PLAU promotes cell proliferation and migration of head and neck cancer via STAT3 signaling pathway.

It was reported that within the head and neck cancer (HNC) cell line CAL21 the epithelial-mesenchymal transition (EMT) and cell proliferation were promoted by Urokinase-Type Plasminogen Activator (PLAU) proteinase through TNFRSF12A. Additionally, in this paper HNC cell lines refer to Fadu and Tu686. A novel PLAU-STAT3 axis was found to be involved in HNC cell line proliferation and metastasis. PLAU expression in HNC samples was upregulated, besides, the elevated expression of PLAU was linked to the lower overall survival (OS) and disease-free survival (DFS). Ectopic PLAU expression promoted cell proliferation and migration, while PLAU knockdown exhibited opposite results. RNA-seq data identified the JAK-STAT signaling pathway, confirmed by western blotting. A recovery assay using S3I-201, a selective inhibitor of signal transducer and activator of transcription 3 (STAT3), indicated that PLAU promoted HNC cell line progression via STAT3 signaling in vitro. The oncogenic role of PLAU in HNC tumor growth in vivo was confirmed using xenograft models. In summary, we identified the tumorigenic PLAU function in the HNC progress. PLAU may represent a potential prognostic biomarker of HNC and the PLAU-STAT3 pathway might be considered a therapeutic target of HNC.

Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model.

Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson's disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction. Inhibition of EHMT1/2 with the specific inhibitor A-366 or shRNA suppressed histone methylation and alleviated synaptic damage in primary neurons that were treated with PFFs. In addition, the synaptic damage and motor impairment in mice that were injected with PFFs were repressed by treatment with the EHMT1/2 inhibitor A-366. Thus, our findings reveal the role of histone H3 modification by EHMT1/2 in synaptic damage and motor impairment in a PFF animal model, suggesting the involvement of epigenetic dysregulation in PD pathogenesis.

Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy bodies (LB) in the substantia nigra (SN). Evidence shows that microglia-mediated neuroinflammation plays a key role in PD pathogenesis. Using TNF-α as an indicator for microglial activation, we established a cellular model to screen compounds that could inhibit neuroinflammation. From 2471 compounds in a small molecular compound library composed of FDA-approved drugs, we found 77 candidates with a significant anti-inflammatory effect. In this study, we further characterized pazopanib, a pan-VEGF receptor tyrosine kinase inhibitor (that was approved by the FDA for the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma). We showed that pretreatment with pazopanib (1, 5, 10 µM) dose-dependently suppressed LPS-induced BV2 cell activation evidenced by inhibiting the transcription of proinflammatory factors iNOS, COX2, Il-1ß, and Il-6 through the MEK4-JNK-AP-1 pathway. The conditioned medium from LPS-treated microglia caused mouse DA neuronal MES23.5 cell damage, which was greatly attenuated by pretreatment of the microglia with pazopanib. We established an LPS-stimulated mouse model by stereotactic injection of LPS into mouse substantia nigra. Administration of pazopanib (10 mg·kg-1·d-1, i.p., for 10 days) exerted significant anti-inflammatory and neuronal protective effects, and improved motor abilities impaired by LPS in the mice. Together, we discover a promising candidate compound for anti-neuroinflammation and provide a potential repositioning of pazopanib in the treatment of PD.

A novel interleukin-1 receptor-associated kinase 4 from blunt snout bream (Megalobrama amblycephala) is involved in inflammatory response via MyD88-mediated NF-κB signal pathway.

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a crucial role in the Toll-like receptor/IL-1R signal pathway, which mediates the downstream signal transduction involved in innate and adaptive immunity. In the present study, an IRAK4 homologue (named as MaIRAK4) from blunt snout bream (Megalobrama amblycephala) was cloned and characterized. The open reading frame (ORF) of MaIRAK4 contains 1422 nucleotides, encoding a putative protein of 473 amino acids. Protein structural analysis revealed that MaIRAK4 has an N-terminal death domain (DD) and a central kinase domain (S_TKc), similar to those of mammals and other fishes. Multiple sequence alignment demonstrated that MaIRAK4 is highly homologous with that of grass carp (97.67%). The qRT-PCR analysis showed that MaIRAK4 expressed widely in all examined tissues, including heart, liver, spleen, kidney, head-kidney, gill, intestine and muscle, with the highest expression in the liver and spleen. After stimulation with LPS, MaIRAK4 expression upregulated significantly and reached a peak at 6 h and 12 h post LPS stimulation in the spleen and head-kidney, respectively. After challenge with Aeromonas hydrophila, MaIRAK4 expression peaked at 48 h and 72 h in spleen/head-kidney and liver, respectively. These results implied that MaIRAK4 is involved in the host defense against bacterial infection. Subcellular localization analysis indicated that MaIRAK4 distributed in the cytoplasm. Co-immunoprecipitation and subcellular co-localization assay revealed that MaIRAK4 can combine with MaMyD88 through DD domain. MaIRAK4 overexpression can induce slightly the NF-κB promoter activity in HEK 293 cells. However, the activity of NF-κB promoter was dramatically enhanced after co-transfection with MaIRAK4 and MaMyD88 plasmids. The results showed that MaIRAK4 was involved in NF-κB signal pathway mediated by maMyD88. The expression level of pro-inflammatory cytokines (IL-1ß, IL-6, IL-8 and TNF-α) decreased significantly after the siRNA-mediated knockdown of MaIRAK4. Together, these results suggest that MaIRAK4 plays an important function in the innate immunity of M. amblycephala by inducing cytokines expression.

Mobilization of soil phosphate after 8 years of warming is linked to plant phosphorus-acquisition strategies in an alpine meadow on the Qinghai-Tibetan Plateau.

Phosphorus (P) is essential for productivity of alpine grassland ecosystems, which are sensitive to global warming. We tested the hypotheses that (1) mobilized 'calcium-bound inorganic P' (Ca-Pi ) is a major source of plant-available P in alpine meadows with alkaline soils after long-term warming, (2) mobilization of Ca-Pi is linked to effective plant carboxylate-releasing P-acquisition strategies under warming, and (3) the mobilization is also related to plant nitrogen (N)-acquisition. We conducted an 8-year warming experiment in an alpine meadow (4635 m above sea level) on the Qinghai-Tibetan Plateau. A significant increase in P concentration in both aboveground and belowground biomass indicates an increased mobilization and assimilation of P by plants under warming. We observed a significant decrease in Ca-Pi , no change in moderately-labile organic P, and an increase in highly resistant organic P after warming. There was no increase in phosphatase activities. Our results indicate that Ca-Pi , rather than organic P was the major source of plant-available P for alpine meadows under warming. Higher leaf manganese concentrations of sedges and forbs after warming indicate that carboxylates released by these plants are a key mechanism of Ca-Pi mobilization. The insignificant increase in Rhizobiales after warming and the very small cover of legumes show a minor role of N-acquisition strategies in solubilizing phosphate. The insignificant change in relative abundance of mycorrhizal fungi and bacteria related to P cycling after warming shows a small contribution of microorganisms to Ca-Pi mobilization. The significant increase in leaf N and P concentrations and N:P ratio of grasses and no change in sedge leaf N:P ratio reflect distinct responses of plant nutrient status to warming due to differences in P-acquisition strategies. We highlight the important effects of belowground P-acquisition strategies, especially plant carboxylate-releasing P-acquisition strategies on responses of plants to global changes in alpine meadows.

Increase in internetwork functional connectivity in the human brain with attention capture.

Attention is often extolled for its selective neural properties. Yet, when powerfully captured by a salient unexpected event, attention can give rise to a broad cascade of systemic effects for evaluating and adaptively responding to the event. Using graph theory analysis combined with fMRI, we show here that the extensive psychophysiological and cognitive changes associated with such attention capture are related to large-scale distributed changes in the brain's functional connectivity. Novel task-irrelevant "oddball" stimuli presented to subjects during the performance of a target-search task triggered an increase in internetwork functional connectivity that degraded the brain's network modularity, thereby facilitating the integration of information. Furthermore, this phenomenon habituated with repeated oddball presentations, mirroring the behavior. These functional network connectivity changes are remarkably consistent with those previously obtained with conscious target perception, thus raising the possibility that large-scale internetwork connectivity changes triggered by attentional capture and awareness rely on common neural network dynamics.NEW & NOTEWORTHY The selective properties of attention have been extensively studied. There are some circumstances in which attention can have widespread and systemic effects, however, such as when it is captured by an unexpected, salient stimulus or event. How are such effects propagated in the human brain? Using graph theory analysis of fMRI data, we show here that salient task-irrelevant events produced a global increase in the functional integration of the brain's neural networks.

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes. Recent studies suggest that changes in lysine acetylation and deacetylation of many proteins, including histones and nonhistone proteins, might be tightly associated with PD pathogenesis. Here, we summarize the changes in lysine acetylation of both histones and nonhistone proteins, as well as the related lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), in PD patients and various PD models. We discuss the potential roles and underlying mechanisms of these changes in PD and highlight that restoring the balance of lysine acetylation/deacetylation of histones and nonhistone proteins is critical for PD treatment. Finally, we discuss the advantages and disadvantages of different KAT/KDAC inhibitors or activators in the treatment of PD models and emphasize that SIRT1 and SIRT3 activators and SIRT2 inhibitors are the most promising effective therapeutics for PD.

Tyrosine hydroxylase down-regulation after loss of Abelson helper integration site 1 (AHI1) promotes depression via the circadian clock pathway in mice.

Abelson helper integration site 1 (AHI1) is associated with several neuropsychiatric and brain developmental disorders, such as schizophrenia, depression, autism, and Joubert syndrome. Ahi1 deficiency in mice leads to behaviors typical of depression. However, the mechanisms by which AHI1 regulates behavior remain to be elucidated. Here, we found that down-regulation of expression of the rate-limiting enzyme in dopamine biosynthesis, tyrosine hydroxylase (TH), in the midbrains of Ahi1-knockout (KO) mice is responsible for Ahi1-deficiency-mediated depressive symptoms. We also found that Rev-Erbα, a TH transcriptional repressor and circadian regulator, is up-regulated in the Ahi1-KO mouse midbrains and Ahi1-knockdown Neuro-2a cells. Moreover, brain and muscle Arnt-like protein 1 (BMAL1), the Rev-Erbα transcriptional regulator, is also increased in the Ahi1-KO mouse midbrains and Ahi1-knockdown cells. Our results further revealed that AHI1 decreases BMAL1/Rev-Erbα expression by interacting with and repressing retinoic acid receptor-related orphan receptor α, a nuclear receptor and transcriptional regulator of circadian genes. Of note, Bmal1 deficiency reversed the reduction in TH expression induced by Ahi1 deficiency. Moreover, microinfusion of the Rev-Erbα inhibitor SR8278 into the ventral midbrain of Ahi1-KO mice significantly increased TH expression in the ventral tegmental area and improved their depressive symptoms. These findings provide a mechanistic explanation for a link between AHI1-related behaviors and the circadian clock pathway, indicating an involvement of circadian regulatory proteins in AHI1-regulated mood and behavior.

Pharmacological activation of REV-ERBα represses LPS-induced microglial activation through the NF-κB pathway.

REV-ERBα, the NR1D1 (nuclear receptor subfamily 1, group D, member 1) gene product, is a dominant transcriptional silencer that represses the expression of genes involved in numerous physiological functions, including circadian rhythm, inflammation, and metabolism, and plays a crucial role in maintaining immune functions. Microglia-mediated neuroinflammation is tightly associated with various neurodegenerative diseases and psychiatric disorders. However, the role of REV-ERBα in neuroinflammation is largely unclear. In this study, we investigated whether and how pharmacological activation of REV-ERBα affected lipopolysaccharide (LPS)-induced neuroinflammation in mouse microglia in vitro and in vivo. In BV2 cells or primary mouse cultured microglia, application of REV-ERBα agonist GSK4112 or SR9011 dose-dependently suppressed LPS-induced microglial activation through the nuclear factor kappa B (NF-κB) pathway. In BV2 cells, pretreatment with GSK4112 inhibited LPS-induced phosphorylation of the inhibitor of NF-κB alpha (IκBα) kinase (IκK), thus restraining the phosphorylation and degradation of IκBα, and blocked the nuclear translocation of p65, a NF-κB subunit, thereby suppressing the expression and secretion of the proinflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor α (TNFα). Moreover, REV-ERBα agonist-induced inhibition on neuroinflammation protected neurons from microglial activation-induced damage, which were also demonstrated in mice with their ventral midbrain microinjected with GSK4112, and then stimulated with LPS. Our results reveal that enhanced REV-ERBα activity suppresses microglial activation through the NF-κB pathway in the central nervous system.

miR-30a can inhibit DNA replication by targeting RPA1 thus slowing cancer cell proliferation.

Cell proliferation was inhibited following forced over-expression of miR-30a in the ovary cancer cell line A2780DX5 and the gastric cancer cell line SGC7901R. Interestingly, miR-30a targets the DNA replication protein RPA1, hinders the replication of DNA and induces DNA fragmentation. Furthermore, ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) were phosphorylated after DNA damage, which induced p53 expression, thus triggering the S-phase checkpoint, arresting cell cycle progression and ultimately initiating cancer cell apoptosis. Therefore, forced miR-30a over-expression in cancer cells can be a potential way to inhibit tumour development.

Development and internal-external validation of the ATHE Scale: predicting acute large vessel occlusion due to underlying intracranial atherosclerosis prior to endovascular treatment.

OBJECTIVE: The diagnosis of intracranial atherosclerosis (ICAS) associated with large vessel occlusion (LVO) before endovascular treatment (EVT) remains a clinical challenge. This study was aimed at developing a predictive model for ICAS-LVO in the anterior circulation preceding EVT. METHODS: Patients from two national stroke centers who had undergone EVT for acute ischemic stroke in the anterior circulation were evaluated. Those from one center served as the derivation cohort, whereas patients from another center functioned as the external validation cohort. ICAS-LVO was characterized as stenosis exceeding 70% or stenosis surpassing 50% accompanied by distal blood flow disruption or recurrent occlusion evidence during the intervention. A random forest algorithm helped to identify key predictors within the derivation cohort. Utilizing these predictors, the authors formulated a logistic regression model from the derivation cohort data, and the model was then internally validated through a bootstrapping method. Subsequently, a predictive score based on this model was constructed and evaluated in both cohorts. RESULTS: Among all the patients, 470 from the derivation cohort and 147 from the external validation cohort met the inclusion criteria. After random forest regression, the key predictors of ICAS-LVO included the absence of atrial fibrillation, the presence of truncal-type occlusion, the absence of a hyperdense artery sign, and a lower baseline examination National Institutes of Health Stroke Scale (NIHSS) score (ATHE Scale). Incorporating these variables into the logistic regression model yielded an area under the curve (AUC) of 0.920 (95% CI 0.894-0.947) for ICAS-LVO prediction. After bootstrapping validation, the model produced a mean AUC of 0.915. Subsequently, the ATHE score, derived from these predictors, registered an AUC of 0.916 (95% CI 0.887-0.939, p < 0.001) in the derivation cohort and 0.890 (95% CI 0.828-0.936, p < 0.001) in the external validation cohort. CONCLUSIONS: The ATHE Scale, incorporating atrial fibrillation, truncal-type occlusion, hyperdense artery sign, and baseline examination NIHSS score, is an accurate, objective tool for predicting ICAS-LVO prior to EVT.

Solar overall water-splitting by a spin-hybrid all-organic semiconductor.

Direct solar-to-hydrogen conversion from pure water using all-organic heterogeneous catalysts remains elusive. The challenges are twofold: (i) full-band low-frequent photons in the solar spectrum cannot be harnessed into a unified S1 excited state for water-splitting based on the common Kasha-allowed S0 → S1 excitation; (ii) the H+ → H2 evolution suffers the high overpotential on pristine organic surfaces. Here, we report an organic molecular crystal nanobelt through the self-assembly of spin-one open-shell perylene diimide diradical anions (:PDI2-) and their tautomeric spin-zero closed-shell quinoid isomers (PDI2-). The self-assembled :PDI2-/PDI2- crystal nanobelt alters the spin-dependent excitation evolution, leading to spin-allowed S0S1 → 1(TT) → T1 + T1 singlet fission under visible-light (420 nm~700 nm) and a spin-forbidden S0 → T1 transition under near-infrared (700 nm~1100 nm) within spin-hybrid chromophores. With a triplet-triplet annihilation upconversion, a newly formed S1 excited state on the diradical-quinoid hybrid induces the H+ reduction through a favorable hydrophilic diradical-mediated electron transfer, which enables simultaneous H2 and O2 production from pure water with an average apparent quantum yield over 1.5% under the visible to near-infrared solar spectrum.

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice.

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.

[Study of emotion recognition under stress based on physiological signals by PSO-kNN method].

In this paper, experiments were designed for inducing neutral, terrified, excited, annoying emotions, and also low, middle, high, three levels of tension emotions of stress state, respectively. Based on the multi physiological signals generated by the subjects in emotions, such as heart rate and respiration rate and so on, we extracted features from these data which had been eliminated the baseline. Then the Particle Swarm Optimization method was adopted to optimize the features selection from the features of multi physiological signals, and combined with k-Nearest Neighbor algorithm, different emotions and varying degree tensions were classified. The result shows that the classification accuracy of the kNN method with SPO and baseline eliminated is better than the traditional kNN method.

Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the p300/NF-κB/NLRP3 pathway.

Neuroinflammation is a pathological change that is involved in the progression of Parkinson's disease. Dysfunction of chaperone-mediated autophagy (CMA) has proinflammatory effects. However, the mechanism by which CMA mediates inflammation and whether CMA affects microglia and microglia-mediated neuronal damage remain to be elucidated. In the present study, we found that LAMP2A, a limiting protein for CMA, was decreased in lipopolysaccharide (LPS)-treated primary microglia. Activation of CMA by the activator CA significantly repressed LPS-induced microglial activation, whereas CMA dysfunction exacerbated microglial activation. We further identified that the protein p300 was a substrate of CMA. Degradation of p300 by CMA reduced p65 acetylation, thereby inhibiting the transcription of proinflammatory factors and the activation of the NLRP3 inflammasome. Furthermore, CA pretreatment inhibited microglia-mediated inflammation and, in turn, attenuated neuronal death in vitro and in vivo. Our findings suggest repressive effects of CMA on microglial activation through the p300-associated NF-κB signaling pathway, thus uncovering a mechanistic link between CMA and neuroinflammation.

[An integrated system of blood pressure measurement with bluetooth communication].

The development of the integrated blood pressure system with bluetooth communication function is introduced. Experimental results show that the system can complete blood pressure measurement and data transmission wireless effectively, which can be used in m-Health in future.

Development of an organic acid compound disinfectant to control food-borne pathogens and its application in chicken slaughterhouses.

During poultry slaughter, cross-contamination of chicken carcasses with microorganisms (including drug-resistant bacteria) can occur because of incomplete disinfection during the pre-cooling process, and surface contact with contaminated tools and equipment. The use of disinfectants is the most common way to reduce the risk of cross-contamination and bacterial spread, as they can effectively reduce the number of bacteria. We developed a disinfectant consisting of organic acids and sodium dodecyl sulfate (SDS) and tested its bactericidal effects at different concentrations against Salmonella and Campylobacter. The main effective components in the disinfectant were citric acid, lactic acid, and SDS, and together they exerted a synergistic bactericidal effect. The bactericidal efficacy of the disinfectant increased with increasing concentrations of the 3 active ingredients. To reach a 100% reduction rate during a 15-s treatment in vitro, for Salmonella, the lowest concentrations of citric acid, lactic acid, and SDS were 0.06, 0.08, and 0.02%, respectively; and for Campylobacter, the lowest concentrations were 0.02, 0.025, and 0.0125%, respectively. The disinfectant remained effective in presence of interfering substances (e.g., 15% fetal bovine serum). Further experiments showed that the disinfectant inactivated sensitive bacteria as well as 23 drug-resistant strains of Salmonella and Campylobacter. Treatment with the disinfectant for 15 s decreased the concentrations of all tested strains by more than 4.7 log colony forming units per mL, and the reduction rate was as high as 100%. In on-site disinfection tests in chicken slaughterhouses, the disinfectant significantly reduced the number of pathogenic bacteria on carcasses during the pre-cooling process, and on tools (such as knives and gloves) during the segmentation process. Thus, this disinfectant has potential uses in preventing cross-contamination of food-borne pathogens (including resistant bacteria) in slaughterhouses.

Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer.

Accurate identification of molecular targets of disease plays an important role in diagnosis, prognosis, and therapies. Breast cancer (BC) is one of the most common malignant cancers in women worldwide. Thus, the objective of this study was to accurately identify a set of molecular targets and small molecular drugs that might be effective for BC diagnosis, prognosis, and therapies, by using existing bioinformatics and network-based approaches. Nine gene expression profiles (GSE54002, GSE29431, GSE124646, GSE42568, GSE45827, GSE10810, GSE65216, GSE36295, and GSE109169) collected from the Gene Expression Omnibus (GEO) database were used for bioinformatics analysis in this study. Two packages, LIMMA and clusterProfiler, in R were used to identify overlapping differential expressed genes (oDEGs) and significant GO and KEGG enrichment terms. We constructed a PPI (protein-protein interaction) network through the STRING database and identified eight key genes (KGs) EGFR, FN1, EZH2, MET, CDK1, AURKA, TOP2A, and BIRC5 by using six topological measures, betweenness, closeness, eccentricity, degree, MCC, and MNC, in the Analyze Network tool in Cytoscape. Three online databases GSCALite, Network Analyst, and GEPIA were used to analyze drug enrichment, regulatory interaction networks, and gene expression levels of KGs. We checked the prognostic power of KGs through the prediction model using the popular machine learning algorithm support vector machine (SVM). We suggested four TFs (TP63, MYC, SOX2, and KDM5B) and four miRNAs (hsa-mir-16-5p, hsa-mir-34a-5p, hsa-mir-1-3p, and hsa-mir-23b-3p) as key transcriptional and posttranscriptional regulators of KGs. Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients.

Orthorhombic Cobalt Ditelluride with Te Vacancy Defects Anchoring on Elastic MXene Enables Efficient Potassium-Ion Storage.

The fast and reversible potassiation/depotassiation of anode materials remains an elusive yet intriguing goal. Herein, a class of the P-doping-induced orthorhombic CoTe2 nanowires with Te vacancy defects supported on MXene (o-P-CoTe2 /MXene) is designed and prepared, taking advantage of the synergistic effects of the conductive o-P-CoTe2 arrays with rich Te vacancy defects and the elastic MXene sheets with self-autoadjustable function. Consequently, the o-P-CoTe2 /MXene superstructure exhibits boosted potassium-storage performance, in terms of high reversible capacity (373.7 mAh g-1 at 0.2 A g-1 after 200 cycles), remarkable rate capability (168.2 mAh g-1 at 20 A g-1 ), and outstanding long-term cyclability (0.011% capacity decay per cycle over 2000 cycles at 2 A g-1 ), representing the best performance in transition-metal-dichalcogenides-based anodes to date. Impressively, the flexible full battery with o-P-CoTe2 /MXene anode achieves a satisfying energy density of 275 Wh kg-1 and high bending stability. The kinetics analysis and first-principles calculations reveal superior pseudocapacitive property, high electronic conductivity, and favorable K+ ion adsorption and diffusion capability, corroborating fast K+ ion storage. Especially, ex situ characterizations confirm o-P-CoTe2 /MXene undergoes reversible evolutions of initially proceeding with the K+ ion insertion, followed by the conversion reaction mechanism.

General Anesthesia vs. Local Anesthesia During Endovascular Treatment for Acute Large Vessel Occlusion: A Propensity Score-Matched Analysis.

OBJECTIVE: To date, no consensus still exists on the anesthesia strategy of endovascular treatment (EVT) for acute ischemic stroke (AIS) due to large vessel occlusion (LVO). We aimed to compare the 90-day outcomes, puncture-to-recanalization time (PRT), successful recanalization rate, and symptomatic intracranial hemorrhage (sICH) of patients undergoing general anesthesia (GA) or local anesthesia (LA) ± conscious sedation (CS) during the procedure. METHODS: We selected patients from the Acute Ischemic Stroke Cooperation Group of Endovascular Treatment (ANGEL) registry and divided them into the GA group and the LA ± CS group. The two groups underwent 1:1 matching under propensity score matching (PSM) analysis. Then, we compared the primary outcome including the 90-day modified Rankin Scale (mRS) 0-2, secondary outcome including the 90-day mRS, the 90-day mRS 0-1, the 90-day mRS 0-3, PRT, and successful recanalization rate as well as the safety outcome including sICH, any ICH, and 90-day mRS 6. RESULTS: Among the 705 enrolled patients, 263 patients underwent GA and 442 patients underwent LA ± CS. After 1:1 PSM according to the baseline characteristics, each group has 216 patients. Patients with GA had the higher median 90-day mRS [3 (1-5) vs. 2 (1-4), p < 0.001], the lower 90-day mRS 0-2 rate (43.5 vs. 56.5%, p = 0.007), higher mortality (19.9 vs.10.2%, p = 0.005), and longer PRT [92 (60-140) vs. 70 (45-103) min, p < 0.001]. There were no differences in sICH and successful recanalization rate between both the groups. CONCLUSION: In the real-world setting, LA ± CS might provide more outcomes benefits than GA in patients with AIS-LVO during the procedure.