Progress of engineered bacteria for tumour therapy.

Finding novel therapeutic modalities, improving drug delivery efficiency and targeting, and reducing the immune escape of tumor cells are currently hot topics in the field of tumor therapy. Bacterial therapeutics have proven highly effective in preventing tumor spread and recurrence, used alone or in combination with traditional therapies. In recent years, a growing number of researchers have significantly improved the targeting and penetration of bacteria by using genetic engineering technology, which has received widespread attention in the field of tumor therapy. In this paper, we provide an overview and assessment of the advancements made in the field of tumor therapy using genetically engineered bacteria. We cover three major aspects: the development of engineered bacteria, their integration with other therapeutic techniques, and the current state of clinical trials. Lastly, we discuss the limitations and challenges that are currently being faced in the utilization of engineered bacteria for tumor therapy.

Importance of the Posterior Plate in Three-Column Tibial Plateau Fractures: A Finite Element Analysis and Clinical Validation.

OBJECTIVE: Dual-plate fixation was thought to be the gold standard for treating complicated bicondylar tibial plateau fractures, yet it was found to be hard to accommodate the posterior column in three-column fractures. Currently, column-specific fixation is becoming more and more recognized, but no comprehensive investigation has been performed to back it up. Therefore, the objective of this study was to validate the importance of posterior column fixation in the three-column tibial fractures by a finite element (FE) analysis and clinical study. METHODS: In FE analysis, three models were developed: the longitudinal triple-plate group (LTPG), the oblique triple-plate group (OTPG), and the dual-plate group (DPG). Three loading scenarios were simulated. The distribution of the displacement and the equivalent von Mises stress (VMS) in each structure was calculated. The comparative measurements including the maximum posterior column collapse (MPCC), the maximum total displacement of the model (MTD), the maximum VMS of cortical posterior column (MPC-VMS), and the maximum VMS located on each group of plates and screws (MPS-VMS). The clinical study evaluated the indicators between the groups with or without the posterior plate, including operation time, blood loss volume, full-weight bearing period, Hospital for Special Surgery Knee Scoring system (HSS), Rasmussen score, and common postoperative complications. RESULTS: In the FE analysis, the MPCC, the MPC-VMS, and the MTD were detected in much lower amounts in LTPG and OTPG than in DPG. In comparison with DPG, the LTPG and OTPG had larger MPS-VMS. In the clinical study, 35 cases were included. In the triple-plate (14) and dual-plate (21) groups, the operation took 115.6 min and 100.5 min (p < 0.05), respectively. Blood loss in both groups was 287.0 mL and 206.6 mL (p < 0.05), and the full-weight bearing period was 14.5 weeks and 16.2 weeks (p < 0.05). At the final follow-up, the HSS score was 85.0 in the triple-plate group and 77.5 in the dual-plate (p < 0.05), the Rasmussen score was 24.1 and 21.6 (p < 0.05), there were two cases with reduction loss (9.5%) in the dual-plate group and one case of superficial incision infection found in the triple-plate group. CONCLUSION: The posterior implant was beneficial in optimizing the biomechanical stability and functional outcomes in the three-column tibial plateau fractures.

Mechanistic insights into diversified photoluminescence behaviours of BF2 complexes of N-benzoyl 2-aminobenzothiazoles.

Many BF2 complexes of heteroaromatics are well known for their dual-state emission (DSE) properties. However, AIE and ACQ effects have also been observed in certain cases. To date, no rational explanations have been proposed for these uncommon photoluminescence (PL) behaviours. The current research prepared four BF2 complexes of N-benzoyl 2-aminobenzothiazoles with diversified photoluminescence (PL) properties as model compounds and utilized quantum chemical calculation tools to address this issue. Theoretical calculations revealed that the electron-donating groups (EDGs) at the para-position of the exocyclic phenyl ring exert significant influence on their ground-state electronic structures and vertical excitation features. Potential energy curve (PEC) analysis showed that the exocyclic phenyl ring and NMe2 could not function as effective rotors due to elevated energy barriers. Only the NPh2 of BFBB-3 could spontaneously rotate ∼60° to induce the formation of an emissive twisted intramolecular charge transfer (TICT) state. The two-channel model involving both vibronic relaxation and S0/S1 surface crossing revealed that the drastic narrowing of the S1/S0 energy gap in the region approaching minimun energy conical intersection (MECI) led to the generation of a dark state in BFBB-1. The small energy barrier to access the dark-state region makes the resulting fast internal conversion a competitive channel for excited-state deactivation. In contrast, the presence of EDGs in BFBB-2 and 4 inhibits this pathway, thereby resulting in intense fluorescence emissions in solution. In addition, crystallographic analysis illustrated that the F atoms perpendicular to the polyheterocycle promoted a slipped face-to-face packing mode and enhanced intermolecular interactions. The efficiencies of their solid-state emissions are mainly affected by the degree of π-π overlaps.

Therapeutic Potential of Danyankang Capsule in High-Fat Diet-Induced Cholelithiasis and Its Impact on Liver FXR Signaling and Gut Microbiota.

Cholelithiasis, commonly known as gallstones, represents a prevalent hepatobiliary disorder. This study aimed to elucidate the therapeutic role and mechanism of Danyankang capsulein treating cholelithiasis induced by a high-fat diet in C57BL/6 mice. The therapeutical potential of Danyankang was assessed through biochemical analyses, histopathological examinations, protein detection, and 16S rDNA sequencing. A high-fat diet resulted in cholelithiasis manifestation in mice, with discernable abnormal serum biochemical indices and disrupted biliary cholesterol homeostasis. Danyankang treatment notably ameliorated liver inflammation symptoms and rectified serum and liver biochemical abnormalities. Concurrently, it addressed biliary imbalances. Elevated expressions of toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB)/pNF-κB, HMGCR, CYP7A1, and CYP8B1 observed at the inception of cholelithiasis, were notably reduced upon Danyankang administration. Furthermore, 16S rDNA analysis revealed a decline in species number and diversity of the intestinal flora in cholelithiasis-treated mice, while the decline was reversed with Danyankang treatment. Danyankang capsules reduced the abundance of Verrucomicrobiota and increased the abundance of Actinobacteriota and Proteobacteria. In conclusion, the present study demonstrates that Danyankang exerts potent therapeutic efficacy against high-fat diet-induced cholelithiasis. This beneficial outcome is potentially linked to the inhibition of the TLR4/pNF-κB and SHP/CYP7A1/CYP8B1 signaling pathways, as well as the enhancement of intestinal flora species abundance.

Effect of salting and dehydration treatments on the physicochemical and gel properties of hen and duck egg yolks, plasma and granules.

BACKGROUND: Salted hen egg yolks are less oily and less flavorful than salted duck egg yolks. However, hen eggs have a more adequate market supply and have a broader application prospect than duck eggs. In the present study, egg yolks, plasma, and granules were dehydrated by adding 1% NaCl to simulate traditional curing process of salted egg yolk. The changes in the pickling process of hen egg yolks (HEY) and duck egg yolks (DEY) plasma and granules were compared to reveal the gelation mechanism and the underlying causes of quality differences in salted HEY and DEY. Salted HEY can be compared with the changes in DEY during the pickling process to provide a theoretical basis for the quality improvement of salted HEY to salted DEY. RESULTS: The results showed that both plasma and granules were involved in gel formation, but exhibited different aggregation behaviors. Based on the intermolecular forces, the HEY proteins achieved aggregation mainly through hydrophobic interactions and DEY proteins mainly through covalent binding. According to spin-spin relaxation time, HEY gels immobilized a large amount of lipid and interacted strongly with lipids. DEY gels showed much free lipid and had weak interaction with lipid. The microstructure showed that HEY proteins were easily unfolded to form a homogeneous three-dimensional gel network structure after salting, whereas heterogeneous aggregates were formed to hinder the gel development in DEY. Changes in protein secondary structure content showed that pickling can promote the transformation of the α-helices to ß-sheets structure in HEY gels, whereas more α-helices structure was formed in DEY gels. CONCLUSION: The present study has demonstrated that different gelation behaviors of hen and duck egg yolk proteins (especially in plasma) through salting treatment led to the difference in the quality of salted HEY and DEY. © 2024 Society of Chemical Industry.

TRIM65 promotes vascular smooth muscle cell phenotypic transformation by activating PI3K/Akt/mTOR signaling during atherogenesis.

BACKGROUND AND AIMS: Tripartite motif (TRIM65) is an important member of the TRIM protein family, which is a newly discovered E3 ligase that interacts with and ubiquitinates various substrates and is involved in diverse pathological processes. However, the function of TRIM65 in atherosclerosis remains unarticulated. In this study, we investigated the role of TRIM65 in the pathogenesis of atherosclerosis, specifically in vascular smooth muscle cells (VSMCs) phenotype transformation, which plays a crucial role in formation of atherosclerotic lesions. METHODS AND RESULTS: Both non-atherosclerotic and atherosclerotic lesions during autopsy were collected singly or pairwise from each individual (n = 16) to investigate the relationship between TRIM65 and the development of atherosclerosis. In vivo, Western diet-fed ApoE-/- mice overexpressing or lacking TRIM65 were used to assess the physiological function of TRIM65 on VSMCs phenotype, proliferation and atherosclerotic lesion formation. In vitro, VSMCs phenotypic transformation was induced by platelet-derived growth factor-BB (PDGF-BB). TRIM65-overexpressing or TRIM65-abrogated primary mouse aortic smooth muscle cells (MOASMCs) and human aortic smooth muscle cells (HASMCs) were used to investigate the mechanisms underlying the progression of VSMCs phenotypic transformation, proliferation and migration. Increased TRIM65 expression was detected in α-SMA-positive cells in the medial and atherosclerotic lesions of autopsy specimens. TRIM65 overexpression increased, whereas genetic knockdown of TRIM65 remarkably inhibited, atherosclerotic plaque development. Mechanistically, TRIM65 overexpression activated PI3K/Akt/mTOR signaling, resulting in the loss of the VSMCs contractile phenotype, including calponin, α-SMA, and SM22α, as well as cell proliferation and migration. However, opposite phenomena were observed when TRIM65 was deficient in vivo or in vitro. Moreover, in cultured PDGF-BB-induced TRIM65-overexpressing VSMCs, inhibition of PI3K by treatment with the inhibitor LY-294002 for 24 h markedly attenuated PI3K/Akt/mTOR activation, regained the VSMCs contractile phenotype, and blocked the progression of cell proliferation and migration. CONCLUSIONS: TRIM65 overexpression enhances atherosclerosis development by promoting phenotypic transformation of VSMCs from contractile to synthetic state through activation of the PI3K/Akt/mTOR signal pathway.

Oxygen-Activated Boron Nitride for Selective Photocatalytic Coupling of Methanol to Ethylene Glycol.

The controllable photocatalytic C-C coupling of methanol to produce ethylene glycol (EG) is a highly desirable but challenging objective for replacing the current energy-intensive thermocatalytic process. Here, we develop a metal-free porous boron nitride catalyst that demonstrates exceptional selectivity in the photocatalytic production of EG from methanol under mild conditions. Comprehensive experiments and calculations are conducted to thoroughly investigate the reaction mechanism, revealing that the OB3 unit in the porous BN plays a critical role in the preferential activation of C-H bond in methanol to form ⋅CH2OH via a concerted proton-electron transfer mechanism. More prominent energy barriers are observed for the further dehydrogenation of the ⋅CH2OH intermediate on the OB3 unit, inhibiting the formation of some other by-products during the catalytic process. Additionally, a small downhill energy barrier for the coupling of ⋅CH2OH in the OB3 unit promotes the selective generation of EG. This study provides valuable insights into the underlying mechanisms and can serve as a guide for the design and optimization of photocatalysts for efficient and selective EG production under mild conditions.

Macrophage ß-arrestin-1 deteriorates DSS-induced colitis through interaction with NF-κB signaling.

ß-arrestin-1 has been demonstrated to participate in the regulation of inflammatory reactions in several diseases. Thus, this study aimed to investigate the role of macrophage ß-arrestin-1 in the pathogenesis and progression of ulcerative colitis (UC). A myeloid ß-arrestin-1 conditional knockout mouse model was generated to explore the role of macrophage ß-arrestin-1. DSS was employed for the establishment of an ulcerative colitis mouse model, using TNF-α as an inflammatory stressor in vitro. The expression level of ß-arrestin-1 was detected via western blot and immunofluorescence assays, whilst disease severity was evaluated by clinical score and H&E staining in the DSS-induced colitis model. In the in vitro experiments, the levels of inflammatory cytokines were examined using real-time PCR. NF-κB activation was detected through the double luciferase reporter system, western blot, and electrophoretic mobility shift assay (EMSA). BAY11-7082 was used to inhibit NF-κB activation. Our results exposed that the level of ß-arrestin-1 was increased in monocytes/macrophages derived from DSS-induced colitis mice or under the TNF-α challenge. Moreover, conditionally knocking out the expression of myeloid ß-arrestin-1 alleviated disease severity, while knocking out the expression of ß-arrestin-1 decreased the levels of inflammatory cytokines. Additionally, NF-κB was identified as a central regulatory element of ß-arrestin-1 promoter, and using BAY11-7082 to inhibit NF-κB activation lowered the level of ß-arrestin-1 under TNF-α challenge. ß-arrestin-1 led to the activation of the NF-κB signaling pathway by enhancing binding to IκBα and IKK under the TNF-α challenge. Taken together, our findings demonstrated macrophage ß-arrestin-1 contributes to the deterioration of DSS-induced colitis through the interaction with NF-κB signaling, thus highlighting a novel target for the treatment of UC.

UV-A radiation increases biomass yield by enhancing energy flow and carbon assimilation in the edible cyanobacterium Nostoc sphaeroides.

Ultraviolet (UV) A radiation (315-400 nm) is the predominant component of solar UV radiation that reaches the Earth's surface. However, the underlying mechanisms of the positive effects of UV-A on photosynthetic organisms have not yet been elucidated. In this study, we investigated the effects of UV-A radiation on the growth, photosynthetic ability, and metabolome of the edible cyanobacterium Nostoc sphaeroides. Exposures to 5-15 W m-2 (15-46 µmol photons m-2 s-1) UV-A and 4.35 W m-2 (20 µmol photons m-2 s-1) visible light for 16 days significantly increased the growth rate and biomass production of N. sphaeroides cells by 18%-30% and 15%-56%, respectively, compared to the non-UV-A-acclimated cells. Additionally, the UV-A-acclimated cells exhibited a 1.8-fold increase in the cellular nicotinamide adenine dinucleotide phosphate (NADP) pool with an increase in photosynthetic capacity (58%), photosynthetic efficiency (24%), QA re-oxidation, photosystem I abundance, and cyclic electron flow (87%), which further led to an increase in light-induced NADPH generation (31%) and ATP content (83%). Moreover, the UV-A-acclimated cells showed a 2.3-fold increase in ribulose-1,5-bisphosphate carboxylase/oxygenase activity, indicating an increase in their carbon-fixing capacity. Gas chromatography-mass spectrometry-based metabolomics further revealed that UV-A radiation upregulated the energy-storing carbon metabolism, as evidenced by the enhanced accumulation of sugars, fatty acids, and citrate in the UV-A-acclimated cells. Therefore, our results demonstrate that UV-A radiation enhances energy flow and carbon assimilation in the cyanobacterium N. sphaeroides.IMPORTANCEUltraviolet (UV) radiation exerts harmful effects on photo-autotrophs; however, several studies demonstrated the positive effects of UV radiation, especially UV-A radiation (315-400 nm), on primary productivity. Therefore, understanding the underlying mechanisms associated with the promotive effects of UV-A radiation on primary productivity can facilitate the application of UV-A for CO2 sequestration and lead to the advancement of photobiological sciences. In this study, we used the cyanobacterium Nostoc sphaeroides, which has an over 1,700-year history of human use as food and medicine, to explore its photosynthetic acclimation response to UV-A radiation. As per our knowledge, this is the first study to demonstrate that UV-A radiation increases the biomass yield of N. sphaeroides by enhancing energy flow and carbon assimilation. Our findings provide novel insights into UV-A-mediated photosynthetic acclimation and provide a scientific basis for the application of UV-A radiation for optimizing light absorption capacity and enhancing CO2 sequestration in the frame of a future CO2 neutral, circular, and sustainable bioeconomy.

Core and variable antimicrobial resistance genes in the gut microbiomes of Chinese and European pigs.

Monitoring the prevalence of antimicrobial resistance genes (ARGs) is vital for addressing the global crisis of antibiotic-resistant bacterial infections. Despite its importance, the characterization of ARGs and microbiome structures, as well as the identification of indicators for routine ARG monitoring in pig farms, are still lacking, particularly concerning variations in antimicrobial exposure in different countries or regions. Here, metagenomics and random forest machine learning were used to elucidate the ARG profiles, microbiome structures, and ARG contamination indicators in pig manure under different antimicrobial pressures between China and Europe. Results showed that Chinese pigs exposed to high-level antimicrobials exhibited higher total and plasmid-mediated ARG abundances compared to those in European pigs ( P<0.05). ANT(6)-Ib, APH(3')-IIIa, and tet(40) were identified as shared core ARGs between the two pig populations. Furthermore, the core ARGs identified in pig populations were correlated with those found in human populations within the same geographical regions. Lactobacillus and Prevotella were identified as the dominant genera in the core microbiomes of Chinese and European pigs, respectively. Forty ARG markers and 43 biomarkers were able to differentiate between the Chinese and European pig manure samples with accuracies of 100% and 98.7%, respectively. Indicators for assessing ARG contamination in Chinese and European pigs also achieved high accuracy ( r=0.72-0.88). Escherichia flexneri in both Chinese and European pig populations carried between 21 and 37 ARGs. The results of this study emphasize the importance of global collaboration in reducing antimicrobial resistance risk and provide validated indicators for evaluating the risk of ARG contamination in pig farms.

Triple-Phase Photocatalytic H2O2 Production on a Janus Fiber Membrane with Asymmetric Hydrophobicity.

Photocatalytic O2 reduction is an intriguing approach to producing H2O2, but its efficiency is often hindered by the limited solubility and mass transfer of O2 in the aqueous phase. Here, we design and fabricate a two-layered (2L) Janus fiber membrane photocatalyst with asymmetric hydrophobicity for efficient photocatalytic H2O2 production. The top layer of the membrane consists of superhydrophobic polytetrafluoroethylene (PTFE) fibers with a dispersed modified carbon nitride (mCN) photocatalyst. Amphiphilic Nafion (Naf) ionomer is sprayed onto this layer to modulate the microenvironment and achieve moderate hydrophobicity. In contrast, the bottom layer consists of bare PTFE fibers with high hydrophobicity. The elaborate structural configuration and asymmetric hydrophobicity feature of the optimized membrane photocatalyst (designated as 2L-mCN/F-Naf; F, PTFE) allow most mCN to be exposed with gas-liquid-solid triple-phase interfaces and enable rapid mass transfer of gaseous O2 within the hierarchical membrane, thus increasing the local O2 concentration near the mCN photocatalyst. As a result, the optimized 2L-mCN/F-Naf membrane photocatalyst shows remarkable photocatalytic H2O2 production activity, achieving a rate of 5.38 mmol g-1 h-1 under visible light irradiation.

O-GlcNAcylation orchestrates porcine oocyte maturation through maintaining mitochondrial dynamics and function.

O-linked ß-N-acetylglucosamine (O-GlcNAc) modification exists widely in cells, playing a crucial role in the regulation of important biological processes such as transcription, translation, metabolism, and the cell cycle. O-GlcNAc modification is an inducible reversible dynamic protein post-translational modification, which regulates complex cellular activities through transient glycosylation and deglycosylation. O-GlcNAc glycosylation is specifically regulated by O-GlcNAc glycosyltransferase (O-GlcNAc transferase, OGT) and O-GlcNAc glycoside hydrolase (O-GlcNAcase). However, the mechanisms underlying the effects of O-GlcNAc modification on the female reproductive system, especially oocyte quality, remain unclear. Here, we found that after OGT was inhibited, porcine oocytes failed to extrude the first polar body and exhibited abnormal actin and microtubule assembly. Meanwhile, the mitochondrial dynamics and function were also disrupted after inhibition of OGT function, resulting in the occurrence of oxidative stress and autophagy. Collectively, these results inform our understanding of the importance of the glycosylation process for oocyte maturation, especially for the maturation quality of porcine oocytes, and the alteration of O-GlcNAc in oocytes to regulate cellular events deserves further investigation.

Utilization of cannulated screw fixation of Jail and TiRobot-assisted percutaneous indirect reduction technique for AO/OTA type 41B2 tibial plateau fracture treatment.

PURPOSE: The present study was designed to investigate the precise procedure and effectiveness of percutaneous minimally invasive fixation assisted by TiRobot in managing AO/OTA type 41B2 tibial plateau fracture to provide an alternative solution for clinical application. METHODS: In total, 10 participants with AO/OTA type 41B2 tibial plateau fractures diagnosed by preoperative imaging examinations were enrolled in this study between May 2019 and May 2022. They were 5 males and 5 females, with an average age of 45.6 ± 11.3 years old (range 27-62 years old). All of them had closed fractures, including 6 cases with anterior cruciate ligament (ACL) tibial insertion avulsion fractures, 1 case with medial collateral ligament (MCL) tear, and 4 cases with a lateral meniscus tear. From injury through surgery, the entire time frame was 4.0 ± 1.5 days (range, 2-7 days). Following indirect percutaneous reduction assisted by TiRobot, the Jail method was used to treat all patients with minimally invasive internal fixation. Patients with ligament or meniscus injurieswere treated with arthroscopic surgery in one stage. The standardized functional exercise was performed postoperatively. The knee function was measured using the Hospital for Special Surgery (HSS) score, and the fracture reduction was assessed through the Rasmussen radiology score. RESULTS: All patients were followed up for 12.7 ± 6.8 months (6-24 months).The fracture healing time was 11.8 ± 0.8 weeks (10-13 weeks), and the X-rays revealed satisfactory fracture reduction.The knee joint's Rasmussen score was 17.8 ± 0.4 (in the range of 17-18) a year after the procedure, with 8 patients receiving outstanding ratings and 2 cases receiving satisfactory scores. The HSS score was 93.8 ± 2.3 (range, 89 to 96), of which 10 cases were excellent. The motion range of the kneewas 138.7°±2.7° (range, -5° to 0° to 135°). No adverse effects or serious complications, such as internal fixation failure, postoperative infection, popliteal vascular injury, and common peroneal nerve injury, were observed during the last follow-up visit. CONCLUSIONS: The intelligent assistance and accurate guidance of TiRobot can simplify and standardize procedures of percutaneous minimally invasive fixation in theSchatzker type Ⅲ tibial plateau fracture treatment. This technique increases the precision of indirect percutaneous reduction and screw fixation while minimizing bone grafting.

Selective Electrocatalytic Conversion of Nitric Oxide to High Value-Added Chemicals.

The artificial disturbance in the nitrogen cycle has necessitated an urgent need for nitric oxide (NO) removal. Electrochemical technologies for NO conversion have gained increasing attention in recent years. This comprehensive review presents the recent advancements in selective electrocatalytic conversion of NO to high value-added chemicals, with specific emphasis on catalyst design, electrolyte composition, mass diffusion, and adsorption energies of key intermediate species. Furthermore, the review explores the synergistic electrochemical co-electrolysis of NO with specific carbon source molecules, enabling the synthesis of a range of valuable chemicals with C─N bonds. It also provides in-depth insights into the intricate reaction pathways and underlying mechanisms, offering valuable perspectives on the challenges and prospects of selective NO electrolysis. By advancing comprehension and fostering awareness of nitrogen cycle balance, this review contributes to the development of efficient and sustainable electrocatalytic systems for the selective synthesis of valuable chemicals from NO.

Perioperative toripalimab and chemotherapy in locally advanced gastric or gastro-esophageal junction cancer: a randomized phase 2 trial.

Perioperative chemotherapy is the standard treatment for locally advanced gastric or gastro-esophageal junction cancer, and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. In this randomized, open-label, phase 2 study (NEOSUMMIT-01), patients with resectable gastric or gastro-esophageal junction cancer clinically staged as cT3-4aN + M0 were randomized (1:1) to receive either three preoperative and five postoperative 3-week cycles of SOX/XELOX (chemotherapy group, n = 54) or PD-1 inhibitor toripalimab plus SOX/XELOX, followed by toripalimab monotherapy for up to 6 months (toripalimab plus chemotherapy group, n = 54). The primary endpoint was pathological complete response or near-complete response rate (tumor regression grade (TRG) 0/1). The results showed that patients in the toripalimab plus chemotherapy group achieved a higher proportion of TRG 0/1 than those in the chemotherapy group (44.4% (24 of 54, 95% confidence interval (CI): 30.9%-58.6%) versus 20.4% (11 of 54, 95% CI: 10.6%-33.5%)), and the risk difference of TRG 0/1 between toripalimab plus chemotherapy group and chemotherapy group was 22.7% (95% CI: 5.8%-39.6%; P = 0.009), meeting a prespecified endpoint. In addition, a higher pathological complete response rate (ypT0N0) was observed in the toripalimab plus chemotherapy group (22.2% (12 of 54, 95% CI: 12.0%-35.6%) versus 7.4% (4 of 54, 95% CI: 2.1%-17.9%); P = 0.030), and surgical morbidity (11.8% in the toripalimab plus chemotherapy group versus 13.5% in the chemotherapy group) and mortality (1.9% versus 0%), and treatment-related grade 3-4 adverse events (35.2% versus 29.6%) were comparable between the treatment groups. In conclusion, the addition of toripalimab to chemotherapy significantly increased the proportion of patients achieving TRG 0/1 compared to chemotherapy alone and showed a manageable safety profile. ClinicalTrials.gov registration: NCT04250948 .

Hydrogen sulfide attenuates atherosclerosis induced by low shear stress by sulfhydrylating endothelium NFIL3 to restrain MEST mediated endothelial mesenchymal transformation.

BACKGROUND: Endothelial-mesenchymal transition (EndMT) induced by low shear stress plays an important role in the development of atherosclerosis. However, little is known about the correlation between hydrogen sulfide (H2S), a protective gaseous mediator in atherosclerosis and the process of EndMT. METHODS: We constructed a stable low-shear-stress-induced(2 dyn/cm2) EndMT model, acombined with the pretreatment method of hydrogen sulfide slow release agent(GYY4137). The level of MEST was detected in the common carotid artery of ApoE-/- mice with local carotid artery ligation. The effect of MEST on atherosclerosis development in vivo was verified using ApoE-/- mice were given tail-vein injection of endothelial-specific overexpressed and knock-down MEST adeno-associated virus (AAV). RESULTS: These findings confirmed that MEST is up-regulated in low-shear-stress-induced EndMT and atherosclerosis. In vivo experiments showed that MEST gene overexpression significantly promoted EndMT and aggravated the development of atherosclerotic plaques and MEST gene knockdown significantly inhibited EndMT and delayed the process of atherosclerosis. In vitro, H2S inhibits the expression of MEST and EndMT induced by low shear stress and inhibits EndMT induced by MEST overexpression. Knockdown of NFIL3 inhibit the up regulation of MEST and EndMT induced by low shear stress in HUVECs. CHIP-qPCR assay and Luciferase Reporter assay confirmed that NFIL3 binds to MEST DNA, increases its transcription and H2S inhibits the binding of NFIL3 and MEST DNA, weakening NFIL3's transcriptional promotion of MEST. Mechanistically, H2S increased the sulfhydrylation level of NFIL3, an important upstream transcription factors of MEST. In part, transcription factor NFIL3 restrain its binding to MEST DNA by sulfhydration. CONCLUSIONS: H2S negatively regulate the expression of MEST by sulfhydrylation of NFIL3, thereby inhibiting low-shear-stress-induced EndMT and atherosclerosis.

Modulating Charge Separation of Oxygen-Doped Boron Nitride with Isolated Co Atoms for Enhancing CO2 -to-CO Photoreduction.

To alleviate the greenhouse effect and address the related energy crisis, solar-driven reduction of carbon dioxide (CO2 ) to value-added products is considered as a sustainable strategy. However, the insufficient separation and rapid recombination of photogenerated charge carriers during photocatalysis greatly limit their reduction efficiency and practical application potential. Here, isolated Cobalt (Co) atoms are successfully decorated into oxygen-doped boron nitride (BN) via an in situ pyrolysis method, achieving greatly improved catalytic activity and selectivity to the carbon monoxide (CO) product. X-ray absorption fine spectroscopy demonstrates that the isolated Co atoms are stabilized by the O and N atoms with an unsaturated CoO2 N1 configuration. Further experimental investigation and theoretical simulations confirm that the decorated Co atoms not only work as the real active center during the CO2 reduction process, but also perform as the electron pump to promote the electron/hole separation and transfer, resulting in greatly accelerated reaction kinetics and improved activity. In addition, the CoO2 N1 coordination geometry is favorable to the conversion from *CO2 to *COOH, which shall be considered as a selectivity-determining step for the evolution of the CO products. The surface modulation strategy at the atomic level opens a new avenue for regulating the reaction kinetics for photocatalytic CO2 reduction.

TFEB-vacuolar ATPase signaling regulates lysosomal function and microglial activation in tauopathy.

Transcription factor EB (TFEB) mediates gene expression through binding to the coordinated lysosome expression and regulation (CLEAR) sequence. TFEB targets include subunits of the vacuolar ATPase (v-ATPase), which are essential for lysosome acidification. Single-nucleus RNA sequencing of wild-type and PS19 (Tau) transgenic mice expressing the P301S mutant tau identified three unique microglia subclusters in Tau mice that were associated with heightened lysosome and immune pathway genes. To explore the lysosome-immune relationship, we specifically disrupted the TFEB-v-ATPase signaling by creating a knock-in mouse line in which the CLEAR sequence of one of the v-ATPase subunits, Atp6v1h, was mutated. CLEAR mutant exhibited a muted response to TFEB, resulting in impaired lysosomal acidification and activity. Crossing the CLEAR mutant with Tau mice led to higher tau pathology but diminished microglia response. These microglia were enriched in a subcluster low in mTOR and HIF-1 pathways and were locked in a homeostatic state. Our studies demonstrate a physiological function of TFEB-v-ATPase signaling in maintaining lysosomal homeostasis and a critical role of the lysosome in mounting a microglia and immune response in tauopathy and Alzheimer's disease.

Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 µM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.