Causal relationship between the immune cells and ankylosing spondylitis: univariable, bidirectional, and multivariable Mendelian randomization.

Background: Ankylosing spondylitis (AS) is an autoimmune disease that affects millions of individuals. Immune cells have been recognized as having a crucial role in the pathogenesis of AS. However, their relationship has not been fully explored. Methods: We chose to employ Mendelian randomization (MR) to investigate the potential correlation between immune cells and AS. We sourced the data on immune cells from the latest genome-wide association studies (GWASs). We obtained data on AS from the FinnGen consortium. Our comprehensive univariable MR analysis covered 731 immune cells to explore its potential causal relationship with AS. The primary analysis method was inverse-variance weighted (IVW). Additionally, we used Cochran's Q test and the MR-Egger intercept test to assess the presence of pleiotropy and heterogeneity. We examined whether our results could be influenced by individual single-nucleotide polymorphisms (SNPs) using the leave-one-out test. We conducted a bidirectional MR to investigate the reverse relationship. We also applied multivariable MR to decrease the potential influence between the immune cells. Results: Overall, our univariable MR analysis revealed eight immune cells associated with AS. Among these, four immune cells contributed to an increased risk of AS, while four immune cells were identified as protective factors for AS. However, the Bonferroni test confirmed only one risk factor and one protective factor with a significance level of p < 6.84E-05. CD8 on effector memory CD8+ T cell could increase the risk of AS (p: 1.2302E-05, OR: 2.9871, 95%CI: 1.8289-4.8786). HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 1.2301E-06, OR: 0.5446, 95%CI: 0.4260-0.6962). We also identified a bidirectional relationship between CD4 on CD39+ activated CD4 regulatory T cells and AS utilizing the bidirectional MR. To address potential confounding among immune cells, we employed multivariable MR analysis, which revealed that only one immune cell had an independent effect on AS. HLA DR on CD33dim HLA DR+ CD11b+ could decrease the risk of AS (p: 2.113E-06, OR: 0.0.5423, 95%CI: 0.4210-0.6983). Our findings were consistently stable and reliable. Conclusions: Our findings indicated a potential link between immune cells and AS, which could provide a new idea for future research. Nevertheless, the specific underlying mechanisms require further exploration.

High-level production of chitinase by multi-strategy combination optimization in Bacillus licheniformis.

In view of the extensive potential applications of chitinase (ChiA) in various fields such as agriculture, environmental protection, medicine, and biotechnology, the development of a high-yielding strain capable of producing chitinase with enhanced activity holds significant importance. The objective of this study was to utilize the extracellular chitinase from Bacillus thuringiensis as the target, and Bacillus licheniformis as the expression host to achieve heterologous expression of ChiA with enhanced activity. Initially, through structural analysis and molecular dynamics simulation, we identified key amino acids to improve the enzymatic performance of chitinase, and the specific activity of chitinase mutant D116N/E118N was 48% higher than that of the natural enzyme, with concomitant enhancements in thermostability and pH stability. Subsequently, the expression elements of ChiA(D116N/E118N) were screened and modified in Bacillus licheniformis, resulting in extracellular ChiA activity reached 89.31 U/mL. Further efforts involved the successful knockout of extracellular protease genes aprE, bprA and epr, along with the gene clusters involved in the synthesis of by-products such as bacitracin and lichenin from Bacillus licheniformis. This led to the development of a recombinant strain, DW2△abelA, which exhibited a remarkable improvement in chitinase activity, reaching 145.56 U/mL. To further improve chitinase activity, a chitinase expression frame was integrated into the genome of DW2△abelA, resulting in a significant increas to 180.26 U/mL. Optimization of fermentation conditions and medium components further boosted shake flask enzyme activity shake flask enzyme activity, achieving 200.28 U/mL, while scale-up fermentation experiments yielded an impressive enzyme activity of 338.79 U/mL. Through host genetic modification, expression optimization and fermentation optimization, a high-yielding ChiA strain was successfully constructed, which will provide a solid foundation for the extracellular production of ChiA.

Removing crosstalk signals in neuron activity by time multiplexed excitations in a two-photon all-optical physiology system.

The two-photon all-optical physiology system has attracted great interest in deciphering neuronal circuits in vivo, benefiting from its advantages in recording and modulating neuronal activities at single neuron resolutions. However, the interference, or crosstalk, between the imaging and photostimulation beams introduces a significant challenge and may impede the future application of voltage indicators in two-photon all-optical physiology system. Here, we propose the time multiplexed excitation method to distinguish signals from neuronal activities and crosstalks from photostimulation. In our system, the laser pulses of the imaging beam and photostimulation beam are synchronized, and a time delay is introduced into these pulses to separate the fluorescence signal generated by these two beams. We demonstrate the efficacy of our system in eliminating crosstalk signals from photostimulation and evaluate its influence on both genetically encoded calcium indicators (GECIs) and genetically encoded voltage indicators (GEVIs) through in vivo experiments.

Transcription factor NtNAC56 regulates jasmonic acid-induced leaf senescence in tobacco.

Leaf senescence is a vital aspect of plant physiology and stress responses and is induced by endogenous factors and environmental cues.. The plant-specific NAC (NAM, ATAF1/2, CUC2) transcription factor family influences growth, development, and stress responses in Arabidopsis (Arabidopsis thaliana) and other species. However, the roles of NACs in tobacco (Nicotiana tabacum) leaf senescence are still unclear. Here, we report that NtNAC56 regulates leaf senescence in tobacco. Transgenic plants overexpressing NtNAC56 (NtNAC56-OE) showed induction of senescence-related genes and exhibited early senescence and lower chlorophyll content compared to wild-type (WT) plants and the Ntnac56-19 mutant. In addition, root development and seed germination were inhibited in the NtNAC56-OE lines. Transmission electron microscopy observations accompanied by physiological and biochemical assays revealed that NtNAC56 overexpression triggers chloroplast degradation and reactive oxygen species accumulation in tobacco leaves. Transcriptome analysis demonstrated that NtNAC56 activates leaf senescence-related genes and jasmonic acid (JA) biosynthesis pathway genes. In addition, the JA content of NtNAC56-OE plants was higher than in WT plants, and JA treatment induced NtNAC56 expression. We performed DNA affinity purification sequencing to identify direct targets of NtNAC56, among which we focused on LIPOXYGENASE 5 (NtLOX5), a key gene in JA biosynthesis. A dual-luciferase reporter assay and a yeast one-hybrid assay confirmed that NtNAC56 directly binds to the TTTCTT motif in the NtLOX5 promoter. Our results reveal a mechanism whereby NtNAC56 regulates JA-induced leaf senescence in tobacco and provide a strategy for genetically manipulating leaf senescence and plant growth.

Bioactive poly(salicylic acid)-poly(citric acid) scaffolds improve diabetic wound repair via regulating HIF-1α, Nrf2 and macrophage.

Diabetic wounds environment is over-oxidized, over-inflammatory, leading to difficulties in regenerating blood vessels, and retardation of healing in diabetic wounds. Therefore, diabetic wounds can be treated from the perspective of scavenging oxidative free radicals and reducing the level of inflammation. Herein, we report a bioactive poly(salicylic acid)-poly(citric acid) (FPSa-PCG) hydrogel for diabetic wound repair. The FPSa-PCG hydrogel shows abilities of antioxidation, anti-inflammation, and regulation of macrophage phenotype. The FPSa-PCG hydrogel showed good biocompatibility, and obtain the abilities of promotion of macrophages migration, reduction of ROS generation, suppression of the M1-type macrophage polarization. FPSa and PCG could synergistically enhance the angiogenesis through upregulating the mRNA expression of HIF1Α, VEGF, and CD31 in endothelial cells and reduce the ROS level of macrophages through upregulating the mRNA expression of Nrf2. The in vivo diabetic wound model confirmed the promoting effect of FPSa-PCG hydrogel on wound closure in diabetes. The further studies found that FPSa-PCG hydrogel could induce the CD31 protein expression in the subcutaneous tissue and inhibit the TNF-a protein expression. This work shows that the simple composition FPSa-PCG hydrogel has a promising therapeutic potential in the treatment of diabetic wounds.

Posterior Lateral Endoscopic Cervical Discectomy Through a Lateral Mass Approach in the Treatment of Cervical Spondylotic Radiculopathy.

OBJECTIVE: The present study outlines the feasibility, safety, and short-term clinical outcomes of posterior lateral endoscopic cervical discectomy (PLECD) through a lateral mass approach for treating cervical spondylotic radiculopathy (CSR). METHODS: This single-center retrospective observational study involved 30 patients with single-level CSR who had failed conservative treatment and presented with clinical symptoms consistent with imaging findings undergoing PLECD via a lateral mass approach. Primary outcomes included the visual analog scale (VAS) for neck and arm pain, the Japanese Orthopedic Association (JOA) score, and the modified MacNab criteria. Radiographic follow-up consisted of static and dynamic cervical radiographs and computed tomographic scans. RESULTS: Thirty patients (13 men and 17 women; mean age 48.8 ± 11.9 years) underwent this procedure, and the mean operative time was 74.90 ± 13.52 minutes. Mean follow-up was 7.37 ± 2.17 months. The VAS scores for the neck and arm decreased significantly at the last follow-up (neck, 26.80 ± 4.75 to 9.87 ± 1.78; arm, 71.30 ± 8.48 to 14.73 ± 4.00) (P < 0.05). The JOA score also decreased from 13.47 ± 1.36 to 15.90 ± 0.92 at the last follow-up (P < 0.05). Twenty-nine patients demonstrated satisfactory outcomes based on the modified MacNab criteria at the last follow-up. All patients exhibited a positive clinical response, experiencing relief from symptoms. Postoperative computed tomography (CT) scans confirmed the complete removal of lesions. CONCLUSIONS: PLECD through a lateral mass approach, as an alternative to conventional "keyhole" approaches, proves to be a novel and viable therapeutic option for CSR, demonstrating both high efficacy and safety.

CircMTA2 Drives Gastric Cancer Progression through Suppressing MTA2 Degradation via Interacting with UCHL3.

Our previous study has reported that metastasis-associated protein 2 (MTA2) plays essential roles in tumorigenesis and aggressiveness of gastric cancer (GC). However, the underlying molecular mechanisms of MTA2-mediated GC and its upstream regulation mechanism remain elusive. In this study, we identified a novel circular RNA (circRNA) generated from the MTA2 gene (circMTA2) as a crucial regulator in GC progression. CircMTA2 was highly expressed in GC tissues and cell lines, and circMTA2 promoted the proliferation, invasion, and metastasis of GC cells both in vitro and in vivo. Mechanistically, circMTA2 interacted with ubiquitin carboxyl-terminal hydrolase L3 (UCHL3) to restrain MTA2 ubiquitination and stabilize MTA2 protein expression, thereby facilitating tumor progression. Moreover, circMTA2 was mainly encapsulated and transported by exosomes to promote GC cell progression. Taken together, these findings uncover that circMTA2 suppresses MTA2 degradation by interacting with UCHL3, thereby promoting GC progression. In conclusion, we identified a cancer-promoting axis (circMTA2/UCHL3/MTA2) in GC progression, which paves the way for us to design and synthesize targeted inhibitors as well as combination therapies.

Mechanisms underlying morphological and functional changes of cilia in fibroblasts derived from patients bearing ARL3T31A and ARL3T31A/C118F mutations.

ARL3 is essential for cilia development, and mutations in ARL3 are closely associated with ciliopathies. In a previous study, we observed distinct phenotypes of retinal dystrophy in patients with heterozygous ARL3T31A and compound heterozygous ARL3T31A/C118F mutations, indicating that different mutation types may exert diverse effects on their functions. Here, we generated transformed immortal fibroblast cells from patients carrying heterozygous ARL3T31A and compound heterozygous ARL3T31A/C118F mutations, and systematically evaluated their cilia morphology and function, which were further validated in ARPE-19 cells. Results showed that both ARL3T31A and ARL3T31A/C118F mutations led to a decrease in cilium formation. The ARL3T31A/C118F mutations caused significantly elongated cilia and impaired retrograde transport, whereas the ARL3T31A mutation did not induce significant changes in fibroblasts. RNA-sequencing results indicated that compared to ARL3T31A , ARL3T31A/C118F fibroblasts exhibited a higher enrichment of biological processes related to neuron projection development, tissue morphogenesis, and extracellular matrix (ECM) organization, with noticeable alterations in pathways such as ECM-receptor interaction, focal adhesion, and TGF-ß signaling. Similar changes were observed in the proteomic results in ARPE-19 cells. Core regulated genes including IQUB, UNC13D, RAB3IP, and GRIP1 were specifically downregulated in the ARL3T31A/C118F group, and expressions of IQUB, NPM2, and SLC38A4 were further validated. Additionally, IQUB showed a rescuing effect on the overlong cilia observed in ARL3T31A/C118F fibroblasts. Our results not only enhance our understanding of ARL3-related diseases but also provide new insights into the analysis of heterozygous and compound heterozygous mutations in genetics.

A novel mussel-inspired desensitizer based on radial mesoporous bioactive nanoglass for the treatment of dentin exposure: An in vitro study.

OBJECTIVES: The dentin exposure always leads to dentin hypersensitivity and the acid-resistant/abrasion-resistant stability of current therapeutic approaches remain unsatisfatory. Inspired by the excellent self-polymerization/adherence activity of mussels and the superior mineralization ability of bioactive glass, a novel radial mesoporous bioactive nanoglass coated with polydopamine (RMBG@PDA) was developed for prevention and management of dentin hypersensitivity. METHODS: Radial mesoporous bioactive nanoglass (RMBG) was synthesized by the sol-gel process combined with the cetylpyridine bromide template self-assembly technique. RMBG@PDA was synthesized by a self-polymerization process involving dopamine and RMBG in an alkaline environment. Then, the nanoscale morphology, chemical structure, crystalline phase and Zeta potential of RMBG and RMBG@PDA were characterized. Subsequently, the ion release ability, bioactivity, and cytotoxicity of RMBG and RMBG@PDA in vitro were investigated. Moreover, an in vitro experimental model of dentin hypersensitivity was constructed to evaluate the effectiveness of RMBG@PDA on dentinal tubule occlusion, including resistances against acid and abrasion. Finally, the Young's modulus and nanohardness of acid-etched dentin were also detected after RMBG@PDA treatment. RESULTS: RMBG@PDA showed a typical nanoscale morphology and noncrystalline structure. The use of RMBG@PDA on the dentin surface could effectively occlude dentinal tubules, reduce dentin permeability and achieve excellent acid- and abrasion-resistant stability. Furthermore, RMBG@PDA with excellent cytocompatibility held the capability to recover the Young's modulus and nanohardness of acid-etched dentin. CONCLUSION: The application of RMBG@PDA with superior dentin tubule occlusion ability and acid/abrasion-resistant stability can provide a therapeutic strategy for the prevention and the management of dentin hypersensitivity.

Separation of lignin derivatives from hemp fiber using supercritical CO2, ethanol, and water at different temperatures.

The process of lignin extraction often involves intricate chemical transformations, influencing its potential for high-value utilization. By investigating the process of lignin derivatives extraction from hemp fibers using supercritical CO2, ethanol, and water, we identified the relationship between the chemical structure of lignin derivatives and temperature. This discovery contributes to controlling the chemical structure of lignin derivatives through temperature modulation. We observed that lignin derivatives extracted within the temperature range of 100-120 °C exhibited the lowest average molecular weight and polydispersity index, presenting a disordered microstructure with the highest hydroxyl content. Lignin derivatives extracted between 140 and 160 °C showed an increase in average molecular weight and polydispersity index, decreased hydroxyl content, and a gradual transformation of microstructure into spherical particles. At 180 °C, the average molecular weight and polydispersity index of lignin derivatives decreased, the microstructure of lignin derivatives showed fewer spherical particles, while its hydroxyl content exhibited a partial recovery. Chemical analysis revealed a lower degree of condensation in lignin derivatives at 100-120 °C. Between 120 and 160 °C, the degree of condensation increased. At 180 °C, extensive degradation occurred in lignin derivatives. This research advances innovative techniques for lignin derivative separation, contributing to their utilization in higher-value applications.

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

VHL suppresses autophagy and tumor growth through PHD1-dependent Beclin1 hydroxylation.

The Von Hippel-Lindau (VHL) protein, which is frequently mutated in clear-cell renal cell carcinoma (ccRCC), is a master regulator of hypoxia-inducible factor (HIF) that is involved in oxidative stresses. However, whether VHL possesses HIF-independent tumor-suppressing activity remains largely unclear. Here, we demonstrate that VHL suppresses nutrient stress-induced autophagy, and its deficiency in sporadic ccRCC specimens is linked to substantially elevated levels of autophagy and correlates with poorer patient prognosis. Mechanistically, VHL directly binds to the autophagy regulator Beclin1, after its PHD1-mediated hydroxylation on Pro54. This binding inhibits the association of Beclin1-VPS34 complexes with ATG14L, thereby inhibiting autophagy initiation in response to nutrient deficiency. Expression of non-hydroxylatable Beclin1 P54A abrogates VHL-mediated autophagy inhibition and significantly reduces the tumor-suppressing effect of VHL. In addition, Beclin1 P54-OH levels are inversely correlated with autophagy levels in wild-type VHL-expressing human ccRCC specimens, and with poor patient prognosis. Furthermore, combined treatment of VHL-deficient mouse tumors with autophagy inhibitors and HIF2α inhibitors suppresses tumor growth. These findings reveal an unexpected mechanism by which VHL suppresses tumor growth, and suggest a potential treatment for ccRCC through combined inhibition of both autophagy and HIF2α.

Intravenous Tirofiban Versus Alteplase Before Endovascular Treatment in Acute Ischemic Stroke: A Pooled Analysis of the DEVT and RESCUE BT Trials.

BACKGROUND: The present study aimed to evaluate the efficacy and safety of intravenous tirofiban versus alteplase before endovascular treatment (EVT) in acute ischemic stroke patients with intracranial large vessel occlusion. METHODS: This was a post hoc analysis using data from 2 multicenter, randomized trials: the DEVT trial (Direct Endovascular Treatment for Large Vessel Occlusion Stroke) from May 2018 to May 2020 and the RESCUE BT trial (Intravenous Tirofiban Before Endovascular Thrombectomy for Acute Ischemic Stroke) from October 2018 to October 2021. Patients with acute intracranial large vessel occlusion within 4.5 hours from last known well were dichotomized into 2 groups: tirofiban plus EVT versus alteplase bridging with EVT. The primary outcome was functional independence (modified Rankin Scale score of 0-2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 3-month mortality. Multivariable logistic regression (adjusting for baseline systolic blood pressure, occlusion site, onset-to-puncture time, anesthesia, and first choice of EVT) and propensity score overlap weighting (balance in demographic covariates, stroke characteristics, and initial management between groups) were performed. RESULTS: One-hundred and eighteen alteplase-treated patients in the DEVT trial and 98 tirofiban-treated patients in the RESCUE BT trial were included (median age, 70 years; 115 [53.2%] men). The rate of functional independence was 60.2% in the tirofiban group compared with 46.6% in the alteplase group (adjusted odds ratio, 1.25 [95% CI, 0.60-2.63]). Compared with alteplase, tirofiban was not associated with increased risk of symptomatic intracranial hemorrhage (6.8% versus 9.2%; P=0.51) and mortality (17.8% versus 19.4%; P=0.76). The propensity score overlap weighting analyses showed consistent outcomes. CONCLUSIONS: Among patients with intracranial large vessel occlusion within 4.5 hours of onset, tirofiban plus EVT was comparable to alteplase bridging with EVT regarding the efficacy and safety outcomes. These findings should be interpreted as preliminary and require confirmation in a randomized trial. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifiers: ChiCTR-IOR-17013568 and ChiCTR-INR-17014167.

Tuning the Catalytic Selectivity Toward C2+ Oxygenate Products by Manipulating Cu Oxidation States in CO Electroreduction.

Enhancing the reaction selectivity for multicarbon products (C2+) is an important goal for the electrochemical CO(2) reduction (ECO(2)R) process. Cuprous compounds have demonstrated promising C2+ selectivity in the ECO(2)R process, but further investigation is necessary to thoroughly elucidate their catalytic behavior toward C2+ oxygenate production. In this study, copper nitride-based materials with varying reduction rates were employed as precatalysts. Consequently, a relationship between the selectivity toward C2+ oxygenates and the Cu oxidation state during the ECOR process is established. Results of theoretical and experimental analyses reveal that the Cu0/Cu+ interface plays a key role in enhancing *CO adsorption while lowering the formation energy of *CH2CO, thereby promoting acetate production. This work highlights the significance of the Cu0/Cu+ interface in the regulation of C2+ oxygenate production and paves the way for the development of highly selective catalysts in the future.

The Mechanism of Astragaloside IV in NOD-like Receptor Family Pyrin Domain Containing 3 Inflammasome-mediated Pyroptosis after Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is one of the most common subtypes of stroke. OBJECTIVES: This study aimed to investigate the mechanism of Astragaloside IV (AS-IV) on inflammatory injury after ICH. METHODS: The ICH model was established by the injection of collagenase and treated with ASIV (20 mg/kg or 40 mg/kg). The neurological function, water content of the bilateral cerebral hemisphere and cerebellum, and pathological changes in brain tissue were assessed. The levels of interleukin-1 beta (IL-1ß), IL-18, tumor necrosis factor-alpha, interferon-gamma, and IL-10 were detected by enzyme-linked immunosorbent assay. The levels of Kruppel-like factor 2 (KLF2), NOD-like receptor family pyrin domain containing 3 (NLRP3), GSDMD-N, and cleaved-caspase-1 were detected by reverse transcription-quantitative polymerase chain reaction and Western blot assay. The binding relationship between KLF2 and NLRP3 was verified by chromatin-immunoprecipitation and dual-luciferase assays. KLF2 inhibition or NLRP3 overexpression was achieved in mice to observe pathological changes. RESULTS: The decreased neurological function, increased water content, severe pathological damage, and inflammatory response were observed in mice after ICH, with increased levels of NLRP3/GSDMD-N/cleaved-caspase-1/IL-1ß/IL-18 and poorly-expressed KLF2 in brain tissue. After AS-IV treatment, the neurological dysfunction, high brain water content, inflammatory response, and pyroptosis were alleviated, while KLF2 expression was increased. KLF2 bonded to the NLRP3 promoter region and inhibited its transcription. Down-regulation of KLF2 or upregulation of NLRP3 reversed the effect of AS-IV on inhibiting pyroptosis and reducing inflammatory injury in mice after ICH. CONCLUSION: AS-IV inhibited NLRP3-mediated pyroptosis by promoting KLF2 expression and alleviated inflammatory injury in mice after ICH.

Clinical decision support system based on deep learning for evaluating implantable collamer lens size and vault after implantable collamer lens surgery: a retrospective study.

OBJECTIVES: To aid doctors in selecting the optimal preoperative implantable collamer lens (ICL) size and to enhance the safety and surgical outcomes of ICL procedures, a clinical decision support system (CDSS) is proposed in our study. DESIGN: A retrospective study of patients after ICL surgery. SETTING: China Tertiary Myopia Prevention and Control Center. PARTICIPANTS: 2772 eyes belonging to 1512 patients after ICL surgery. Data were collected between 2018 and 2022. OUTCOME MEASURES: A CDSS is constructed and used to predict vault at 1 month postoperatively and preoperative ICL dimensions using various artificial intelligence methods. Accuracy metrics as well as area under curve (AUC) parameters are used to determine the CDSS prediction methods. RESULTS: Among the ICL size prediction models, conventional neural networks (CNNs) achieve the best prediction accuracy at 91.37% and exhibit the highest AUC of 0.842. Regarding the prediction model for vault values 1 month after surgery, CNN surpasses the other methods with an accuracy of 85.27%, which has the uppermost AUC of 0.815. Thus, we select CNN as the prediction algorithm for the CDSS. CONCLUSIONS: This study introduces a CDSS to assist doctors in selecting the optimal ICL size for patients while improving the safety and postoperative outcomes of ICL surgery.

Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA-specific CAR-T therapy: A retrospective analysis of LEGEND-2.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has shown profound efficacy and manageable toxicity in patients with relapsed/refractory multiple myeloma (RRMM). However, determining the best course of treatment for post-CAR-T therapy relapse remains a significant challenge. We conducted a retrospective analysis of patients from the phase I LEGEND-2 study (NCT03090659) enrolled at the Xi'an site, analysing the first salvage line of therapy and outcomes in patients with RRMM who progressed after receiving LCAR-B38M CAR-T therapy. Of 45 eligible patients, 34 (76%) had progressive disease (PD). Overall response rate (ORR) to salvage treatment was 50.0%. Median progression-free survival (PFS) after starting salvage treatment was 16.3 months. Median PFS of patients receiving proteasome inhibitor (PI)-based combination therapy was longer (28.2 months) than that of patients receiving a second BCMA CAR-T (including LCAR-B38M; 3.9 months, p = 0.0022) or chemotherapy (1.67 months, p = 0.0001). All patients with extramedullary disease at baseline (n = 11) progressed after CAR-T therapy; ORR to salvage therapy was 25.0% and median PFS was 9.7 months. In conclusion, salvage therapy in patients with PD after receiving LCAR-B38M CAR-T cells produced moderate efficacy, with better outcomes for PI-based salvage regimens.

Highly Bioactive MXene-M2-Exosome Nanocomposites Promote Angiogenic Diabetic Wound Repair through Reconstructing High Glucose-Derived Immune Inhibition.

The repair of diabetic wounds remains challenging, primarily due to the high-glucose-derived immune inhibition which often leads to the excessive inflammatory response, impaired angiogenesis, and heightened susceptibility to infection. However, the means to reduce the immunosuppression and regulate the conversion of M2 phenotype macrophages under a high-glucose microenvironment using advanced biomaterials for diabetic wounds are not yet fully understood. Herein, we report two-dimensional carbide (MXene)-M2 macrophage exosome (Exo) nanohybrids (FM-Exo) for promoting diabetic wound repair by overcoming the high-glucose-derived immune inhibition. FM-Exo showed the sustained release of M2 macrophage-derived exosomes (M2-Exo) up to 7 days and exhibited broad-spectrum antibacterial activity. In the high-glucose microenvironment, relative to the single Exo, FM-Exo could significantly induce the optimized M2a/M2c polarization ratio of macrophages by activating the PI3K/Akt signaling pathway, promoting the proliferation, migration of fibroblasts, and angiogenic ability of endothelial cells. In the diabetic full-thickness wound model, FM-Exo effectively regulated the polarization status of macrophages and promoted their transition to the M2 phenotype, thereby inhibiting inflammation, promoting angiogenesis through VEGF secretion, and improving proper collagen deposition. As a result, the healing process was accelerated, leading to a better healing outcome with reduced scarring. Therefore, this study introduced a promising approach to address diabetic wounds by developing bioactive nanomaterials to regulate immune inhibition in a high-glucose environment.

An All-in-One Platform for On-Site Multiplex Foodborne Pathogen Detection Based on Channel-Digital Hybrid Microfluidics.

Recently, significant progress has been made in the development of microdevices for point-of-care infectious disease detection. However, most microdevices only allow limited steps, such as DNA amplification on the chip, while sample preparation, such as lysis and DNA extraction, is conducted off the chip using the traditional method. In this study, an all-in-one platform was developed, which incorporated all necessary procedures for nucleic acid detection. Our on-chip DNA extraction method utilized the magnetic bead-based technology on a hybrid channel-digital microfluidics (C-DMF) microdevice. It yielded high recovery rates, varying from 88.43% to 95.83%, with pathogen concentrations of 103-106 CFU/mL. In particular, the on-chip method exhibited significantly higher efficacy compared to the traditional off-chip manual method, for the DNA extraction of E. coli and S. aureus, representing Gram-negative and Gram-positive bacteria, respectively, at a sample concentration of 103 CFU/mL. To address the need for rapid and accessible diagnostics, colorimetric LAMP amplification was integrated into the proposed microdevice. The results were visually detectable with the naked eye, making it user-friendly for non-specialists. In addition, this platform demonstrated impressive sensitivity in simultaneously detecting common foodborne pathogens in spiked meat samples, achieving the LOD of 102-103 CFU/mL. The entire process, from sampling to result, was fully automated and only required approximately 60 min, offering promising applicability in resource-limited and on-site testing scenarios.

A tungsten phosphide cocatalyst enhanced bismuth tungstate photoanode with the robust built-in electric field towards highly efficient photoelectrochemical water splitting.

The use of low-cost and effective cocatalyst is a potential strategy to optimize the effectiveness of photoelectrochemical (PEC) water splitting. In this study, tungsten phosphide (WP) is introduced as a remarkably active cocatalyst to enhance the PEC efficiency of a Bi2WO6 photoanode. The onset potential of Bi2WO6/WP demonstrates a negative shift, while the photocurrent density demonstrates a significant 5.5-fold increase compared to that of unmodified Bi2WO6 at 1.23 VRHE (reversible hydrogen electrode). The loading of WP cocatalyst facilitates the rapid transfer of holes, increasing the range of visible light absorption, the water adsorption ability as well as promoting the separation of photogenerated electrons and holes via the built-in electric field between Bi2WO6 and WP. This study proposes a strategy to hinder the recombination of electron-hole pairs by using WP cocatalyst as a hole capture agent, improve the photoelectric conversion efficiency, and enhance the overall photoelectrochemical properties of Bi2WO6 photoanode.