FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury.

Introduction: Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dysfunction, which contributes to ferroptosis, further exacerbates the challenges of peripheral nerve repair. Methods: In this study, we established an in vitro model of Schwann cells model treated with TBHP and an in vivo sciatic nerve crush injury model in rats. These models were used to investigate the effects of fibroblast growth factor 21 (FGF21) on PNI, both in vitro and in vivo, and to explore the potential mechanisms linking injury-induced ferroptosis and mitochondrial dysfunction. Results: Our findings reveal that PNI triggers abnormal accumulation of lipid reactive oxygen species (ROS) and inactivates mitochondrial respiratory chain complex III, leading to mitochondrial dysfunction. This dysfunction catalyzes the oxidation of excessive polyunsaturated fatty acids, resulting in antioxidant imbalance and loss of ferroptosis suppressor protein 1 (FSP1), which drives lipid peroxidation. Additionally, irregular iron metabolism, defective mitophagy, and other factors contribute to the induction of ferroptosis. Importantly, we found that FGF21 attenuates the abnormal accumulation of lipid ROS, restores mitochondrial function, and suppresses ferroptosis, thus promoting PNI repair. Notably, glutathione peroxidase 4 (GPX4), a downstream target of nuclear factor E2-related factor 2 (Nrf2), and the ERK/Nrf2 pathway are involved in the regulation of ferroptosis by FGF21. Conclusion: FGF21 promotes peripheral nerve repair by inhibiting ferroptosis caused by mitochondrial dysfunction. Therefore, targeting mitochondria and ferroptosis represents a promising therapeutic strategy for effective PNI repair.

Falcarindiol improves functional recovery and alleviates neuroinflammation after spinal cord injury by inhibiting STAT/MAPK signaling pathways.

Spinal cord injury (SCI) is a devastating trauma in the central nervous system (CNS), leading to motor and sensory impairment. Neuroinflammation is one of the critical contributors to the progression of secondary injury. Falcarindiol has been reported to efficaciously mitigate lipopolysaccharide (LPS)-mediated inflammation in RAW 264.7 cells. The role of falcarindiol in SCI recovery remains unclear. In this present study, traumatic SCI mice models and LPS-stimulated murine microglia cell line (BV2 cells) were performed to explore the pharmacological effects and the underlying mechanisms of falcarindiol in improving SCI repair with detection of motor function recovery, morphological changes, numbers of survival neurons and protein expression levels of inflammation or apoptosis-related proteins. Our study found that falcarindiol intervention could promote motor function recovery and reduce spinal cord tissue damage in mice following SCI. Mechanistically, falcarindiol intervention suppressed apoptosis-driven neuronal cell death and mitigated inflammatory reactions following SCI. Additionally, falcarindiol inhibited the activation of signal transducer and activator of transcription (STAT) and mitogen-activated protein kinases (MAPK) signaling pathways in vivo and in vitro. This suppression of STAT and MAPK activation by falcarindiol was reversed by STAT3 agonist Colivelin TFA and MAPK agonist C16-PAF in BV2 cells, respectively. Moreover, the study further demonstrated that the anti-inflammation role of falcarindiol was obstructed by Colivelin TFA but not by C16-PAF in LPS-stimulated BV2 cells, suggesting that falcarindiol may efficaciously ameliorate neuroinflammation through inhibiting the activation of STAT signaling pathway following SCI. Collectively, our study indicates that falcarindiol may be a novel drug candidate for the treatment and management of SCI.

Enhanced-electrochemiluminescence biosensor for detecting miRNA-21 based on a CuO-mediated click reaction and catalytic hairpin self-assembly.

MicroRNAs (miRNAs) are closely associated with cancer and have been considered cancer biomarkers. Herein, we propose an electrochemiluminescence (ECL) biosensor for detecting miRNA-21 based on target-induced catalytic hairpin self-assembly (CHA) and CuO-mediated azide-alkyne cycloaddition. Two hairpin DNAs were employed: one was immobilized on magnetic beads (HP2) and another was labeled with CuO (HP1-CuO). HP1 and HP2 formed a duplex through CHA induced by miRNA-21, resulting in the immobilization of CuO on magnetic beads and in the recycling of miRNA-21. After magnetic separation, CuO was treated with hydrochloric acid to release Cu2+, which concentration is quantitatively proportional to the target concentration. Subsequently, Cu2+ was reduced to Cu+, which catalyzed the click reaction between Fc-C CH and SH-DNA-N3+ immobilized on a Au/g-C3N4 modified electrode. Thus, the ECL of Au/g-C3N4 was quenched by Fc, and miRNA-21 was indirectly detected through a change in ECL intensity. Benefiting from the amplification effect of CuO nanoparticle loading, CHA-based target recycling, and the catalytic effect of click reaction, the proposed ECL biosensor showed high sensitivity. Experimental results indicate that the ECL biosensor proposed for detecting miRNA-21 exhibits a wide linear range from 1 fM to 1 nM and a low detection limit of 0.26 fM (3σ/S). Furthermore, the ECL sensor was capable of measuring miRNA-21 in real serum with high selectivity, indicating its notable applicable potential in biomedicine and clinical diagnosis.

Non-destructive visual detection of fresh food spoilage.

Two coumarin derivatives SWJT-33 and SWJT-34 were synthesized as probes for the detection of cadaverine (Cad). Among them, SWJT-34 exhibits high selectivity and low detection limits for Cad using fluorescence or UV-vis spectrum. The detection limits for Cad were calculated to be 0.018 µM by fluorescence spectrum and 0.34 µM by UV-vis spectrum, which was much lower than those of most of reported probes. The probe could realize colorimetric and ratiometric detection of Cad because an aza-Michael addition reaction occurred between SWJT-34 and Cad to form the Schiff base compound as a product. In addition, SWJT-34 could be fabricated as portable test strips for the selective detection of Cad in vapor, and the corresponding detection limits were calculated to be 1.88 ppm in the fluorescent mode and 57 ppm in UV-vis mode, respectively. Additionally, these test strips could be used to test the freshness of Rottweiler shrimp and pork at different temperatures.

Secure Consensus Control of Multiagent Systems Under DoS Attacks: A Switching-Scheme-Based Active Defense Method.

This article studies the secure consensus control problem of multiagent systems (MASs) with a nonzero input leader subject to denial-of-service (DoS) attacks. The introduction of backup topologies makes it possible for MASs to actively defend against DoS attacks. Subsequently, a novel active defense method consisting of two types of state observers, an adaptive topology switching mechanism, and switching controllers is proposed, which can ensure the leader-follower bound consensus even if DoS attacks hinder the interaction between agents. Within such a defense framework, the switching mechanism, driven by the predefined performance index and designed monitoring function, can automatically search for a healthy communication graph among backup topologies. Concurrently, the observer-based switching control strategy will be modified to match the corresponding topology, in which the universal observer and controller parameters in different topologies are obtained by solving linear matrix inequalities. It should be highlighted that the developed defense scheme not only removes the limitations of existing results on the duration and frequency of DoS attacks but also ensures the same upper bound of consensus error before and after DoS attacks. Finally, several simulation examples for different systems illustrate the efficiency and superiority of the theoretical results.

Self-supported electrochemical sensor based on uniform palladium nanoparticles functionalized porous graphene film for monitoring H2O2 released from living cells.

Graphene film has been considered a promising material for the construction of self-supported electrodes due to its favorable flexibility and high conductivity. However, the film fabricated from pristine graphene or conventional graphene sheet reduced graphene oxide processes limited electrocatalytic performance. Decorating active metal species or incorporating heteroatoms into the graphene framework have been proved to be effective methods to enhance the electrocatalytic efficiency of graphene film-based self-supported electrodes. Herein, we present a freestanding electrode composed of uniform Pd nanoparticles decorating N,S co-doped porous graphene film (Pd/NSPGF) and explore its practical application in differentiating various human colon cell types by in situ tracking the amount of H2O2 secreted from live cells. Our findings reveal that, on the one hand, the NSPGF has abundant surface and inner pores, which promote active site exposure, and mass diffusion during electrochemical reactions; on the other hand, the substitutional doping of the graphene framework with heteroatoms (e.g., N or S) can tailor its electronic and chemical properties, and facilitate the uniform loading of high-density Pd nanoparticles. Moreover, the intrinsic activity of Pd/NSPGF is regulated by the interaction of Pd nanoparticles with the NSPGF support. Taking the advantages of morphology and composition, the self-supported Pd/NSPGF electrode displays remarkable electrochemical performance with a wide linear range up to 2.0 mM, low detection limit of 0.1 µM (S/N = 3), high sensitivity of 665 µA cm-2 mM-1, and good selectivity. When applied in real-time tracking of the H2O2 released from normal human colon epithelial cells and human colorectal cancer cells, the Pd/NSPGF-based electrochemical sensing system can distinguish the cell types by testing the number of extracellular H2O2 molecules released per cell, which holds considerable potential for early detection and monitoring of disease-related clinical specimens.

Improving the catalytic performance of carbonyl reductase based on the functional loops engineering.

Vibegron functions as a potent and selective ß3-adrenergic receptor agonist, with its chiral precursor (2S,3R)-aminohydroxy ester (1b) being crucial to its synthesis. In this study, loop engineering was applied to the carbonyl reductase (EaSDR6) from Exiguobacterium algae to achieve an asymmetric reduction of the (rac)-aminoketone ester 1a. The variant M5 (A138L/A190V/S193A/Y201F/N204A) was obtained and demonstrated an 868-fold increase in catalytic efficiency (kcat/Km = 260.3 s-1 mM-1) and a desirable stereoselectivity (>99% enantiomeric excess, e.e.; >99% diastereomeric excess, d.e.) for the target product 1b in contrast to the wild-type EaSDR6 (WT). Structural alignment with WT indicated that loops 137-154 and 182-210 potentially play vital roles in facilitating catalysis and substrate binding. Moreover, molecular dynamics (MD) simulations of WT-1a and M5-1a complex illustrated that M5-1a exhibits a more effective nucleophilic attack distance and more readily adopts a pre-reaction state. The interaction analysis unveiled that M5 enhanced hydrophobic interactions with substrate 1a on cavities A and B while diminishing unfavorable hydrophilic interactions on cavity C. Computational analysis of binding free energies indicated that M5 displayed heightened affinity towards substrate 1a compared to the WT, aligning with its decreased Km value. Under organic-aqueous biphasic conditions, the M5 mutant showed >99% conversion within 12 h with 300 g/L substrate 1a (highest substrate loading as reported). This study enhanced the catalytic performance of carbonyl reductase through functional loops engineering and established a robust framework for the large-scale biosynthesis of the vibegron intermediate.

Differences in Grain Yield and Nitrogen Uptake between Tetraploid and Diploid Rice: The Physiological Mechanisms under Field Conditions.

Research indicates that, owing to the enhanced grain-filling rate of tetraploid rice, its yield has notably improved compared to previous levels. Studies conducted on diploid rice have revealed that optimal planting density and fertilization rates play crucial roles in regulating rice yield. In this study, we investigated the effects of different nitrogen application and planting density treatments on the growth, development, yield, and nitrogen utilization in tetraploid (represented by T7, an indica-japonica conventional allotetraploid rice) and diploid rice (Fengliangyou-4, represented by FLY4, a two-line super hybrid rice used as a reference variety for the approval of super rice with a good grain yield performance). The results indicated that the highest grain-filling rate of T7 could reach 77.8% under field experimental conditions due to advancements in tetraploid rice breeding. This is a significant improvement compared with the rate seen in previous research. Under the same conditions, T7 exhibited a significantly lower grain yield than FLY4, which could be attributed to its lower grain-filling rate, spikelets per panicle, panicle number m-2, and harvest index score. Nitrogen application and planting density displayed little effect on the grain yield of both genotypes. A higher planting density significantly enhanced the leaf area index and biomass accumulation, but decreased the harvest index score. Compared with T7, FLY4 exhibited a significantly higher nitrogen use efficiency (NUEg), which was mainly due to the higher nitrogen content in the straw. Increasing nitrogen application significantly decreased NUEg due to its minimal effect on grain yield combined with its significant enhancement of nitrogen uptake. Our results suggest that the yield and grain-filling rate of T7 have been improved compared with those of previously tested polyploid rice, but are still lower than those of FLY4, and the yield of tetraploid rice can be further improved by enhancing the grain-filling rate, panicle number m-2, and spikelets per panicle via genotype improvement.

Extracorporeal shock wave therapy in treating ischial non-union following Bernese periacetabular osteotomy: A case report.

BACKGROUND: Extracorporeal shock wave therapy (ESWT) is increasingly being recognized as an advantageous alternative for treating non-union due to its efficacy and minimal associated complications. Non-union following Bernese periacetabular osteotomy (PAO) is particularly challenging, with a reported 55% delayed union and 8% non-union. Herein, we highlight a unique case of ischial non-union post-PAO treated successfully with a structured ESWT regimen. CASE SUMMARY: A 50-year-old patient, diagnosed with left ischial non-union following the PAO, underwent six cycles of ESWT treatment across ten months. Each cycle, spaced four weeks apart, consisted of five consecutive ESWT sessions without anesthesia. Regular X-ray follow-ups showed progressive disappearance of the fracture line and fracture union. The patient ultimately achieved a satisfactory asymptomatic recovery and bone union. CONCLUSION: The results from this case suggest that this ESWT regimen can be a promising non-invasive treatment strategy for non-union following PAO.

Therapeutic potential of EVs loaded with CB2 receptor agonist in spinal cord injury via the Nrf2/HO-1 pathway.

BACKGROUND: Spinal cord injury (SCI) poses a challenge due to limited treatment options. Recently, the effect and mechanism of Exo-loaded cannabinoid receptor type 2 (CB2) agonist AM1241(Exo + AM1241) have been applied in other inflammatory diseases but not in SCI. METHODS: The SCI model was set up using C57BL/6 mice, followed by the treatment of Exo, AM1241, and Exo + AM1241. We assessed the effects of the following treatments on motor function recovery using BMS, and evaluated histological changes, apoptosis activity, inflammation, and oxidative stress in the SCI mice model. Additionally, the effect of following treatments on spinal cord neural stem cells (NSCs) was evaluated under lipopolysaccharides (LPS) induced inflammatory and oxidative models and, glutamate (Gluts) induced cell apoptosis models. RESULT: Our results demonstrated that Exo + AM1241 treatment significantly improved motor function recovery, after SCI by decreasing proinflammatory cytokines, and suppressing astrocyte/microglia (GFAP/Iba1) activation in the injury zone. Additionally, this treatment reduces pro-apoptotic proteins (Bax and caspase 3), increases the levels of the anti-apoptotic protein Bcl-2, enhances antioxidant defenses by boosting SOD and GSH, and lowers oxidative stress markers such as MDA. It also activates the Nuclear factor erythroid-2 (Nrf2) related factor 2 signaling pathway, thereby enhancing tissue protection against damage and cell death.

Whole exome sequencing identifies a novel mutation in Annexin A4 that is associated with recurrent spontaneous abortion.

Background: Recurrent spontaneous abortion (RSA) is a multifactorial disease, the exact causes of which are still unknown. Environmental, maternal, and genetic factors have been shown to contribute to this condition. The aim of this study was to investigate the presence of mutations in the ANXA4 gene in patients with RSA. Methods: Genomic DNA was extracted from 325 patients with RSA and 941 control women with a normal reproductive history for whole-exome sequencing (WES). The detected variants were annotated and filtered, and the pathogenicity of the variants was predicted through the SIFT online tool, functional enrichment analyses, Sanger sequencing validation, prediction of changes in protein structure, and evolutionary conservation analysis. Furthermore, plasmid construction, Western blotting, RT-qPCR, and cell migration, invasion and adhesion assays were used to detect the effects of ANXA4 mutations on protein function. Results: An ANXA4 mutation (p.G8D) in 1 of the 325 samples from patients with RSA (RSA-219) was identified through WES. This mutation was not detected in 941 controls or included in public databases. Evolutionary conservation analysis revealed that the amino acid residue affected by the mutation (p.G8D) was highly conserved among 13 vertebrate species, and the SIFT program and structural modeling analysis predicted that this mutation was harmful. Furthermore, functional assays revealed that this mutation could inhibit cell migration, invasion and adhesion. Conclusion: Our study suggests that an unreported novel ANXA4 mutation (p.G8D) plays an important role in the pathogenesis of RSA and may contribute to the genetic diagnosis of RSA.

NAD+-boosting agent nicotinamide mononucleotide potently improves mitochondria stress response in Alzheimer's disease via ATF4-dependent mitochondrial UPR.

Extensive studies indicate that mitochondria dysfunction is pivotal for Alzheimer's disease (AD) pathogenesis; while cumulative evidence suggests that increased mitochondrial stress response (MSR) may mitigate neurodegeneration in AD, explorations to develop a MSR-targeted therapeutic strategy against AD are scarce. We combined cell biology, molecular biology, and pharmacological approaches to unravel a novel molecular pathway by which NAD+-boosting agent nicotinamide mononucleotide (NMN) regulates MSR in AD models. Here, we report dyshomeostasis plasma UPRmt-mitophagy-mediated MSR profiles in AD patient samples. NMN restores NAD+ metabolic profiles and improves MSR through the ATF4-dependent UPRmt pathway in AD-related cross-species models. At the organismal level, NAD+ repletion with NMN supplementation ameliorates mitochondrial proteotoxicity, decreases hippocampal synaptic disruption, decreases neuronal loss, and brain atrophy in mice model of AD. Remarkably, omics features of the hippocampus with NMN show that NMN leads to transcriptional changes of genes and proteins involved in MSR characteristics, principally within the astrocyte unit rather than microglia and oligodendrocytes. In brief, our work provides evidence that MSR has an active role in the pathogenesis of AD, as reducing mitochondrial homeostasis via atf4 depletion in AD mice aggravates the hallmarks of the disease; conversely, bolstering mitochondrial proteostasis by NMN decreases protein aggregation, restores memory performance, and delays disease progression, ultimately translating to increased healthspan.

Analysis of factors influencing the occurrence of diabetes insipidus following neuroendoscopic transsphenoidal resection of pituitary adenomas and risk assessment.

Objective: Studies have revealed a higher prevalence of diabetes insipidus in patients following resection of pituitary adenoma surgery. By comprehensively analysing the clinical history of patients undergoing endoscopic transnasal sphenoidal resection for pituitary adenomas, the factors influencing development of postoperative diabetes insipidus were investigated and a predictive model was developed to assess its risk. Methods: A retrospective analysis was conducted on the medical records of 281 patients with pituitary adenomas who underwent neuroendoscopic transsphenoidal resection at our institution between October 2020 and October 2022. The Mann-Whitney U test, chi-square test, and logistic regression analysis were used to identify the independent factors that potentially contribute to the development of postoperative diabetes insipidus. Additionally, a nomogram was constructed to evaluate the predicted risk of postoperative diabetes insipidus in patients with pituitary adenomas. Results: Diabetes insipidus occurred in 100 (35.59 %) of the 281 enrolled patients. The results of the multifactorial logistic regression analysis revealed that diabetes, hypertension, cardiopathy, preoperative serum cortisol level, cerebrospinal fluid leakage, and tumour texture independently influenced the occurrence of postoperative diabetes insipidus (P < 0.05). A nomogram was developed to evaluate the risk of postoperative diabetes insipidus in patients with pituitary adenoma. Conclusions: Multiple independent risk factors associated with the patient and tumour were identified in predicting diabetes insipidus. Early recognition of these risk factors may contribute to the prevention or reduction of diabetes insipidus incidence following pituitary adenoma surgery.

Clinical drug interactions between voriconazole and 38 other drugs: a retrospective analysis of adverse events.

Background: Voriconazole (VRZ) is involved in a variety of drug‒drug interactions (DDIs), but few studies have reported adverse events (AEs) associated with the DDIs of VRZ. The primary goal of this study was to analyse the potential risk factors for AEs caused by DDIs between VRZ and other drugs via the OpenVigil FDA platform and to provide a reference for preventing VRZ DDIs and monitoring clinically related adverse drug events. Methods: A retrospective pharmacovigilance study was conducted to investigate the AEs related to DDIs between VRZ and four categories of drugs: proton pump inhibitors (PPIs), non-steroidal anti-inflammatory drugs (NSAIDs), immunosuppressants, and other antibacterial drugs. AE information for the target drugs from the first quarter of 2004 to the third quarter of 2022 was downloaded from the OpenVigil FDA data platform. Four frequency statistical models-the reporting ratio method, Ω shrinkage measure model, combination risk ratio model, and the chi-square statistics model-were used to analyse the AEs related to DDIs and evaluate the correlation and influence of sex and age between the drug(s) and the target AEs detected. Results: A total of 38 drugs were included, with 262 AEs detected by at least one of the four models and 48 AEs detected by all four models. Some 77 detected AEs were significantly positively correlated with DDIs and were related to higher reporting rates of AEs than when used alone. Graft-versus-host disease was the AE that had the strongest correlation with the drug interaction between VRZ and immunosuppressants (tacrolimus, mycophenolate mofetil, cyclophosphamide, and cyclosporine), and multiple organ dysfunction syndrome was correlated with VRZ in combination with other antibacterial drugs (linezolid, meropenem, cefepime, and vancomycin). Significant sex and age differences in the target AEs were detected for five and nine target drugs, respectively. For VRZ in combination with linezolid, aggravated conditions and respiratory failure should be given more attention in male patients, and mycophenolate mofetil and respiratory failure in female patients. When conditions are aggravated, febrile neutropenia and septic shock should be of particular concern in patients over 18 years of age who use VRZ in combination with ceftazidime, ciprofloxacin, or cytarabine. In patients aged under 18, septic shock should be considered when VRZ is used in combination with meropenem and dexamethasone. Conclusion: AEs related to DDIs should receive more attention when VRZ is used in combination with PPIs (renal impairment), NSAIDs (constipation and renal failure), immunosuppressants (graft versus host disease, septic shock) and other antibacterial drugs (multiple organ dysfunction syndrome, febrile neutropenia, and respiratory failure). Considering the influence of sex and age differences in VRZ DDIs, these factors need to be considered when assessing the risk of AEs in patients receiving VRZ and other drugs.

Angiotensin 1 peptide-conjugated CdSe/ZnS quantum dots for cardiac-specific hydrogen sulfide targeted therapy in myocardial ischemia-reperfusion injury.

Introduction: Myocardial ischemia/reperfusion (I/R) injury remains a major obstacle in cardiovascular therapies. Hydrogen sulfide (H2S) shows promise for mitigating I/R injury, but conventional delivery methods, such as NaHS injections or adenovirus-mediated CSE gene therapy, face low efficiency and systemic side effects. This study explores the use of angiotensin 1 (AT1) peptide-conjugated CdSe/ZnS quantum dots (QDs) for targeted delivery of cystathionine-γ-lyase (CSE) plasmids to the myocardium, aiming to boost local H2S production and minimize I/R injury. Methods: CdSe/ZnS QDs were conjugated with AT1 peptides to create a nanocarrier system capable of delivering the CSE plasmid specifically to the myocardium. In vivo fluorescence imaging confirmed heart-specific accumulation. Myocardial infarct size, cardiac function, cell death, and oxidative stress were evaluated. Endoplasmic reticulum stress and mitophagy markers, including CHOP/GRP78/eIF2α, were analyzed, and the CHOP gene's role was further assessed using an adenovirus vector. Results: The AT1-conjugated nanocarriers significantly increased CSE expression in the myocardium, as confirmed by fluorescence imaging, without affecting other organs. This localized delivery reduced myocardial infarct size, improved cardiac function, and decreased oxidative stress and cell death. Importantly, a reduction in endoplasmic reticulum stress and mitophagy markers was observed, suggesting that cardioprotection was mediated via the CHOP/GRP78/eIF2α signaling pathway. Reintroduction of CHOP using an adenovirus vector reversed these protective effects, confirming the pathway's involvement. Discussion: This study demonstrates that AT1 peptide-conjugated QDs can effectively deliver CSE plasmids to the heart, providing significant protection against I/R injury through enhanced localized H2S production. This approach offers a promising, targeted, and side-effect-free therapy for myocardial I/R injury, with potential for clinical translation.

Meta-analysis of probiotics efficacy in the treatment of minimum hepatic encephalopathy.

OBJECTIVE: This study aims to systematically evaluate the efficacy of probiotics in treating minimum hepatic encephalopathy (MHE). METHODS: A systematic search was conducted across three major databases: PubMed, China National Knowledge Infrastructure and Wanfang. The search period spanned from the inception of each database to 9 March 2023. The objective was to identify all randomised controlled trials (RCTs) examining the efficacy of probiotic preparations in treating MHE. The search terms included 'probiotics' along with other clinically relevant terms to comprehensively capture all pertinent studies. RESULTS: A total of 18 RCTs were included. The meta-analysis showed that probiotic treatment outperformed control groups in reducing blood ammonia levels (standard mean difference [MD] = -2.68, 95% confidence interval [CI]: -3.90 to -1.46, p < .0001), improving the remission rate of MHE (risk ratio [RR] = 2.79, 95% CI: 1.23-6.35, p = .01) and lowering alanine aminotransferase levels (MD = -11.10, 95% CI: -16.17 to -6.03, p < .0001). It also significantly reduced the Model for End-Stage Liver Disease scores (MD = -2.55, 95% CI: -3.56 to -1.54, p < .00001) and the incidence of MHE (RR = .18, 95% CI: .09-.34, p < .00001). CONCLUSION: Our study demonstrates that probiotics effectively improve blood ammonia levels, liver function and cognitive function in patients with MHE. They significantly enhance the remission rate of MHE and effectively reduce its incidence, providing solid new evidence for treating MHE with probiotics.

A Multi-Strategy Improved Northern Goshawk Optimization Algorithm for Optimizing Engineering Problems.

Northern Goshawk Optimization (NGO) is an efficient optimization algorithm, but it has the drawbacks of easily falling into local optima and slow convergence. Aiming at these drawbacks, an improved NGO algorithm named the Multi-Strategy Improved Northern Goshawk Optimization (MSINGO) algorithm was proposed by adding the cubic mapping strategy, a novel weighted stochastic difference mutation strategy, and weighted sine and cosine optimization strategy to the original NGO. To verify the performance of MSINGO, a set of comparative experiments were performed with five highly cited and six recently proposed metaheuristic algorithms on the CEC2017 test functions. Comparative experimental results show that in the vast majority of cases, MSINGO's exploitation ability, exploration ability, local optimal avoidance ability, and scalability are superior to those of competitive algorithms. Finally, six real world engineering problems demonstrated the merits and potential of MSINGO.

Intratumoral CXCL13+ CD160+ CD8+ T cells promote the formation of tertiary lymphoid structures to enhance the efficacy of immunotherapy in advanced gastric cancer.

BACKGROUND: Stage IV gastric cancer is a highly heterogeneous and lethal tumor with few therapeutic strategies. The combination of programmed cell death protein 1 inhibitors and chemotherapy is currently the standard frontline treatment regimen for advanced gastric cancer. Nevertheless, it remains a great challenge to screen the beneficiaries of immunochemotherapy and expand indications for this treatment regimen. METHODS: We conducted a pathological assessment to ascertain the importance of tertiary lymphoid structures based on the tissue samples collected from patients with stage IV gastric cancer (n=15) both prior to and following immunochemotherapy treatment. Additionally, we used spatial (n=10) and single-cell transcriptional analysis (n=97) to investigate the key regulators of tertiary lymphoid structures (TLSs). Multiplex immunofluorescence and image analysis (n=34) were performed to explore the association between tumor-infiltrating CXCL13+ CD160+ CD8+ T cells and TLSs. The relationship between CXCL13+ CD160+ CD8+ T cells and the responsiveness to immunotherapy was also evaluated by multiplex immunofluorescence and image analysis approaches (n=15). Furthermore, we explored the intrinsic characteristics of CXCL13+ CD160+ CD8+ T cells through various experimental techniques, including quantitative reverse transcription-PCR, western blot, and flow cytometry. RESULTS: We found that responders exhibited higher levels of TLSs and CXCL13+ CD160+ CD8+ T cells in biopsy tissues prior to immunochemotherapy compared with non-responders. Following conversion therapy, responders also had a higher percentage of mature TLSs and a higher number of CXCL13+ CD160+ CD8+ T cells in surgical resections. Moreover, we discovered that vitamin B6 in CD160+ CD8+ T cells could reduce the ubiquitination modification of HIF-1α by MDM2, thereby attenuating the degradation of HIF-1α. Consequently, this led to the transcriptional upregulation of CXCL13 expression, facilitating the recruitment of CXCR5+ B cells and the formation of TLSs. CONCLUSION: The number and maturity of TLSs, along with the extent of CXCL13+ CD160+ CD8+ T-cell infiltration, might function as potential indicators for assessing the effectiveness of immunotherapy in treating gastric malignancies. Furthermore, our research suggests that vitamin B6 could enhance the secretion of CXCL13 by CD160+ CD8+ T cells by reducing the degradation of HIF-1α. Additionally, we demonstrate that vitamin B6 supplementation or targeting pyridoxal kinase could substantially improve the efficacy of immunotherapies for gastric cancer.

Biomass Derived Self-Doped Carbon Nanosheets Enable Robust Hole Transport Layers with Ion Buffer for Perovskite Solar Cells.

The diffusion of iodine species and lead leakage during device degradation represent the main obstacles restricting the commercial application of perovskite solar cells (PSCs). Cobalt loaded ultrathin carbon nanosheets (Co(III)-CNS) derived from biomass are prepared as ion buffer material to construct robust hole transport layers (HTLs). The carbon nanosheets containing trivalent cobalt ions can facilitate the oxidation of the hole transport material while preserving the structural integrity and electrical properties of HTLs under thermal stress, thereby ensuring efficient carrier transport. The two-dimensional ultrathin graphitized lamellar structure of Co(III)-CNS is conducive to alleviate the corrosive effects of the outward diffusion of iodine species on HTLs and silver electrodes, while avoiding irreversible degradation of PSCs. With the improvement of HTL composition and the related interfaces, Co(III)-CNS doped devices can maintain intact device structure under thermal stress and remain above 80 % of the original power conversion efficiency (PCE) after thermal aging at 85 °C for 720 h. Notably, the chemical interactions between heteroatoms of self-doped carbon nanosheets and the mobile lead ions can effectively alleviate lead leakage and avoid the potential impacts of device degradation on ecosystem. Ultimately, the Co(III)-CNS doped PSCs with enhanced thermal stability exhibit a champion PCE of 22.32 %.