Switching CO2 Electroreduction Pathways between Ethylene and Ethanol via Tuning Microenvironment of the Coating on Copper Nanofibers.

Engineering the microenvironment of electrode surface is one of the effective means to tune the reaction pathways in CO2RR. In this work, we prepared copper nanofibers with conductive polypyrrole coating by polymerization of pyrrole using polyvinyl pyrrolidone (PVP) as template. As a result, the obtained copper nanofibers Cu/Cu2+1O/SHNC, exhibited a superhydrophobic surface, which demonstrated very high selectivity for ethanol with a Faraday efficiency (FE) of 66.5% at -1.1 V vs reversible hydrogen electrode (RHE) in flow cell. However, the catalyst Cu/Cu2+1O/NC, which was prepared under the same conditions but without PVP, possessed a hydrophobic surface and exhibited high selectivity towards ethylene at the given potentials. The mechanism for switch of reaction pathways from ethylene to ethanol in CO2RR was studied. Incorporating pyrrolidone groups into the polymer coating results in the formation of a superhydrophobic surface. This surface weakens the hydrogen bonding interaction between interfacial water molecules and facilitates the transfer of CO2, thereby enhancing the local CO2/H2O ratio. The high coverage of *CO promotes the coupling of *CO and *CHO to form C2 intermediates, and reduces the reaction energy for the formation of *CHCHOH (ethanol path) at the interface. This ensures that the reaction pathway is directed towards ethanol.

Evidence for large-scale climate forcing of dense shelf water variability in the Ross Sea.

Antarctic Bottom Water (AABW), which supplies the lower limb of the thermohaline circulation, originates from dense shelf water (DSW) forming in Antarctic polynyas. Here, combining a long mooring record of DSW measurements with numerical simulations and satellite data, we show that significant correlation exists between interannual variability of DSW production in the Ross Sea polynyas, where DSW contributes between 20-40% of the global AABW production, and the Southern Annular Mode (SAM). The correlation is largest when the Amundsen Sea Low (ASL) is weakened and shifted east of the Ross Sea. During positive SAM phases, enhanced offshore winds and lower air temperatures over the western Ross Sea increase sea ice production and promote DSW formation, with the opposite response during negative SAM phases. These processes ultimately modulate AABW thickness in the open ocean. A projected positive shift of the SAM and eastward displacement of the ASL thus has implications for the future of DSW and AABW formation.

Dietary black soldier fly oil enhances growth performance, flesh quality, and health status of largemouth bass (Micropterus salmoides).

The study aimed to assess the effects of dietary black soldier fly oil (BSFO) on the growth performance, flesh quality, and health status of largemouth bass (Micropterus salmoides). Six iso-nitrogenous and isolipid diets were formulated by substituting fish oil and soybean oil (1/2, wt/wt) with BSFO in percentages of 0%, 20%, 40%, 60%, 80%, and 100%, respectively. The diets were fed to 960 fish (initial body weight = 16.5 g) in four replicates for 8 weeks. Indicators related to growth performance, body composition, hematology, flesh quality, expression of genes related to inflammatory cytokines and apoptosis, and the response of fish to Aeromonas veronii challenge were analyzed. The results showed that the weight gain rate was numerically improved in all BSFO substitution groups, ranging from 9.3% to 44.0% compared to the control group. The highest survival rate and the lowest hepatosomatic index and condition factor were observed in the BFSO20 group. In terms of flesh quality, the water-holding capacity of the dorsal muscle was elevated with higher levels of dietary BSFO. However, significant changes in texture properties (cohesiveness, gluing, and chewiness) were observed in the BSFO20 group (P < 0.05). Six hematological parameters related to glycolipid and liver function were optimized in most of the BFSO substitution groups. Furthermore, the expressions of six inflammation- and apoptosis-related genes (IL-1ß, Bcl-xl, BAX, caspase8, TNF-α, and IL-10) were significantly affected by dietary BSFO (P < 0.05). Following bacterial challenge, the seven-day cumulative survival rates of fish were considerably increased from 10.0% in the control group to 60.0% and 66.7% in the BSFO80 and BSFO100 groups, respectively. One-variable linear regression analysis revealed that various parameters related to fish growth, flesh quality, and health status were significantly influenced by dietary BSFO substitution levels in a dose-dependent manner (P < 0.05). In conclusion, substituting around 20% of dietary fish oil and soybean oil with BSFO is promising in improving the growth performance and flesh quality of M. salmoides. However, to enhance immunity and disease resistance, it is recommended to further increase the inclusion of BSFO in the diet.

Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.

AIMS: To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). RESULTS: GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. CONCLUSIONS: GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.

Causal Relationships Between Retinal Diseases and Psychiatric Disorders Have Implications for Precision Psychiatry.

Observational studies and clinical trials have reported potential associations between retinal diseases and psychiatric disorders. However, the causal associations between them have remained elusive. In this study, we used bi-directional two-sample Mendelian randomization (MR) analysis to explore unconfounded causal relationships between retinal diseases and psychiatric disorders using large-scale genome-wide association study (GWAS) summary statistics of over 500,000 participants of European ancestry from the FinnGen project, the Psychiatric Genomics Consortium, the European Bioinformatics Institute, and the UK Biobank. Our MR analysis revealed significant causal relationships between major retinal diseases and specific psychiatric disorders. Specifically, susceptibility to dry age-related macular degeneration was associated with a reduced risk of anorexia nervosa (OR = 0.970; 95% CI = 0.930 ~ 0.994; P = 0.025). Furthermore, we found some evidence that exposure to diabetic retinopathy was associated with an increased risk of schizophrenia (OR = 1.021; 95% CI 1.012 ~ 1.049; P = 0.001), and exposure to retinal detachments and breaks was associated with an increased risk of attention deficit hyperactivity disorder (OR = 1.190; 95% CI 1.063 ~ 1.333; P = 0.003). These causal relationships were not confounded by biases of pleiotropy and reverse causation. Our study highlights the importance of preventing and managing retinal disease as a potential avenue for improving the prevention, management and treatment of major psychiatric disorders.

In situ green architecture of the 3D FeZn-N-C based electrocatalyst for efficient oxygen reduction.

We prepared a 3D FeZn-N-C based catalyst by green in situ growth of 1D Fe-N-C carbon nanotubes by introducing ferrocyanide ions on the surface of 2D exfoliated MOF-5. The 1D/2D FeZn-N-C based electrocatalyst is conducive to O2 diffusion and ionic/electron transfer, exhibiting an excellent ORR catalytic performance and a peak power density of 294 mW cm-2 for Zn-air batteries.

The origin and morphological character evolution of the paleotropical woody bamboos.

The woody bamboos (Bambusoideae) exhibit distinctive biological traits within Poaceae, such as highly lignified culms, rapid shoot growth, monocarpic mass flowering and nutlike or fleshy caryopses. Much of the remarkable morphological diversity across the subfamily exists within a single hexaploid clade, the paleotropical woody bamboos (PWB), making it ideal to investigate the factors underlying morphological evolution in woody bamboos. However, the origin and biogeographical history of PWB remain elusive, as does the effect of environmental factors on the evolution of their morphological characters. We generated a robust and time-calibrated phylogeny of PWB using single nucleotide polymorphisms retrieved from optimized double digest restriction site associated DNA sequencing, and explored the evolutionary trends of habit, inflorescence, and caryopsis type in relation to environmental factors including climate, soil, and topography. We inferred that the PWB started to diversify across the Oligocene-Miocene boundary and formed four major clades, that is, Melocanninae, Racemobambosinae s.l. (comprising Dinochloinae, Greslanlinae, Racemobambosinae s.str. and Temburongiinae), Hickeliinae and Bambusinae s.l. (comprising Bambusinae s.str. plus Holttumochloinae). The ancestor of PWB was reconstructed as having erect habit, indeterminate inflorescence and basic caryopsis. The characters including climbing/scrambling habit, determinate inflorescence, and nucoid/bacoid caryopsis have since undergone multiple changes and reversals during the diversification of PWB. The evolution of all three traits was correlated with, and hence likely influenced by, aspects of climate, topography, and soil, with climate factors most strongly correlated with morphological traits, and soil factors least so. However, topography had more influence than climate or soil on the evolution of erect habit, whereas both factors had greater effect on the evolution of bacoid caryopsis than did soil. Our results provide novel insights into morphological diversity and adaptive evolution in bamboos for future ecological and evolutionary research.

Defense systems of soil microorganisms in response to compound contamination by arsenic and polycyclic aromatic hydrocarbons.

Arsenic and PAHs impose environmental stress on soil microorganisms, yet their compound effects remain poorly understood. While soil microorganisms possess the ability to metabolize As and PAHs, the mechanisms of microbial response are not fully elucidated. In our study, we established two simulated soil systems using soil collected from Xixi Wetland Park grassland, Hangzhou, China. The As-600 Group was contaminated with 600 mg/kg sodium arsenite, while the As-600-PAHs-30 Group received both 600 mg/kg sodium arsenite and 30 mg/kg PAHs (phenanthrene:fluoranthene:benzo[a]pyrene = 1:1:1). These systems were operated continuously for 270 days, and microbial responses were assessed using high-throughput sequencing and metagenomic analysis. Our findings revealed that compound contamination significantly promoted the abundance of microbial defense-related genes, with general defense genes increasing by 11.07 % âˆ¼ 74.23 % and specific defense genes increasing by 44.13 % âˆ¼ 55.74 %. The dominate species Rhodococcus adopts these general and specific defense mechanisms to resist compound pollution stress and gain ecological niche advantages, making it a candidate strain for soil remediation. Our study contributes to the assessment of ecological damage caused by As and PAHs from a microbial perspective and provides valuable insights for soil remediation.

Integrated immuno-transcriptomic analysis of ovarian cancer identifies a four-chemokine-dominated subtype with antitumor immune-active phenotype and favorable prognosis.

BACKGROUND: Ovarian cancer (OV) is a heterogeneous disease but has traditionally been treated as an immunologically cold malignancy. The relationship between the immune-active cancer phenotype typified by a T helper 1 (Th-1) immune response and clinical outcome in OV remains uncertain. METHODS: A cohort-scale compendium of transcriptomic data from 2850 OV samples from 19 individual datasets was compiled for integrative immuno-transcriptomic analysis. The immunological constant of rejection was used as a metric to assess the Th-1/cytotoxic response orientation and investigate the clinical-biological significance of immune polarization towards a Th-1 immune response. Single-cell RNA sequencing data from 39 OV samples were analyzed to elucidate the variability of the immune microenvironment, and immunohistochemical validation was performed on 39 samples from the Harbin Medical University Cancer Hospital. RESULTS: Our results demonstrated the prognostic significance of a Th-1/cytotoxic immune profile within the tumor microenvironment (TME) using the immunological constant of rejection classification to OV samples. Specifically, patients with tumors expressing high levels of ICR markers showed significantly improved survival. A gene panel consisting of four chemokines (CXCL9, CXCL10, CXCL11 and CXCL13) was identified as critical players in mediating the establishment of an active T-cell-inflamed antitumor phenotype. This 4-chemokine signature, which was extensively validated in external multicenter cohorts through transcriptomic profiling and in an independent in-house cohort through immunohistochemistry, introduced a novel immune classification in OV and identified a chemokine-dominated subtype associated with an active antitumor immune phenotype and favorable prognosis. Single-cell transcriptomic analysis revealed that chemokine-dominated tumors increase CXCR3 + NK and T cell recruitment to the TME primarily through the overexpression of macrophage-derived CXCL9/10/11. CONCLUSIONS: This study provides new insights into understanding immune heterogeneity within the TME and paves the way for tailoring appropriate therapeutic interventions for patients with differing immune profiles.

Chemokine receptors are required for effector T cell trafficking to GVHD tissues but not to bone marrow.

In allogeneic hematopoietic stem cell transplantation (alloSCT), alloreactive donor T cells mediate the graft-versus-leukemia (GVL) effect but also attack nonhematopoietic tissues causing graft-versus-host disease (GVHD). Reducing alloreactive T cell trafficking to GVHD target tissues while allowing their access to bone marrow (BM) and spleen, major sites of malignant hematopoiesis, is a rational strategy for reducing the GVHD risk when using alloreactive T cells as a therapeutic. Here we show that effector T cell (Teff) entry into BM and spleen in unmanipulated mice and in mice transplanted without alloreactive T cells is augmented by pertussis toxin-sensitive (PTX) chemokine receptor signaling. However, unexpectedly, in the presence of a GVH response, chemokines no longer draw T cells into BM and spleen but remain critical for their recruitment to GVHD target tissues. Consistent with this, PTX-treated Teff cells were as efficacious as untreated T cells in killing leukemia cells in BM and spleen in mice with a concurrent GVHD response. These results suggest a strategy to improve the safety of alloreactive T cell therapeutics in treating leukemias in the context of an alloSCT.

Intraglandular dissemination: a special pathological feature.

Intraglandular dissemination is an important pathological feature of thyroid cancer, yet the biological characteristics of this phenomenon remain relatively underexplored. This paper aims to provide a comprehensive overview of its biological behaviors, protein expressions, and identification methods. Several retrospective studies have found that thyroid cancers with intraglandular dissemination have higher rates of lymph node metastasis, capsule invasion, and vascular invasion, exhibiting more aggressive biological behavior. Immunohistochemistry results show abnormal expression of proteins such as FKBP5, CENPF, CX26, KIF11, PTK7, which are associated with poor prognosis in thyroid cancers with intraglandular dissemination, offering potential guidance for specific targeted therapy in the future. Moreover, adjunctive techniques including ultrasound, fine-needle aspiration, and genetic testing offer valuable support in accurately identifying these cases, facilitating moreproactive treatment and closer follow-up.

Does Tranexamic Acid Reduce Elbow Swelling and Improve Early Function Following Arthroscopic Arthrolysis? A Double-Blind Randomized Controlled Trial.

BACKGROUND: Tranexamic acid (TXA) reduces bleeding and hematoma rates in open elbow arthrolysis. However, its effects on arthroscopic elbow arthrolysis remain unclear. This study aims to evaluate the effect of TXA on elbow arthroscopic procedures and compare bleeding volume, hemarthrosis, visual analog scale (VAS) for pain, range of motion (ROM), and Mayo Elbow Performance Score (MEPS) in the early postoperative period between patients who received intra-articular TXA and those who did not. METHODS: A prospective, double-blind, randomized controlled trial enrolling 80 patients with stiff elbows who underwent arthroscopic arthrolysis was performed from January 2021 to December 2022. Intra-articularly, 1 g of TXA in 100 ml of saline or placebo (control group) was administered after the arthroscopic operation according to randomization. Parameters were recorded and compared between the groups, including bleeding volume of drainage, hemoglobin (Hgb) level, ratio of arm and forearm circumference of the surgical side to the contralateral side, grading of hematoma, VAS, ROM and MEPS within one week postoperatively. And during one year follow-up, ROM and MEPS were recorded. RESULTS: All patients enrolled in this study demonstrated significant improvements in ROM (flexion-extension) and MEPS one week postoperatively, with no significant differences observed between the two groups. Compared to the control group, the TXA group exhibited significant differences in the bleeding volume of drainage (61.45±47.7 ml vs. 89.8±47.0 ml, p=0.030) and a higher Hgb level 24 hours postoperatively (13.5±1.5 g/dL vs. 12.6±1.8 g/dL p=0.049). While the ratio of arm and forearm circumferences significantly increased 24 hours postoperatively compared to preoperative values in TXA group (1.05±0.06 vs. 1.02±0.04 and 1.02±0.06 vs. 0.98±0.04, with p=0.019 and p=0.005, respectively), this difference vanished one week postoperatively for the ratio of arm circumference. However, it persisted for the ratio of forearm circumference (1.02±0.07 vs. 0.98±0.04, p=0.003). Furthermore, there was no significant difference in MEPS, VAS or ROM between the two groups one week postoperatively. CONCLUSION: Patients with stiff elbows who underwent arthroscopic arthrolysis achieved satisfactory clinical outcomes very early postoperatively. Compared to the control group, patients who underwent arthroscopic elbow arthrolysis with intra-articular administration of TXA exhibited significantly less bleeding volume of drainage and slightly higher Hgb levels postoperatively. One week postoperatively, slightly more swelling in the upper arm region was noted in the control group compared to the TXA group. These findings suggest that the intra-articular injection of TXA after arthroscopic release for elbow stiffness may statistically reduce complications related to postoperative bleeding. However, it's clinical relevance needs further investigation.

The transcriptional landscape and clinico-biological characterization of human endogenous retroviruses in esophageal squamous cell carcinoma.

Human endogenous retroviruses (HERVs) are emerging as critical elements in host genomic regulation. Aberrant HERV transcription has been implicated in developmental and tissue-specific aging and pathological processes. In this study, we presented a comprehensive locus-specific characterization of the HERV expression landscape in esophageal squamous cell carcinoma (ESCC). We demonstrated the transcriptional diversity among patients and identified 12 clinically relevant HERVs in the SCH cohort, which were experimentally validated by Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) in the CAMS cohort. ESCC patients were stratified into three HERV-based subtypes (HERVhigh, HERVmedian and HERVlow) with distinct clinical and biological characteristics. The HERVhigh subtype was associated with worse survival, increased CD4+ T cells infiltration and decreased metabolic activity, whereas the HERVlow subtype was characterized by abundant CD8+ T cells, increased metabolic activity, and better survival. The HERV-based tumor subtyping was further robustly validated by RNA sequencing and RT-qPCR in two additional external cohorts. Our findings demonstrate the clinical significance of HERVs for tumor subtyping and prognosis, provide insights into the functional role of HERVs and a valuable resource for developing novel biomarkers and therapeutic targets in ESCC.

A novel theranostic strategy for myocardial infarction through neutralization of endogenous SO2 using an endoplasmic reticulum-targeted fluorescent probe.

Myocardial infarction (MI), one of the leading causes of death worldwide, urgently needs further understanding of the pathological process and effective therapies. SO2 in endoplasmic reticulum in several cardiovascular diseases has been reported to be particularly important. However, the role of endogenous SO2 in endoplasmic reticulum in treating myocardial infarction is still ambiguous and needs to be elucidated. Herein, we developed TPA-HI-SO2 as the first endoplasmic reticulum-targeting fluorescent agent for specific imaging and detection of sulfur dioxide derivatives both in vitro and in vivo. TPA-HI-SO2 shows a highly sensitive and selective response to SO2 derivatives over other anions in aqueous solution with a satisfactory response time and detection limit. Furthermore, TPA-HI-SO2 decreased the SO2 concentration in H9C2 cells treated with H2O2 and in an MI mouse model. Most importantly, TPA-HI-SO2 protects H9C2 cells from H2O2-induced apoptosis and obviously protects against myocardial infarction in vivo through neutralization of endogenous SO2. Taken together, we developed the first ER-targeting ratiometric fluorescent probe for endogenous SO2 with excellent biocompatibility, high selectivity and sensitivity in this paper. More importantly, we demonstrated an obvious increase of the endogenous SO2 concentration in a myocardial infarction mouse model for the first time, which suggests that neutralization of endogenous SO2 in endoplasmic reticulum could be a promising therapeutic strategy for myocardial infarction.

Evaluation of four novel non-grain protein sources completely replacing soybean meal on growth performance, serum biochemistry, amino acid transport and intestinal health of grass carp (Ctenopharyngodon idella) at different water temperatures.

To investigate the effects of non-grain protein source and water temperature on growth and feed utilization differences of grass carp, the effects of different protein sources on the growth performance, serum biochemistry, digestive enzymes, amino acid transport and intestinal health of grass carp were studied at 24 °C, 28 °C and 32 °C. In this study, a total of 1350 grass carp (Ctenopharyngodon idella) (initial weight 5.00 ± 0.02 g) were selected, and Clostridium autoethanogenum protein (CAP), Tenebrio molitor meal (TMM), cottonseed protein concentrate (CPC) and Chlorella powder (CHP) were used as a single protein source to completely replace soybean meal for 56 days. The results showed that the final body weight (FBW), weight gain rate (WGR), specific growth rate (SGR) and protein efficiency ratio (PER) of grass carp increased significantly with the increasing temperature (P < 0.001). The CHP and SBM groups showed no significant differences in FBW, WGR, SGR and PER (P > 0.05), which were higher than the CAP, TMM and CPC groups (P < 0.001). The alanine transaminase (ALT), aspartate aminotransferase (AST), total protein (TP) and triglyceride (TG) concentrations of grass carp at 32 °C were significantly lower than those at 24 °C and 28 °C (P < 0.001). The acid phosphatase (ACP) activity decreased significantly with the increase of temperature (P = 0.001). The amylase (AMS) activity of the TMM, CPC and CHP groups was significantly lower than that of the SBM and CAP groups (P < 0.001), and the ACP and lipase (LPS) activities in the TMM group were significantly lower than those in the SBM group (P < 0.001). In addition, the interaction between temperatures and protein sources significantly affected the gene expression levels of amino acid transport including solute carrier family 1 member 3 (SLC1A3), solute carrier family 7 member 1 (SLC7A1), solute carrier family 7 member 5 (SLC7A5), solute carrier family 15 member 1b (SLC15A1b), solute carrier family 7 member 7 (SLC7A7), target of rapamycin (TOR), 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1), intestinal inflammatory including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-8 (IL-8), interleukin-10 (IL-10) and tight junction proteins (occludin, claudin1, claudin3, claudin7 and claudin11) (P ≤ 0.001). Collectively, our results indicated that CHP could be a potential protein source in the case of complete replacement of soybean meal in grass carp.

Switching Reaction Pathways of CO2 Electroreduction by Modulating Cations in the Electrochemical Double Layer.

Tuning the selectivity of CO2 electroreduction reaction (CO2RR) solely by changing electrolyte is a very attractive topic. In this study, we conducted CO2RR in different aqueous electrolytes over bulk metal electrodes. It was discovered that controlled CO2RR could be achieved by modulating cations in the electrochemical double layer. Specifically, ionic liquid cations in the electrolyte significantly inhibits the hydrogen evolution reaction (HER), while yielding high Faraday efficiencies toward CO (FECO) or formate (FEformate) depending on the alkali metal cations. For example, the product could be switched from CO (FECO=97.3 %) to formate (FEformate=93.5 %) by changing the electrolyte from 0.1 M KBr-0.5 M 1-octyl-3-methylimidazolium bromide (OmimBr) to 0.1 M CsBr-0.5 M OmimBr aqueous solutions over pristine Cu foil electrode. In situ spectroscopy and theoretical calculations reveal that the ordered structure generated by the assembly of Omim+ under an applied negative potential alters the hydrogen bonding structure of the interfacial water, thereby inhibiting the HER. The difference in selectivity in the presence of different cations is attributed to the hydrogen bonding effect caused by Omim+, which alters the solvated structure of the alkali metal cations and thus affects the stabilization of intermediates of different pathways.

Sex differences in the association between plasma branched-chain amino acids and risk of ischemic stroke: A nested case-control study from China.

OBJECTIVES: The aim of this study was to investigate the prospective associations between plasma branched-chain amino acids (BCAAs) and the risk of ischemic stroke in men and women. METHODS: We conducted a nested case-control study within a community-based cohort in China. The cohort consisted of 15,926 participants in 2013-2018. A total of 321 ischemic stroke cases were identified during the follow up and individually matched with 321 controls by date of birth (±1 year) and sex. Females accounted for 55.8% (n = 358, 179 cases vs 179 controls) of the study population. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association between plasma BCAAs and ischemic stroke risk by conditional logistic regression. RESULTS: Elevated plasma isoleucine was associated with a higher risk of ischemic stroke in women. The OR for the highest compared to the lowest quartile was 2.22 (95% CI: 1.11-4.44, P trend = 0.005) after adjustment for body mass index, education attainment, smoking, hypertension, renal function, menopause and physical activity. A similar association was found for total BCAAs (adjusted OR = 2.03, 95% CI: 1.05-3.95, P trend = 0.04). In contrast, no significant association of plasma BCAAs with ischemic stroke risk was observed in men. CONCLUSIONS: Plasma isoleucine and total BCAAs were significantly associated with ischemic stroke risk in women, but not in men, highlighting sex differences in BCAAs metabolism and stroke pathogenesis.

Advancing Tumor-Targeted Chemo-Immunotherapy: Development of the CAR-M-derived Exosome-Drug Conjugate.

Traditional antibody-drug conjugates (ADCs) mainly suppress tumor growth through either chemotherapy with cytotoxic payloads or immunotherapy with immuno-modulators. However, a single therapeutic modality may limit their exploration. Herein, we developed a new type of drug conjugate termed CAR-EDC (CAR-M-derived exosome-drug conjugate) by using CAR-exosomes from CAR-M cells as the targeting drug carrier that contains a high level of CXCL10. CAR-exosomes could significantly enhance the immunological activation and migratory capacity of T lymphocytes and promote their differentiation into CD8+ T cells. It also increased the proportion of M1 macrophages. The CAR-EDC, covalently loaded with SN-38, was internalized into Raji cells through endocytosis mediated by the CAR molecules. It exerted excellent antitumor activity in vivo by virtue of not only chemotherapy by SN38 but also immunotherapy by CXCL10-mediated antitumor immunity. Generally, this study provides an exosome-drug conjugate system with enhanced antitumor effects over traditional ADCs through the synergism of chemotherapy and immunotherapy.