Transgenic mice lacking FGF15/19-SHP phosphorylation display altered bile acids and gut bacteria, promoting nonalcoholic fatty liver disease.

Dysregulated bile acid (BA)/lipid metabolism and gut bacteria dysbiosis are tightly associated with the development of obesity and non-alcoholic fatty liver disease (NAFLD). The orphan nuclear receptor, Small Heterodimer Partner (SHP/NR0B2), is a key regulator of BA/lipid metabolism, and its gene-regulating function is markedly enhanced by phosphorylation at Thr-58 mediated by a gut hormone, fibroblast growth factor-15/19 (FGF15/19). To investigate the role of this phosphorylation in whole-body energy metabolism, we generated transgenic SHP-T58A knock-in mice. Compared with wild-type (WT) mice, the phosphorylation-defective SHP-T58A mice gained weight more rapidly with decreased energy expenditure and increased lipid/BA levels. This obesity-prone phenotype was associated with the upregulation of lipid/BA synthesis genes and downregulation of lipophagy/ß-oxidation genes. Mechanistically, defective SHP phosphorylation selectively impaired its interaction with LRH-1, resulting in de-repression of SHP/LRH-1 target BA/lipid synthesis genes. Remarkably, BA composition and selective gut bacteria which are known to impact obesity, were also altered in these mice. Upon feeding a high-fat diet, fatty liver developed more severely in SHP-T58A mice compared to WT mice. Treatment with antibiotics substantially improved the fatty liver phenotypes in both groups but had greater effects in the T58A mice so that the difference between the groups was largely eliminated. These results demonstrate that defective phosphorylation at a single nuclear receptor residue can impact whole-body energy metabolism by altering BA/lipid metabolism and gut bacteria, promoting complex metabolic disorders like NAFLD. Since posttranslational modifications generally act in gene- and context-specific manners, the FGF15/19-SHP phosphorylation axis may allow more targeted therapy for NAFLD.

Altered dynamic amplitude of low-frequency fluctuation in individuals at high risk for Alzheimer's disease.

The brain's dynamic spontaneous neural activity is significant in supporting cognition; however, how brain dynamics go awry in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) remains unclear. Thus, the current study aimed to investigate the dynamic amplitude of low-frequency fluctuation (dALFF) alterations in patients at high risk for Alzheimer's disease and to explore its correlation with clinical cognitive assessment scales, to identify an early imaging sign for these special populations. A total of 152 participants, including 72 SCD patients, 44 MCI patients and 36 healthy controls (HCs), underwent a resting-state functional magnetic resonance imaging and were assessed with various neuropsychological tests. The dALFF was measured using sliding-window analysis. We employed canonical correlation analysis (CCA) to examine the bi-multivariate correlations between neuropsychological scales and altered dALFF among multiple regions in SCD and MCI patients. Compared to those in the HC group, both the MCI and SCD groups showed higher dALFF values in the right opercular inferior frontal gyrus (voxel P < .001, cluster P < .05, correction). Moreover, the CCA models revealed that behavioural tests relevant to inattention correlated with the dALFF of the right middle frontal gyrus and right opercular inferior frontal gyrus, which are involved in frontoparietal networks (R = .43, P = .024). In conclusion, the brain dynamics of neural activity in frontal areas provide insights into the shared neural basis underlying SCD and MCI.

Retinol dehydrogenase 12 (RDH12) knock out may cause hyperuricemia phenotype in mice.

Hyperuricemia is a chronic metabolic disease caused by purine metabolism disorder. And several gene loci and transporter proteins that associated with uric acid transport functions have been identified. Retinol Dehydrogenase 12 (RDH12), recognized for its role in safeguarding photoreceptors, and our study investigated the potential impact of Rdh12 mutations on other organs and diseases, particularly hyperuricemia. We assessed Rdh12 mRNA expression levels in various tissues and conducted serum biochemical analyses in Rdh12-/- mice. Compared with the wild type, significant alterations in serum uric acid levels and kidney-related biochemical indicators have been revealed. Then further analysis, including quantitative RT-PCR of gene expression in the liver and kidney, highlighted variations in the expression levels of specific genes linked to hyperuricemia. And renal histology assessment exposed mild pathological lesions in the kidneys of Rdh12-/- mice. In summary, our study suggests that Rdh12 mutations impact not only retinal function but also contribute to hyperuricemia and renal disease phenotypes in mice. Our finding implies that individuals with Rdh12 mutations may be prone to hyperuricemia and gout, emphasizing the significance of preventive measures and regular examinations in daily life.

Improved redox homeostasis owing to the up-regulation of one-carbon metabolism and related pathways is crucial for yeast heterosis at high temperature.

Heterosis or hybrid vigor is a common phenomenon in plants and animals; however, the molecular mechanisms underlying heterosis remain elusive, despite extensive studies on the phenomenon for more than a century. Here we constructed a large collection of F1 hybrids of Saccharomyces cerevisiae by spore-to-spore mating between homozygous wild strains of the species with different genetic distances and compared growth performance of the F1 hybrids with their parents. We found that heterosis was prevalent in the F1 hybrids at 40°C. A hump-shaped relationship between heterosis and parental genetic distance was observed. We then analyzed transcriptomes of selected heterotic and depressed F1 hybrids and their parents growing at 40°C and found that genes associated with one-carbon metabolism and related pathways were generally up-regulated in the heterotic F1 hybrids, leading to improved cellular redox homeostasis at high temperature. Consistently, genes related with DNA repair, stress responses, and ion homeostasis were generally down-regulated in the heterotic F1 hybrids. Furthermore, genes associated with protein quality control systems were also generally down-regulated in the heterotic F1 hybrids, suggesting a lower level of protein turnover and thus higher energy use efficiency in these strains. In contrast, the depressed F1 hybrids, which were limited in number and mostly shared a common aneuploid parental strain, showed a largely opposite gene expression pattern to the heterotic F1 hybrids. We provide new insights into molecular mechanisms underlying heterosis and thermotolerance of yeast and new clues for a better understanding of the molecular basis of heterosis in plants and animals.

Chimeric virus-like particles of human norovirus constructed by structure-guided epitope grafting elicit cross-reactive immunity against both GI.1 and GII.4 genotypes.

IMPORTANCE: Human norovirus (HuNoV) is highly infectious and can result in severe illnesses in the elderly and children. So far, there is no effective antiviral drug to treat HuNoV infection, and thus, the development of HuNoV vaccines is urgent. However, NoV evolves rapidly, and currently, at least 10 genogroups with numerous genotypes have been found. The genetic diversity of NoV and the lack of cross-protection between different genotypes pose challenges to the development of broadly protective vaccines. In this study, guided by structural alignment between GI.1 and GII.4 HuNoV VP1 proteins, several chimeric-type virus-like particles (VLPs) were designed through surface-exposed loop grafting. Mouse immunization studies show that two of the designed chimeric VLPs induced cross-immunity against both GI.1 and GII.4 HuNoVs. To our knowledge, this is the first designed chimeric VLPs that can induce cross-immune activities across different genogroups of HuNoV, which provides valuable strategies for the development of cross-reactive HuNoV vaccines.

Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

Exploring the induction of endometrial epithelial cell apoptosis in clinical-type endometritis in yaks through the cyt-c/caspase-3 signaling axis.

Endometritis is a significant contributor to reduced productivity in yaks in Tibet, China. The Cyt-c/Caspase-3 signaling axis plays a crucial role in the mitochondrial pathway that triggers cell apoptosis due to endogenous factors. In this study, we examined the endometrial epithelial tissue of yaks with endometritis using pathological examination, immunohistochemical analysis, TUNEL staining, qRT-PCR, and Western blot. The results indicated significant changes in the apoptotic factors of the Cyt-c/Caspase-3 signaling axis. The expression levels of Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 were significantly increased (P < 0.05), while the expression level of Bcl-2 was significantly decreased. Immunohistochemistry results revealed significant increase in Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 expression in the cytoplasm compared to the healthy group, except for Bcl-2, which showed a significant decrease. Pathological section analysis demonstrated that clinical endometritis in yaks led to structural damage, bleeding, congestion, and inflammatory cell infiltration in the endometrial epithelium. Our study findings indicated that clinical endometritis in yaks can modulate apoptosis of endometrial epithelial cells via the Cyt-c/Caspase-3 signaling pathway, resulting in different levels of damage. This research is pioneering in exploring cell apoptosis induced by clinical endometritis in yaks, offering novel insights and potential strategies for the future prevention and treatment of endometritis in yaks.

Immune profiling of patients with extranodal natural killer/T cell lymphoma treated with daratumumab.

Natural killer/T cell lymphoma (NKTCL) is a highly aggressive, heterogeneous non-Hodgkin lymphoma resulting from malignant proliferation of cytotoxic natural killer (NK) or T cells. Previous studies demonstrated variable expression of CD38 on NKTCL tumors. Daratumumab, a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, was hypothesized to be a novel therapeutic option for patients with relapsed or refractory (R/R) NKTCL. In the phase 2 NKT2001 study (ClinicalTrials.gov Identifier: NCT02927925) assessing the safety and efficacy of daratumumab, a suboptimal overall response rate was seen in R/R NKTCL patients. One patient, whose tumors did not express CD38, responded to treatment, suggesting that the immunomodulatory activities of daratumumab may be sufficient to confer clinical benefit. To understand the suboptimal response rate and short duration of response, we investigated the immune profile of NKTCL patients from NKT2001 in the context of daratumumab anti-tumor activity. Tumor tissue and whole blood were, respectively, analyzed for CD38 expression and patient immune landscapes, which were assessed via cytometry by time-of-flight (CyTOF), multiparameter flow cytometry (MPFC), clonal sequencing, and plasma Epstein-Barr virus (EBV)-DNA level measurements. Changes observed in the immune profiles of NKTCL patients from NKT2001, including differences in B and T cell populations between responders and nonresponders, suggest that modulation of the immune environment is crucial for daratumumab anti-tumor activities in NKTCL. In conclusion, these findings highlight that the clinical benefit of daratumumab in NKTCL may be enriched by B/T cell-related biomarkers.

Interlayer Potassium Single-Atom-Coordinated g-C3N4 for Significantly Boosted Visible Light Photocatalytic H2 Production.

In recent years, graphitic carbon nitride (g-C3N4) has attracted considerable attention because it includes earth-abundant carbon and nitrogen elements and exhibits good chemical and thermal stability owing to the strong covalent interaction in its conjugated layer structure. However, bulk g-C3N4 has some disadvantages of low specific surface area, poor light absorption, rapid recombination of photogenerated charge carriers, and insufficient active sites, which hinder its practical applications. In this study, we design and synthesize potassium single-atom (K SAs)-doped g-C3N4 porous nanosheets (CM-KX, where X represents the mass of KHP added) via supramolecular self-assembling and chemical cross-linking copolymerization strategies. The results show that the utilization of supramolecules as precursors can produce g-C3N4 nanosheets with reduced thickness, increased surface area, and abundant mesopores. In addition, the intercalation of K atoms within the g-C3N4 nitrogen pots through the formation of K-N bonds results in the reduction of the band gap and expansion of the visible-light absorption range. The optimized K-doped CM-K12 nanosheets achieve a specific surface area of 127 m2 g-1, which is 11.4 times larger than that of the pristine g-C3N4 nanosheets. Furthermore, the optimal CM-K12 sample exhibits the maximum H2 production rate of 127.78 µmol h-1 under visible light (λ ≥ 420 nm), which is nearly 23 times higher than that of bare g-C3N4. This significant improvement of photocatalytic activity is attributed to the synergistic effects of the mesoporous structure and K SAs doping, which effectively increase the specific surface area, improve the visible-light absorption capacity, and facilitate the separation and transfer of photogenerated electron-hole pairs. Besides, the optimal sample shows good chemical stability for 20 h in the recycling experiments. Density functional theory calculations confirm that the introduction of K SAs significantly boosts the adsorption energy for water and decreases the activation energy barrier for the reduction of water to hydrogen.

Wickerhamomyces corioli f.a., sp. nov., a novel yeast species discovered in two mushroom species.

Two yeast strains, designated as 19-39-3 and 19-40-2, obtained from the fruiting bodies of Trametes versicolor and Marasmius siccus collected in Yunwu Mountain Forest Park, PR China, have been identified as representing a novel asexual ascomycetous yeast species. From the results of phylogenetic analyses of the sequences of the D1/D2 domains of the large subunit (LSU) rRNA, small subunit (SSU) rRNA and translation elongation factor 1-α (TEF1) genes, it was determined that these strains represent a member of the genus Wickerhamomyces, with Wickerhamomyces alni and Candida ulmi as the closest relatives. The novel species exhibited 6.6 and 6.7% differences in the D1/D2 domains compared with W. alni and C. ulmi, respectively. Additionally, distinct biochemical and physiological differences were observed between the novel species and its related counterparts. No sexual reproduction was observed in these strains, leading to the proposal of the name Wickerhamomyces corioli f.a., sp. nov. for this newly discovered species.

An Organodiphosphate-Containing Polyoxoniobate Ring and Its Assembly into a Three-Dimensional Framework through Hydrogen Bonding.

In this work, a novel organodiphosphate-containing inorganic-organic hybrid polyoxoniobate (PONb) ring {(PO3CH2CH2PO3H)4Nb8O16}4- (Nb8P8) has been achieved by a one-pot hydrothermal method. The ring is constructed from a tetragonal {Nb8O36} motif and four {PO3CH2CH2PO3H} ligands. Interestingly, Nb8P8 can be joined together via K-H2O clusters {K2(H2O)4(OH)2} to form one-dimensional chains {[K2(H2O)4(OH)2]Nb8P8}n and further linked by {Cu(en)2}2+ (en = ethylenediamine) complexes, resulting in a three-dimensional supramolecular framework {[Cu(en)2]2[K2(H2O)4(OH)2]Nb8P8}·3en·H2O (1). 1 exhibits good chemical and thermal stability and has a high water vapor adsorption capacity of ≤224 cm3 g-1 (22.71 mol·mol-1) at 298 K, outperforming most of the known polyoxometalate-based materials. Impedance measurements prove that 1 can transfer protons with moderate conductivity. This study not only contributes to the structural diversity of organodiphosphate-containing PONbs and PONb rings but also provides a reference for the development of PONb-based materials with unique performance.

A visible-light-induced photosensitizer-free decarbonylative Minisci-type reaction.

This study presents a green and practical visible-light-induced photosensitizer-free decarbonylative Minisci-type reaction using aldehydes as alkyl radical precursors. The photocatalytic system exhibits a broad substrate scope and synthetically useful yields. Mechanistic experiments revealed that alkyl radicals could be generated through auto-oxidation of aldehydes under irradiation, which is a mild and effective method for achieving late-stage functionalization of N-heteroarenes. Some biologically active N-heteroarenes could be alkylated using this photocatalytic system smoothly.

Application of a circular-shaped pulsed field ablation catheter with magnetic sensors for pulmonary vein isolation: a multi-centre clinical study report.

AIMS: A few studies have reported the effect and safety of pulsed field ablation (PFA) catheters for ablating atrial fibrillation (AF), which were mainly based on basket-shaped or flower-shaped designs. However, the clinical application of a circular-shaped multi-electrode catheter with magnetic sensors is very limited. To study the efficacy and safety of a PFA system in patients with paroxysmal AF using a circular-shaped multi-electrode catheter equipped with magnetic sensors for pulmonary vein isolation (PVI). METHODS AND RESULTS: A novel proprietary bipolar PFA system was used for PVI, which utilized a circular-shaped multi-electrode catheter with magnetic sensors and allowed for three-dimensional model reconstruction, mapping, and ablation in one map. To evaluate the efficacy, efficiency, and safety of this PFA system, a prospective, multi-centre, single-armed, pre-market clinical study was performed. From July 2021 to December 2022, 151 patients with paroxysmal AF were included and underwent PVI. The study examined procedure time, immediate success rate, procedural success rate at 12 months, and relevant complications. In all 151 patients, all the pulmonary veins were acutely isolated using the studied system. Pulsed field ablation delivery was 78.4 ± 41.8 times and 31.3 ± 16.7 ms per patient. Skin-to-skin procedure time was 74.2 ± 29.8 min, and fluoroscopy time was 13.1 ± 7.6 min. The initial 11 (7.2%) cases underwent procedures with deep sedation anaesthesia, and the following cases underwent local anaesthesia. In the initial 11 cases, 4 cases (36.4%) presented transient vagal responses, and the rest were all successfully preventatively treated with atropine injection and rapid fluid infusion. No severe complications were found during or after the procedure. During follow-up, 3 cases experienced atrial flutter, and 11 cases had AF recurrence. The estimated 12-month Kaplan-Meier of freedom from arrhythmia was 88.4%. CONCLUSION: The PFA system, comprised of a circular PFA catheter with magnetic sensors, could rapidly achieve PVI under three-dimensional guidance and demonstrated excellent safety with comparable effects.

Tumor budding is an optimal indictor of occult cervical metastasis in clinical early-stage buccal mucosa squamous cell carcinoma.

BACKGROUND: Buccal mucosa squamous cell carcinoma (BMSCC) is an aggressive disease. This study investigated the clinicopathological significance of tumor budding (TB), depth of invasion (DOI), and mode of invasion (MOI) on occult cervical metastasis (CM) of BMSCC. METHODS: Seventy-one cT1-2N0 BMSCC patients were included in this retrospective study. TB, DOI, MOI, and other clinicopathological features were reviewed. Risk factors for occult CM, locoregional recurrence-free survival (LRRFS), and overall survival (OS) were analyzed using logistic regression and Cox's proportional hazard models, respectively. RESULTS: Multivariate analysis with the logistic regression model revealed that MOI, DOI, and TB were significantly associated with occult CM in early-stage BMSCC after adjusting for variates. However, multivariate analysis with the Cox's proportional hazard model found only TB to be a prognostic factor for LRRFS (hazard ratio 15.03, 95% confidence interval [CI] 1.94-116.66; p = 0.01; trend test p = 0.03). No significant association was found between MOI, DOI, or TB and OS. CONCLUSIONS: The optimal predictor of occult CM and prognosis of early-stage BMSCC is TB, which may assist clinicians in identifying patients at high risk of cervical metastasis.

Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode.

In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-11) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-12) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 (D-12) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods. Electrochemical biosensors were obtained through the immobilization of ctDNA, G-quadruplexes, poly(dG), and poly(dA), respectively, on the clean surface of GCE. After the incubation of biosensors with D-11 or D-12, the peaks of dGuo and dAdo decreased prominently, and the peak of 8-oxoGua appeared at +0.50 V, suggesting that the interaction between D-11 (D-12) and DNA could result in the oxidative damage of guanine. Unexpected, the as-prepared DNA biosensor possessed satisfactory anti-interference property and good practicability in real samples. UV-vis and fluorescence spectra, and gel electrophoresis assays were employed to further confirm the intercalation mode of D-11 (D-12) towards DNA base pairs. Moreover, D-11 was proved to exhibit stronger anti-proliferation activity than mitionafide and amonafide against both A549 and HeLa cell lines.

Genome sequence of the progenitor of wheat A subgenome Triticum urartu.

Triticum urartu (diploid, AA) is the progenitor of the A subgenome of tetraploid (Triticum turgidum, AABB) and hexaploid (Triticum aestivum, AABBDD) wheat1,2. Genomic studies of T. urartu have been useful for investigating the structure, function and evolution of polyploid wheat genomes. Here we report the generation of a high-quality genome sequence of T. urartu by combining bacterial artificial chromosome (BAC)-by-BAC sequencing, single molecule real-time whole-genome shotgun sequencing 3 , linked reads and optical mapping4,5. We assembled seven chromosome-scale pseudomolecules and identified protein-coding genes, and we suggest a model for the evolution of T. urartu chromosomes. Comparative analyses with genomes of other grasses showed gene loss and amplification in the numbers of transposable elements in the T. urartu genome. Population genomics analysis of 147 T. urartu accessions from across the Fertile Crescent showed clustering of three groups, with differences in altitude and biostress, such as powdery mildew disease. The T. urartu genome assembly provides a valuable resource for studying genetic variation in wheat and related grasses, and promises to facilitate the discovery of genes that could be useful for wheat improvement.

Nakazawaea tricholomae f.a., sp. nov., a Novel Ascomycetous Yeast Species Isolated from Two Mushroom Species in China.

Two yeast strains designated as 20-27-1 and 20-28 were isolated from the fruiting bodies of Tricholoma gambosum and Marasmius maximus, respectively, which were collected in Wudaogou, Weichang county, Chengde area, Hebei Province, China. The multi-locus analysis of the sequences of the rDNA ITS, D1/D2 LSU, and SSU regions, together with partial sequences of two protein-coding genes RPB1 and TEF1 indicates that the two strains are closely related to Nakazawaea ernobii and Nakazawaea holstii, showing the similarity values of 99.3-98.7%, 97.2-97.1%, 91.9-92.5%, and 84.6% in D1/D2 LSU, ITS, TEF1, and RPB1, respectively. Physiologically, the two strains are different from N. ernobii and N. holstii in the assimilation of melibiose, inulin, and DL-lactic acid. Both the phenotypic and phylogenetic analyses indicate that those two strains represent a novel species in the genus Nakazawaea, for which the name Nakazawaea tricholomae f.a., sp. nov. (Fungal Names: FN 571492) is proposed.

lncRNA SYTL5-OT4 promotes vessel co-option by inhibiting the autophagic degradation of ASCT2.

AIMS: Vessel co-option is responsible for tumor resistance to antiangiogenic therapies (AATs) in patients with colorectal cancer liver metastasis (CRCLM). However, the mechanisms underlying vessel co-option remain largely unknown. Herein, we investigated the roles of a novel lncRNA SYTL5-OT4 and Alanine-Serine-Cysteine Transporter 2 (ASCT2) in vessel co-option-mediated AAT resistance. METHODS: SYTL5-OT4 was identified by RNA-sequencing and verified by RT-qPCR and RNA fluorescence in situ hybridization assays. The effects of SYTL5-OT4 and ASCT2 on tumor cells were investigated by gain- and loss-of-function experiments, and those of SYTL5-OT4 on ASCT2 expression were analyzed by RNA immunoprecipitation and co-immunoprecipitation assays. The roles of SYTL5-OT4 and ASCT2 in vessel co-option were detected by histological, immunohistochemical, and immunofluorescence analyses. RESULTS: The expression of SYTL5-OT4 and ASCT2 was higher in patients with AAT-resistant CRCLM. SYTL5-OT4 enhanced the expression of ASCT2 by inhibiting its autophagic degradation. SYTL5-OT4 and ASCT2 promoted vessel co-option by increasing the proliferation and epithelial-mesenchymal transition of tumor cells. Combination therapy of ASCT2 inhibitor and antiangiogenic agents overcame vessel co-option-mediated AAT resistance in CRCLM. CONCLUSION: This study highlights the crucial roles of lncRNA and glutamine metabolism in vessel co-option and provides a potential therapeutic strategy for patients with AAT-resistant CRCLM.

The role and mechanism of miR-425-3p regulating neuronal pyroptosis -mediated inorganic arsenic-induced generalized anxiety disorder.

Pyroptosis plays a critical role in the pathogenesis of mental disorders. However, its specific role and mechanism in arsenic (As)-induced generalized anxiety disorder (GAD) remain elusive. We utilized the data from CtdBbase, Phenopedia and DisGeNet to analyze genes that interact with arsenic poisoning and GAD. Subsequently KEGG and GO enrichment analysis were conducted to preliminatively predict the mechanism of inorganic arsenic-induced GAD. Male Wistar rats were administered water containing NaAsO2 (50, 100 µg/L) to evaluate GAD-like behavior through open field test and elevated plus maze. The expression of differential miRNAs including miR-425-3p, and pyroptosis in the prefrontal cortex of rats were detected. Furthermore, SKNSH cells were stimulated with NaAsO2 to examine the molecular changes, and then miR-425-3p mimic was transfected into SKNSH cells to detect pyroptosis in order to verify the function of miR-425-3p. Inorganic arsenic was confirmed to induce GAD-like behavior in rats, characterized by decreased locomotor activity and exploratory activities. Rats with inorganic arsenic-induced GAD exhibited reduced miR-425-3p expression levels in the prefrontal cortex and increased expression of pyroptosis-related proteins, including NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Treating with different concentrations of NaAsO2 showed that inorganic arsenic exposure downregulates miR-425-3p expression in SKNSH cells and upregulates the expression levels of pyroptosis-related proteins. Dual-luciferase reporter gene experiments demonstrated that miR-425-3p targets the NFKB1. Overexpressing miR-425-3p reversed the inorganic arsenic-induced pyroptosis in SKNSH cells by inhibiting the expression of NF-κB, NLRP3, Caspase-1, GSDMD, IL-1ß, and IL-18. Our findings suggest that inorganic arsenic exposure may induce GAD-like behavior in rats by downregulating miR-425-3p in prefrontal cortex, which targets NF-κB and regulates pyroptosis in neuronal cells.

Spatially and temporally understanding dynamic solid-electrolyte interfaces in carbon dioxide electroreduction.

The ubiquity of solid-liquid interfaces in nature and the significant role of their atomic-scale structure in determining interfacial properties have led to intensive research. Particularly in electrocatalysis, however, a molecular-level picture that clearly describes the dynamic interfacial structures and organizations with their correlation to preferred reaction pathways in electrochemical reactions remains poorly understood. In this review, CO2 electroreduction reaction (CO2RR) is spatially and temporally understood as a result of intricate interactions at the interface, in which the interfacial features are highly relevant. We start with the discussion of current understandings and model development associated with the charged electrochemical interface as well as its dynamic landscape. We further highlight the interactive dynamics from the interfacial field, catalyst surface charges and various gradients in electrolyte and interfacial water structures at interfaces under CO2RR working conditions, with emphasis on the interfacial-structure dependence of catalytic reactivity/selectivity. Significantly, a probing energy-dependent "in situ characterization map" for dynamic interfaces based on various complementary in situ/operando techniques is proposed, aiming to present a comprehensive picture of interfacial electrocatalysis and to provide a more unified research framework. Moreover, recent milestones in both experimental and theoretical aspects to establish the correct profile of electrochemical interfaces are stressed. Finally, we present key scientific challenges with related perspectives toward future opportunities for this exciting frontier.