). We compared the differences in morbidity rates between the two groups. Utilized logistic regression analysis to identify the risk factors associated with PHLF development and ROC curves to compare the predictive value of lactate ratio and other liver function indicators for PHLF. RESULTS: A total of 203 patients were enrolled in the study. Overall morbidity and severe morbidity occurred in 64.5 and 12.8 per cent of patients respectively. 39 patients (19.2%) met the criteria for PHLF, including 15 patients (7.4%) with clinically relevant Post-hepatectomy liver failure (CR-PHLF). With a significantly higher incidence of PHLF observed in the lactate ratio ≥ 1 group compared to the lactate ratio < 1 group (n = 34, 26.8% vs. n = 5, 6.6%, P < 0.001). Multivariable logistic regression analysis revealed that a lactate ratio ≥ 1 was an independent predictor for PHLF (OR: 3.239, 95% CI 1.097-9.565, P = 0.033). Additionally, lactate ratio demonstrated good predictive efficacy for PHLF (AUC = 0.792). CONCLUSIONS: Early assessment of peri-operative arterial lactate concentration level ratios may provide experience in early intervention of complications in patients with hepatocellular carcinoma, which can reduce the likelihood of PHLF occurrence and improve patient prognosis.

CircFOXO3 mediates hypoxia-induced autophagy of endometrial stromal cells in endometriosis.

Endometriosis is a benign gynecological disease that shares some common features of malignancy. Autophagy plays vital roles in endometriosis and influences endometrial cell metastasis, and hypoxia was identified as the initiator of this pathological process through hypoxia inducible factor 1 alpha (HIF-1α). A newly discovered circular RNA FOXO3 (circFOXO3) is critical in cell autophagy, migration, and invasion of various diseases and is reported to be related to hypoxia, although its role in endometriosis remains to be elucidated up to now. In this study, a lower circFOXO3 expression in ectopic endometrium was investigated. Furthermore, we verified that circFOXO3 could regulate autophagy by downregulating the level of p53 protein to mediate the migration and invasion of human endometrial stromal cells (T HESCs). Additionally, the effects of HIF-1α on circFOXO3 and autophagy were examined in T HESCs. Notably, overexpression of HIF-1α could induce autophagy and inhibit circFOXO3 expression, whereas overexpressing of circFOXO3 under hypoxia significantly inhibited hypoxia-induced autophagy. Mechanistically, the direct combination between HIF-1α and HIF-1α-binding site on adenosine deaminase 1 acting on RNA (ADAR1) promoter increased the level of ADAR1 protein, which bind directly with circFOXO3 pre-mRNA to block the cyclization of circFOXO3. All these results support that hypoxia-mediated ADAR1 elevation inhibited the expression of circFOXO3, and then autophagy was induced upon loss of circFOXO3 via inhibition of p53 degradation, participating in the development of endometriosis.

Circulating 25-hydroxyvitamin D concentration can predict bowel resection risk among individuals with inflammatory bowel disease in a longitudinal cohort with 13 years of follow-up.

BACKGROUND: Although the beneficial properties of vitamin D in anti-inflammation and immunity-modulation are promising in the management of inflammatory bowel disease (IBD), data were limited for the critical IBD prognosis. The association between serum vitamin D levels and the risk of bowel resection in individuals with IBD remains largely unknown. MATERIALS AND METHODS: We performed a longitudinal cohort study among 5474 individuals with IBD in the UK Biobank. Serum 25-hydroxyvitamin D [25(OH)D] was measured using direct competitive chemiluminescent immunoassay. Bowel resection events were ascertained via national inpatient data. Multivariable-adjusted Cox proportional hazard regression was used to examine the association between serum 25(OH)D and bowel resection risk, presented with hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) was used to evaluate dose-response associations. RESULTS: During a mean follow-up of 13.1 years, we documented 513 incident bowel resection cases. Compared to participants with vitamin D deficiency, non-deficient participants showed a significantly reduced bowel resection risk in IBD (HR 0.72, 95% CI 0.59-0.87, P=0.001), Crohn's disease (CD, HR 0.74, 95% CI 0.56-0.98, P=0.038), and ulcerative colitis (UC, HR 0.73, 95% CI 0.57-0.95, P=0.020). When comparing extreme quintiles of 25(OH)D level, participants with IBD showed a 34% reduced risk of bowel resection (95% CI 11%-51%, P=0.007) and participants with UC showed a 46% reduced risk (95% CI 19%-64%, P=0.003), while this association was not significant in CD (HR 0.93, 95% CI 0.59-1.45, P=0.740). Linear dose-response associations were observed using the RCS curve (all P-nonlinearity>0.05). CONCLUSION: Increased serum level of 25(OH)D is independently associated with reduced bowel resection risk in IBD. This association was significant in UC but may not be stable in CD. Vitamin D deficiency is a risk factor for bowel resection in individuals with IBD, and may be an effective metric in predicting and risk-screening surgical events.

CobB-mediated deacetylation of the chaperone CesA regulates Escherichia coli O157:H7 virulence.

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a common food-borne pathogen that can cause acute diseases. Lysine acetylation is a post-translational modification (PTM) that occurs in various prokaryotes and is regulated by CobB, the only deacetylase found in bacteria. Here, we demonstrated that CobB plays an important role in the virulence of EHEC O157:H7 and that deletion of cobB significantly decreased the intestinal colonization ability of bacteria. Using acetylation proteomic studies, we systematically identified several proteins that could be regulated by CobB in EHEC O157:H7. Among these CobB substrates, we found that acetylation at the K44 site of CesA, a chaperone for the type-III secretion system (T3SS) translocator protein EspA, weakens its binding to EspA, thereby reducing the stability of this virulence factor; this PTM ultimately attenuating the virulence of EHEC O157:H7. Furthermore, we showed that deacetylation of the K44 site, which is deacetylated by CobB, promotes the interaction between CesA and EspA, thereby increasing bacterial virulence in vitro and in animal experiments. In summary, we showed that acetylation influences the virulence of EHEC O157:H7, and uncovered the mechanism by which CobB contributes to bacterial virulence based on the regulation of CesA deacetylation.

The novel HLA-B*13:01:23 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.

HLA-B*13:01:23 differs from HLA-B*13:01:01:01 by one nucleotide in exon 5.

PtuA and PtuB assemble into an inflammasome-like oligomer for anti-phage defense.

Escherichia coli Septu system, an anti-phage defense system, comprises two components: PtuA and PtuB. PtuA contains an ATPase domain, while PtuB is predicted to function as a nuclease. Here we show that PtuA and PtuB form a stable complex with a 6:2 stoichiometry. Cryo-electron microscopy structure of PtuAB reveals a distinctive horseshoe-like configuration. PtuA adopts a hexameric arrangement, organized as an asymmetric trimer of dimers, contrasting the ring-like structure by other ATPases. Notably, the three pairs of PtuA dimers assume distinct conformations and fulfill unique roles in recruiting PtuB. Our functional assays have further illuminated the importance of the oligomeric assembly of PtuAB in anti-phage defense. Moreover, we have uncovered that ATP molecules can directly bind to PtuA and inhibit the activities of PtuAB. Together, the assembly and function of the Septu system shed light on understanding other ATPase-containing systems in bacterial immunity.

Risk Assessment for Gastrointestinal Diseases via Clinical Dimension and Genome-Wide Polygenic Risk Scores of Type 2 Diabetes: A Population-Based Cohort Study.

OBJECTIVE: We aimed to evaluate whether individuals with type 2 diabetes (T2D) were at higher risk of developing a wide range of gastrointestinal diseases based on a population-based cohort study. RESEARCH DESIGN AND METHODS: This study included 374,125 participants free of gastrointestinal disorders at baseline; of them, 19,719 (5.27%) with T2D were followed-up by linking to multiple medical records to record gastrointestinal disease diagnoses. Multivariable Cox models were used to estimate the hazard ratios (HRs) and CIs. Logistic models were used to examine the associations between polygenic risk scores (PRS) and clinical gastrointestinal phenotypes. RESULTS: During a median follow-up of 12.0 years, we observed the new onset of 15 gastrointestinal diseases. Compared with nondiabetes, participants with T2D had an increased risk of gastritis and duodenitis (HR 1.58, 95% CI 1.51-1.65), peptic ulcer (HR 1.56, 95% CI 1.43-1.71), diverticular disease (HR 1.19, 95% CI 1.14-1.24), pancreatitis (HR 1.45, 95% CI 1.24-1.71), nonalcoholic fatty liver disease (HR 2.46, 95% CI 2.25-2.69), liver cirrhosis (HR 2.92, 95% CI 2.58-3.30), biliary disease (HR 1.18, 95% CI 1.10-1.26), gastrointestinal tract cancers (HR 1.28, 95% CI 1.17-1.40), and hepatobiliary and pancreatic cancer (HR 2.32, 95% CI 2.01-2.67). Positive associations of PRS of T2D with gastritis, duodenitis, and nonalcoholic fatty liver disease were also observed. CONCLUSIONS: In this large cohort study, we found that T2D was associated with increased risks of a wide range of gastrointestinal outcomes. We suggest the importance of early detection and prevention of gastrointestinal disorders among patients with T2D.

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Acupuncture has a positive effect in the treatment of ischemic stroke (IS). A number of studies have confirmed that the role of acupuncture in the treatment of IS, which is closely related to its functions of regulating mitochondrial functions. In the present article, we review the mechanisms of acupuncture underlying improvement of mitochondria in the treatment of IS from 4 aspects： 1) protecting mitochondrial structure integrity, 2) regulative effect on mitochondrial functional activities, including regulating energy metabolism, reducing oxidative stress, suppressing calcium overload, and regulating mitochondrial membrane potential changes, 3) regulating mitochondrial quality control system, including promoting mitochondrial biosynthesis, regulating mitochondrial dynamics and apoptosis, and 4) regula-ting mitochondria-related apoptosis pathways. All of these may provide a theoretical basis for acupuncture in the treatment of IS and a reference for further research.

Plasmodium falciparum utilizes pyrophosphate to fuel an essential proton pump in the ring stage and the transition to trophozoite stage.

During asexual growth and replication cycles inside red blood cells, the malaria parasite Plasmodium falciparum primarily relies on glycolysis for energy supply, as its single mitochondrion performs little or no oxidative phosphorylation. Post merozoite invasion of a host red blood cell, the ring stage lasts approximately 20 hours and was traditionally thought to be metabolically quiescent. However, recent studies have shown that the ring stage is active in several energy-costly processes, including gene transcription, protein translation, protein export, and movement inside the host cell. It has remained unclear whether a low glycolytic flux alone can meet the energy demand of the ring stage over a long period post invasion. Here, we demonstrate that the metabolic by-product pyrophosphate (PPi) is a critical energy source for the development of the ring stage and its transition to the trophozoite stage. During early phases of the asexual development, the parasite utilizes Plasmodium falciparum vacuolar pyrophosphatase 1 (PfVP1), an ancient pyrophosphate-driven proton pump, to export protons across the parasite plasma membrane. Conditional deletion of PfVP1 leads to a delayed ring stage that lasts nearly 48 hours and a complete blockage of the ring-to-trophozoite transition before the onset of parasite death. This developmental arrest can be partially rescued by an orthologous vacuolar pyrophosphatase from Arabidopsis thaliana, but not by the soluble pyrophosphatase from Saccharomyces cerevisiae, which lacks proton pumping activities. Since proton-pumping pyrophosphatases have been evolutionarily lost in human hosts, the essentiality of PfVP1 suggests its potential as an antimalarial drug target. A drug target of the ring stage is highly desired, as current antimalarials have limited efficacy against this stage.

Assembly-mediated activation of the SIR2-HerA supramolecular complex for anti-phage defense.

SIR2-HerA, a bacterial two-protein anti-phage defense system, induces bacterial death by depleting NAD+ upon phage infection. Biochemical reconstitution of SIR2, HerA, and the SIR2-HerA complex reveals a dynamic assembly process. Unlike other ATPases, HerA can form various oligomers, ranging from dimers to nonamers. When assembled with SIR2, HerA forms a hexamer and converts SIR2 from a nuclease to an NAD+ hydrolase, representing an unexpected regulatory mechanism mediated by protein assembly. Furthermore, high concentrations of ATP can inhibit NAD+ hydrolysis by the SIR2-HerA complex. Cryo-EM structures of the SIR2-HerA complex reveal a giant supramolecular assembly up to 1 MDa, with SIR2 as a dodecamer and HerA as a hexamer, crucial for anti-phage defense. Unexpectedly, the HerA hexamer resembles a spiral staircase and exhibits helicase activities toward dual-forked DNA. Together, we reveal the supramolecular assembly of SIR2-HerA as a unique mechanism for switching enzymatic activities and bolstering anti-phage defense strategies.