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Celastrol is an active compound from the root of Tripterygium wilfordii Hook F that shows great potential in the treatment of inflammation, cancer, neurodegeneration, diabetes, and obesity. However, the clinical application of celastrol has been hindered by its low bioavailability and severe systemic toxicity. The aim of this review was to discuss the druggability, molecular targets, and nanocarrier delivery of the natural triterpenoid, celastrol, against chronic diseases. We sequentially investigated the physicochemical properties of celastrol using online tools (pkCSM and SwissADME), reviewed the recent studies on the molecular mechanisms underlying the therapeutic effects of celastrol, and examined the potential of nanoparticle-mediated delivery systems for safe and effective delivery of celastrol. The cancer-related targets and pathways involved were further predicted through network pharmacologic analysis. This review provides molecular insights into the pharmacologic activities and molecular mechanisms underlying celastrol, as well as useful information for the selection of nanocarrier drug delivery system for the clinical delivery of celastrol against various chronic diseases.

Although gastrointestinal stromal tumors (GISTs) has been reported in patients of all ages, its diagnosis is more common in elders. The two most common types of mutation, receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor a (PDGFRA) mutations, hold about 75 and 15% of GISTs cases, respectively. Tumors without KIT or PDGFRA mutations are known as wild type (WT)-GISTs, which takes up for 15% of all cases. WT-GISTs have other genetic alterations, including mutations of the succinate dehydrogenase and serine–threonine protein kinase BRAF and neurofibromatosis type 1. Other GISTs without any of the above genetic mutations are named “quadruple WT” GISTs. More types of rare mutations are being reported. These mutations or gene fusions were initially thought to be mutually exclusive in primary GISTs, but recently it has been reported that some of these rare mutations coexist with KIT or PDGFRA mutations. The treatment and management differ according to molecular subtypes of GISTs. Especially for patients with late-stage tumors, developing a personalized chemotherapy regimen based on mutation status is of great help to improve patient survival and quality of life. At present, imatinib mesylate is an effective first-line drug for the treatment of unresectable or metastatic recurrent GISTs, but how to overcome drug resistance is still an important clinical problem. The effectiveness of other drugs is being further evaluated. The progress in the study of relevant mechanisms also provides the possibility to develop new targets or new drugs.

Abstract Electrocatalysis holds the key to enhancing the efficiency and cost-effectiveness of water splitting devices, thereby contributing to the advancement of hydrogen as a clean, sustainable energy carrier. This study focuses on the rational design of Ru nanoparticle catalysts supported on TiN (Ru NPs/TiN) for the hydrogen evolution reaction in alkaline conditions. The as designed catalysts exhibit a high mass activity of 20 A mg−1 Ru at an overpotential of 63 mV and long-term stability, surpassing the present benchmarks for commercial electrolyzers. Structural analysis highlights the effective modification of the Ru nanoparticle properties by the TiN substrate, while density functional theory calculations indicate strong adhesion of Ru particles to TiN substrates and advantageous modulation of hydrogen adsorption energies via particle-support interactions. Finally, we assemble an anion exchange membrane electrolyzer using the Ru NPs/TiN as the hydrogen evolution reaction catalyst, which operates at 5 A cm−2 for more than 1000 h with negligible degradation, exceeding the performance requirements for commercial electrolyzers. Our findings contribute to the design of efficient catalysts for water splitting by exploiting particle-support interactions.

Abstract Remarkable advances in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells (hPSCs). Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into staged differentiation. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 and the requirement for EphB3/4 signaling in eliciting cell budding morphogenesis. Using this new approach, we model Mitchell-Riley syndrome with RFX6 knockout hPSCs illustrating unexpected morphogenesis defects in the differentiation towards islet cells. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.

Regulated cell death (RCD) is a controlled form of cell death orchestrated by one or more cascading signaling pathways, making it amenable to pharmacological intervention. RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis, facilitating development, and modulating immunity. Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival. Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse, comparable to apoptosis. Moreover, they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs. With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines, a growing number of small-molecule compounds targeting single or multiple pathways have been discovered, providing novel strategies for current cancer therapy. In this review, we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines, mainly including autophagy-dependent cell death, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition (MPT)-driven necrosis, entotic cell death, NETotic cell death, lysosome-dependent cell death, and immunogenic cell death (ICD). Furthermore, we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds. In brief, these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines, ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.

The sub-health state refers to a transitional condition between optimal health and disease, impacting physical, psychological, and social well-being. In this 42-day human intervention trial, we investigated the effects of two pasteurized fermented milks on sub-health symptoms. These pasteurized fermented milks shared the same starter culture and probiotic strains (Lacticaseibacillus paracasei PC-01, Lactiplantibacillus plantarun Lp-6, Lactobacillus helveticus H9, and Bifidobacterium animalis subsp. lactis Probio-M8), differing only in the presence of inulin. Qualified subjects were randomly assigned to the probiotic group (received milk without inulin; n = 49 or synbiotic group (received milk with inulin; n = 51). Outcome measures included Sub-Health Measurement Scale (SHMS) and Pittsburgh Sleep Quality Index (PSQI) scores, fecal metagenomes, metabolomes, and short-chain fatty acids, and serum neurotransmitter levels at baseline, after a 4-week intervention (day 28), and a 2-week-follow-up period (day 42). Our results showed that both pasteurized fermented milks improved sleep quality and alleviated sub-health symptoms, with no significant added benefit from inulin. Fecal metagenome analysis revealed post-interventional changes in gut microbial composition, including increased Bifidobacterium longum and decreased potentially pro-inflammatory bacteria (Blautia sp. and Dorea sp.). Changes in Blautia sp. and B. longum correlated significantly with SHMS and PSQI scores, respectively. Fecal and serum metabolite analysis showed post-interventional modulation of fecal short-chain fatty acids, anti-inflammatory bioactive metabolites, and serum neurotransmitters such as gamma-aminobutyric and serotonin hydrochloride. In conclusion, pasteurized fermented milk intake alleviated sub-health symptoms, affected the gut microbiome, metabolome, and serum metabolites. These findings highlight the potential of pasteurized fermented milk for mitigating sub-health conditions.

Major depressive disorder (MDD) and bipolar disorder (BD) are two of the most prevalent mood disorders that seriously jeopardize both physical and mental health. The current diagnosis of MDD and BD relies primarily on clinical symptoms. However, correctly differentiating between MDD and BD during depressive episode states remains a substantial clinical challenge. The human gut hosts a large and diverse microbiota, which plays a pivotal role in various physiological processes. Emerging evidence suggests that the gut microbiota (GM) exerts beneficial effects on mental health disorders, including MDD, BD, and schizophrenia, through the microbe-gut-brain axis (MGBA). In recent years, the relationship between GM and mood disorders has garnered considerable attention, leading to intensive research in this area. The MGBA is a bidirectional communication system between the gut and the brain. Growing evidence indicates that the brain can influence the GM, which in turn may modulate the brain through this axis. This review aims to explore the changes in the GM of patients with MDD and BD and evaluate the effects of different treatments on their GM, including medication, probiotic, prebiotic and synbiotic interventions, and fecal microbiota transplantation (FMT). By doing so, we seek to identify potential disease-specific biomarkers, improve differential diagnosis, and offer novel therapeutic avenues for these disorders.

Hypobaric hypoxia causes altitude sickness and significantly affects human health. As of now, focusing on rats different proteomic and metabolic changes exposed to different hypoxic times at extreme altitude is blank. Our study integrated in vivo experiments with tandem mass tag (TMT)- and gas chromatography time-of-flight (GC-TOF)-based proteomic and metabolomic assessments, respectively. Male Sprague-Dawley rats were exposed to long-term constant hypoxia for 40 days or short-term constant hypoxia for three days, and their responses were compared with those of a normal control group. Post-hypoxia, serum marker assays related to lipid metabolism revealed significant increases in the levels of low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC) in the liver. In contrast, high-density lipoprotein (HDL) levels were upregulated in the long-term constant hypoxia cohorts and were significantly reduced in the short-term constant hypoxia cohorts. Furthermore, metabolic pathway analysis indicated that glycerolipid and glycerophospholipid metabolisms were the most significantly affected pathways in long-term hypoxia group. Subsequently, RT-qPCR analyses were performed to corroborate the key regulatory elements, including macrophage galactose-type lectin (MGL) and Fatty Acid Desaturase 2 (FADS2). The results of this study provide new information for understanding the effects of different hypobaric hypoxia exposure protocols on protein expression and metabolism in low-altitude animals.

Summary: Background: Previous conventional epidemiological studies found a J-shape relationship between alcohol consumption and dementia, but this result was subject to confounding biases and reverse causation. Therefore, we aimed to investigate the potential linear or non-linear causal association between alcohol consumption and the incident risk of dementia in current drinkers. Methods: This study used data from the UK Biobank to investigate the relationship between alcohol consumption and dementia risk. 313,958 White British current drinkers, who were free of dementia during 2006–2010, were followed up until 2021. Alcohol consumption was self-reported and calculated according to the National Health Service guideline. The primary outcome was all-cause dementia identified through hospital and mortality records. We used multivariable Cox models with restricted cubic splines for conventional analysis and both non-linear and linear Mendelian Randomization (MR) analyses to assess causal relationships, employing a genetic score based on 95 SNPs identified from a meta-genome-wide association study of 941,280 people from Europe. Findings: 313,958 current drinkers consumed an average of 13.6 [IQR: 7.1–25.2] units/week alcohol (men averaged 20.2 [11.1–33.9] units/week and women 9.5 [5.3–16.7] units/week). During a mean follow-up of 13.2 years, 5394 (1.7%) developed dementia. Multivariable Cox model with restricted cubic spline functions identified a J-shaped relationship between alcohol consumption and dementia risk, with the lowest risk at 12.2 units/week. The non-linear MR failed to identify a significant non-linear causal relationship (p = 0.45). Both individual-level (HR: 2.22 95%CI [1.06–4.66]) and summary-level (1.89 [1.53–2.32]) linear MR analyses indicated that higher genetically predicted alcohol consumption increased dementia risk. Interpretation: This study identified a positive linear causal relationship between alcohol consumption and dementia among current drinkers. The J-shaped association found in conventional epidemiological analysis was not supported by non-linear MR analyses. Our findings suggested that there was no safe level of alcohol consumption for dementia. Funding: The Shenzhen Science and Technology Program and the Strategic Priority Research Program of Chinese Academy of Sciences.

Abstract Deploying static wireless sensor nodes is prone to network coverage gaps, resulting in poor network coverage. In this paper, an attempt is made to improve the network coverage by moving the locations of the nodes. A surrogate-assisted sine Phasmatodea population evolution algorithm (SASPPE) is used to evaluate the network coverage. A $$50 \times 50$$ 50 × 50 hill simulation environment was tested for the number of nodes of 30 and 40 and radii of 3, 5 and 7, respectively. The results show that the SASPPE algorithm has the highest coverage, which can be up to 23.624% higher than the PPE algorithm, and up to 5.196% higher than the PPE algorithm, ceteris paribus. The SASPPE algorithm mixes the GSAM with LSAMs, which balances the computational cost of the algorithm and the algorithm’s ability to find optimal results. The use of hierarchical clustering enhances the stable type of the LSAMs. In addition, LSAMs are easy to fall into local optimality when they are modeled with local data, and the use of sine Phasmatodea population evolution algorithm (Sine-PPE) for searching in LSAMs alleviates the time for the algorithm to fall into local optimality. On 30D, 50D, and 100D, the proposed algorithm was tested by 7 test functions. The results show that the algorithm has significant advantages on most functions.

Abstract Background Estimated plasma volume status (ePVS) estimated by the Duarte formula is associated with clinical outcomes in patients with heart failure. It remains unclear the predictive value of the ePVS to the postoperative hypotension (POH) in percutaneous intramyocardial septal radiofrequency ablation (PIMSRA) treating hypertrophic obstructive cardiomyopathy (HOCM). Methods Data of HOCM patients who underwent PIMSRA were retrospectively collected. Preoperative ePVS was calculated using the Duarte formulas which derived from hemoglobin and hematocrit ratios. Clinical variables including physical assessment, biological and echocardiographic parameters were recorded. Patients were labeled with or without POH according to the medical record in the hospital. Univariable and multivariable logistic regression were performed to evaluate the association between ePVS and POH. Using different thresholds derived from quartiles and the best cutoff value of the receiver operating characteristic curve, the diagnostic performance of ePVS was quantified. Results Among the 405 patients included in this study, 53 (13.1%) patients were observed with symptomatic POH. Median (IQR) of ePVS in overall patients was 3.77 (3.27~4.40) mL/g and in patients with POH were higher than those without POH. The ePVS was associated with POH, with the odds ratio of 1.669 (95% CI 1.299 ~ 2.144) per mL/g. After adjusted by potential confounders, ePVS remained independently associated with POH, with the approximate odds ratio in different models. Conclusion The preoperative ePVS derived from the Duarte formulas was independently associated with postoperative hypotension in HOCM patients who underwent PIMSRA and showed prognostic value to the risk stratification of postoperative management. Trial registration NCT06003478 (22/08/2023).

Abstract With the booming fields of computer vision and natural language processing, cross‐modal intersections such as visual question answering (VQA) have become very popular. However, several studies have shown that many VQA models suffer from severe language prior problems. After a series of experiments, the authors found that previous VQA models are in an unstable state, that is, when training is repeated several times on the same dataset, there are significant differences between the distributions of the predicted answers given by the models each time, and these models also perform unsatisfactorily in terms of accuracy. The reason for model instability is that some of the difficult samples bring serious interference to model training, so we design a method to measure model stability quantitatively and further propose a method that can alleviate both model imbalance and instability phenomena. Precisely, the question types are classified into simple and difficult ones different weighting measures are applied. By imposing constraints on the training process for both types of questions, the stability and accuracy of the model improve. Experimental results demonstrate the effectiveness of our method, which achieves 63.11% on VQA‐CP v2 and 75.49% with the addition of the pre‐trained model.

ABSTRACTNeurensin-2 (NRSN2) performs a pro-carcinogenic function in multiple cancers. However, the function of NRSN2 in HPV-infected laryngeal carcinoma (LC) remains unclear. HPV transfection was performed in LC cells. The mRNA and protein levels were monitored using RT-qPCR, immunoblotting, and IF. Cell viability and proliferation were found using the CCK-8 assay and Edu staining. Cell invasion, migration, and apoptosis were probed using the Transwell, wound healing, and flow cytometry, respectively. The autophagosome was observed using TEM. NRSN2 was overexpressed in HPV-transfected LC cells. Inhibition of NRSN2 restrained the autophagy and malignant behavior of HPV-transfected LC cells. Meanwhile, the inhibition of AMPK/ULK1 pathway limited the increased autophagy of HPV-transfected LC cells caused by NRSN2 overexpression. Furthermore, NRSN2 knockdown inhibits autophagy by suppressing AMPK/ULK1 pathway, thereby restraining the malignant behavior of HPV-transfected LC cells. Our research confirmed that HPV transfection increased the autophagy and malignant behavior of LC cells by regulating the NRSN2-mediated activation of the AMPK/ULK1 pathway, offering a new target for cure of LC.

IntroductionEsophagectomy patients who experience unplanned ICU admission (UIA) may experience a heavier economic burden and worse clinical outcomes than those who experience routine intensive care unit (ICU) admission. The aim of this study was to identify the risk factors for postoperative UIA in patients who underwent esophagectomy.MethodsWe retrospectively included patients with esophageal cancer who underwent esophagectomy. The characteristics of postoperative UIA were described, and univariable and multivariable analyses were performed based on the logistic regression model. Furthermore, a recursive partitioning analysis was adopted to stratify the patients according to the risk of UIA.ResultsA total of 628 patients were included in our final analysis, among whom 57 (9.1%) had an UIA. The patients in the UIA cohort had a higher rate of in-hospital mortality (P

With the advancing comprehension of immunology, an increasing number of immunotherapies are being explored and implemented in the field of cancer treatment. The cGAS-STING pathway, a crucial element of the innate immune response, has been identified as pivotal in cancer immunotherapy. We evaluated the antitumor effects of Schisandra chinensis lignan component Schisandrin C (SC) in 4T1 and MC38 tumor-bearing mice, and studied the enhancing effects of SC on the cGAS-STING pathway and antitumor immunity through RNA sequencing, qRT-PCR, and flow cytometry. Our findings revealed that SC significantly inhibited tumor growth in models of both breast and colon cancer. This suppression of tumor growth was attributed to the activation of type I IFN response and the augmented presence of T cells and NK cells within the tumor. Additionally, SC markedly promoted the cGAS-STING pathway activation induced by cisplatin. In comparison to cisplatin monotherapy, the combined treatment of SC and cisplatin exhibited a greater inhibitory effect on tumor growth. The amplified chemotherapeutic efficacy was associated with an enhanced type I IFN response and strengthened antitumor immunity. SC was shown to reduce tumor growth and increase chemotherapy sensitivity by enhancing the type I IFN response activation and boosting antitumor immunity, which enriched the research into the antitumor immunity of S. chinensis and laid a theoretical basis for its application in combating breast and colon cancer.

BackgroundTracheal, Bronchus, and Lung (TBL) cancer continues to represent the majority of cancer-related incidence and mortality in United States (U.S.). While air pollutants are considered essential risk factors, both global and national average concentrations of major harmful air pollutants have significantly decreased over the decades. Green space may have a beneficial effect on human health.MethodsWe obtained data on national and state-level burden of TBL cancer, the annual average concentration of main air pollutants, and levels of green spaces in 2007, 2013, and 2019. According to generalized estimating equation (GEE), we examine the associations among incidence and mortality of TBL cancer, air pollutants, and greenspaces, represented by the Normalized Difference Vegetation Index (NDVI) in different age groups with models adjusted with meteorological, and socio-demographic. We observed additional effects of the interaction between the NDVI, Ozone, PM2.5, and other factors, which helped us to interpret and understand our results. Also, we collated states that witnessed net increments in forest coverage and conducted the same analysis separately.ResultsIn our analysis, the majority of associations between NDVI and air pollutants with TBL cancer remained significantly positive, particularly noticeable among individuals aged 20 to 54. However, our findings did not explore air pollution as a potential mediator between greenspace exposure and TBL cancer. While the associations of PM2.5 with TBL cancer remained positive, the other four pollutants showed positive but statistically insignificant associations. Our interaction analysis yielded that there were positive associations between NDVI and ozone, PM2.5, and tobacco use. Max NDVI acts as a protective factor along with high HDI. Additionally, PM2.5 and HDI also showed a negative association. In 18 states with more forest, NDVI acts as a protective factor along with higher health care coverage, better health status, and participation in physical activities.ConclusionIn the state-level of U.S., the effects of total greenspace with TBL cancer are mixed and could be modified by various socio-economic factors. PM2.5 has a direct correlation with TBL cancer and the effects can be influenced by underlying socioeconomic conditions.

BackgroundPrevious studies have yielded varying conclusions regarding the impact of single-patient room design on nosocomial infection in the intensive care unit (ICU). We aimed to examine the impact of ICU single-patient room design on infection control.MethodsWe conducted a comprehensive search of PubMed, Embase, the Cochrane Library, Web of Science, CNKI, WanFang Data, and CBM databases from inception to October 2023, without language restrictions. We included observational cohort and quasi-experimental studies assessing the effect of single- versus multi-patient rooms on infection control in the ICU. Outcomes measured included the nosocomial infection rate, incidence density of nosocomial infection, nosocomial colonization and infection rate, acquisition rate of multidrug-resistant organisms (MDROs), and nosocomial bacteremia rate. The choice of effect model was determined by heterogeneity.ResultsOur final analysis incorporated 12 studies involving 12,719 patients. Compared with multi-patient rooms in the ICU, single-patient rooms demonstrated a significant benefit in reducing the nosocomial infection rate (odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.59, 0.79; p

Ethnopharmacological relevance:G. uralensis Fisch. (Glycyrrhiza uralensis) is an ancient and widely used traditional Chinese medicine with good efficacy in clearing heat and detoxifying action. Studies suggest that Glycyrrhiza Uralensis Polysaccharides (GUP), one of the major components of G. uralensis, has anti-inflammatory, anti-cancer and hepatoprotective effects., but its exact molecular mechanism has not been explored in depth.Aim of the study: Objectives of our research are about exploring the anti-inflammatory role of GUP and the mechanisms of its action.Materials and methods: ELISA kits, Western blotting, immunofluorescence, quantitative real-time PCR, immunoprecipitation and DMXAA-mediated STING activation mice models were performed to investigate the role of GUP on the cGAS-STING pathway. To determine the anti-inflammatory effects of GUP, cecal ligation and puncture (CLP) sepsis models were employed.Results: GUP could effectively inhibit the activation of the cGAS-STING signaling pathway accompany by a decrease the expression of type I interferon-related genes and inflammatory factors in BMDMs, THP-1, and human PBMCs. Mechanistically, GUP does not affect the oligomerization of STING, but affects the interaction of STING with TBK1 and TBK1 with IRF3. Significantly, GUP had great therapeutic effects on DMXAA-induced agonist experiments in vivo as well as CLP sepsis in mice.Conclusion: Our studies suggest that GUP is an effective inhibitor of the cGAS-STING pathway, which may be a potential medicine for the treatment of inflammatory diseases mediated by the cGAS-STING pathway.

Dexterous grasping is essential for the fine manipulation tasks of intelligent robots; however, its application in stacking scenarios remains a challenge. In this study, we aimed to propose a two-phase approach for grasp detection of sequential robotic grasping, specifically for application in stacking scenarios. In the initial phase, a rotated-YOLOv3 (R-YOLOv3) model was designed to efficiently detect the category and position of the top-layer object, facilitating the detection of stacked objects. Subsequently, a stacked scenario dataset with only the top-level objects annotated was built for training and testing the R-YOLOv3 network. In the next phase, a G-ResNet50 model was developed to enhance grasping accuracy by finding the most suitable pose for grasping the uppermost object in various stacking scenarios. Ultimately, a robot was directed to successfully execute the task of sequentially grasping the stacked objects. The proposed methodology demonstrated the average grasping prediction success rate of 96.60% as observed in the Cornell grasping dataset. The results of the 280 real-world grasping experiments, conducted in stacked scenarios, revealed that the robot achieved a maximum grasping success rate of 95.00%, with an average handling grasping success rate of 83.93%. The experimental findings demonstrated the efficacy and competitiveness of the proposed approach in successfully executing grasping tasks within complex multi-object stacked environments.

Poor seedling emergence is a challenge for direct seeding of rice under deep-sowing field conditions. Here we reveal that UDP-glucosyltransferase OsUGT75A promotes rice seedling emergence under deep-sowing conditions by increasing shoot length. Expression of OsUGT75A was higher in the middle regions of the shoot and in shoots under deep-sowing conditions. Levels of free abscisic acid (ABA) and jasmonates (JA) were higher in shoots of OsUGT75A mutants than in those of wild-type plants, and OsUGT75A mutants were more sensitive to ABA and JA treatments. Reduced shoot length was attributed to higher ABA INSENSITIVE 3 (OsABI3) expression and lower JASMONATE-ZIM domain protein (OsJAZ) expression in shoots. Shoot extension by OsUGT75A is achieved mainly by promotion of cell elongation. An elite haplotype of OsUGT75A associated with increased shoot length was identified among indica rice accessions. OsUGT75A acts to increase seedling emergence under deep-sowing conditions.

Many failures of semiconductor-based oxide confined vertical cavity surface emitting lasers (VCSELs) are closely related to the generation and expansion of defects in the device structure. However, existing research has predominantly focused on the static study of defect morphology, with little attention given to analyzing the dynamic process of defect expansion, which limited our ability to predict device random failures due to lack of understandings on defect generation and expansion. To address this issue, we present a macroscopic phenomenological evolution model that describes the dynamic expansion of defects in VCSELs, in which the expansion of defects is treated as an anisotropic lattice strain diffusion process. We further exploit a diffusion-limited aggregation (DLA) method in solving the diffusion equation, which describes the random propagation and aggregation of strain in the vicinity of highly strained areas, resulting in defect formation when the stress from accumulated strain surpasses the bonding force of the atoms in the lattice. Our simulation result manages to replicate the dendritic expansion morphology of defects, aligning with experimental observations very well. Our model also predicts an accelerated defect expansion process, which is again consistent with the experimental result. This model finds relevance in applications such as random failure prediction through device aging, burn-in condition setting in device screening, and device structural and/or material design improvement for mitigating defect expansion.

Abstract Metabolic reprogramming has been observed in cancer metastasis, whereas metabolic changes required for malignant cells during lymph node metastasis of esophageal squamous cell carcinoma (ESCC) are still poorly understood. Here, we performed single-cell RNA sequencing (scRNA-seq) of paired ESCC tumor tissues and lymph nodes to uncover the reprogramming of tumor microenvironment (TME) and metabolic pathways. By integrating analyses of scRNA-seq data with metabolomics of ESCC tumor tissues and plasma samples, we found nicotinate and nicotinamide metabolism pathway was dysregulated in ESCC patients with lymph node metastasis (LN+), exhibiting as significantly increased 1-methylnicotinamide (MNA) in both tumors and plasma. Further data indicated high expression of N-methyltransferase (NNMT), which converts active methyl groups from the universal methyl donor, S-adenosylmethionine (SAM), to stable MNA, contributed to the increased MNA in LN+ ESCC. NNMT promotes epithelial–mesenchymal transition (EMT) and metastasis of ESCC in vitro and in vivo by inhibiting E-cadherin expression. Mechanically, high NNMT expression consumed too much active methyl group and decreased H3K4me3 modification at E-cadherin promoter and inhibited m6A modification of E-cadherin mRNA, therefore inhibiting E-cadherin expression at both transcriptional and post-transcriptional level. Finally, a detection method of lymph node metastasis was build based on the dysregulated metabolites, which showed good performance among ESCC patients. For lymph node metastasis of ESCC, this work supports NNMT is a master regulator of the cross-talk between cellular metabolism and epigenetic modifications, which may be a therapeutic target.

Uchino initiated the investigation of twisted Rota-Baxter operators on associative algebras. Relevant studies have been extensive in recent times. In this paper, we introduce the notion of a twisted Rota-Baxter operator on a Hom-Lie algebra. By utilizing higher derived brackets, we establish an explicit $ L_{\infty} $-algebra whose Maurer-Cartan elements are precisely twisted Rota-Baxter operators on Hom-Lie algebra s. Additionally, we employ Getzler's technique of twisting $ L_\infty $-algebras to establish the cohomology of twisted Rota-Baxter operators. We demonstrate that this cohomology can be regarded as the Chevalley-Eilenberg cohomology of a specific Hom-Lie algebra with coefficients in an appropriate representation. Finally, we study the linear and formal deformations of twisted Rota-Baxter operators by using the cohomology defined above. We also show that the rigidity of a twisted Rota-Baxter operator can be derived from Nijenhuis elements associated with a Hom-Lie algebra.

High-speed directly modulated distributed feedback (DFB) laser is crucial for high-speed optical communication systems. The modulation bandwidth and frequency chirp of such devices are primarily affected by the differential gain and linewidth enhancement factor (LEF) of the quantum wells (QWs) in the active region. In this work, the optical gain properties of long wavelength AlGaInAs-InP strained quantum wells (QWs) with different crystal orientations are numerically investigated using the multi-bands k.p theory, which considers both valence-band anisotropic and nonparabolicity. Compared to the QW laser grown on a conventional (001) substrate, a higher differential gain, and smaller LEF are observed for the laser grown on the (110) substrate with the ${\rm{(\bar{1}10)}}$ plane as the mirror facet. This is primarily due to the reduced effective mass of the valence band. The dynamic characteristics of (001)-and (110)-oriented DFB laser is theoretically studied using the one-dimensional traveling wave model (1D TWM) at ${\rm{25}}\;^\circ \text{C}$ and ${\rm{95}}\;^\circ \text{C}$. The simulation results show that the lower chirp and wider modulation bandwidth can be achieved for the QW laser grown on (110) substrate.

Abstract Background The combinations of PD-1 inhibitors with paclitaxel/cisplatinum (PD-1 + TP) and fluoropyrimidine/cisplatinum (PD-1 + FP) both have been shown to improve overall survival (OS) and progression-free survival (PFS) in patients with previously untreated, advanced esophageal squamous cell carcinoma (ESCC). However, there is no consensus on which chemotherapy regimen combined with PD-1 has better efficacy. To deal with this important issue in the first-line treatment of patients with ESCC, a network meta-analysis (NMA) was performed. Methods Data were collected from eligible studies searched in Medline, Web of Science, PubMed, the Cochrane Library and Embase. The pooled hazard ratio (HR) for the OS, and PFS, odds ratio (OR) for the objective response rate (ORR) and ≥ 3 grade treatment-related adverse events (≥ 3TRAEs) were estimated to evaluate the efficacy of PD-1 inhibitors combined with TP or FP. Results Five RCTs and one retrospective study involving 3685 patients and evaluating four treatments were included in this NMA. Compared to other treatments, PD-1 + TP was better. For the PFS, the HRs for PD-1 + TP compared to PD-1 + FP, TP and FP were 0.59 (0.44, 0.80), 0.56 (0.51, 0.61) and 0.45 (0.37, 0.56) respectively. For the OS, PD-1 + TP was also a better treatment compared to other treatments. The HRs were 0.74 (0.56, 0.96), 0.64 (0.57, 0.71), 0.53 (0.43, 0.67) respectively. For the ORR, there was no significant difference between PD-1 + TP and PD-1 + FP, and the ORs were 1.2 (0.69, 2.11). Compare with TP and FP, PD-1 + TP had an obvious advantage, ORs were 2.5 (2.04, 3.04) and 2.95 (1.91, 4.63). For ≥ 3TRAEs, PD-1 + TP compared to other treatments, ORs were 1.34 (0.74, 2.46) and 1.13 (0.92, 1.38) and 2.23 (1.35, 3.69). Conclusion PD-1 + TP significantly improved both PFS and OS compared to PD-1 + FP. Taking into account both efficacy and safety, PD-1 + TP may be a superior first-line treatment option for ESCC.

Abstract Background The cGAS-STING signaling pathway is an essential section of the natural immune system. In recent years, an increasing number of studies have shown a strong link between abnormal activation of the cGAS-STING signaling pathway, a natural immune pathway mediated by the nucleic acid receptor cGAS, and the development and progression of autoimmune diseases. Therefore, it is important to identify an effective compound to specifically downregulate this pathway for disease. Methods The effect of Glabridin (Glab) was investigated in BMDMs and Peripheral blood mononuclear cell (PBMC) by establishing an in vitro model of cGAS-STING signaling pathway activation. An activation model stimulated by DMXAA was also established in mice to study the effect of Glab. On the other hand, we investigated the possible mechanism of action of Glab and the effect of Glab on Trex1-deficient mice. Results In this research, we report that Glab, a major component of licorice, specifically inhibits the cGAS-STING signaling pathway by inhibiting the level of type I interferon and inflammatory cytokines (IL-6 and TNF-α). In addition, Glab has a therapeutic effect on innate immune diseases caused by abnormal cytoplasmic DNA in Trex1-deficient mice. Mechanistically, Glab can specifically inhibit the interaction of STING with IRF3. Conclusion Glab is a specific inhibitor of the cGAS-STING signaling pathway and may be used in the clinical therapy of cGAS-STING pathway-mediated autoimmune diseases.

The synthesis of 2D MoWS2 nanosheets involved the liquid-phase exfoliation technique was explored in this paper. The nonlinear optical response of MoWS2 was characterized in the 1 µm wavelength range, and its suitability as a saturable absorber (SA) was confirmed. Experimental demonstrations were conducted by using MoWS2 as an SA in an idler-resonant intracavity KTA optical parametric oscillator (OPO) driven by a dual-loss-modulated Q-switched and mode-locked (QML) YVO4/Nd:YVO4 laser with an acousto-optic modulator (AOM). By appropriately tuning the pump power and the AOM repetition rate, the Q-switched envelope pulse widths for the signal and idler waves could be significantly reduced to be shorter than the cavity round-trip transit time, i.e., the interval between two neighboring mode-locking pulses. Consequently, this enabled the generation of sub-nanosecond single mode-locking pulses with a low repetition rate, high pulse energy, and remarkable stability. With a repetition rate of 1 kHz and maximal pulse energies of 318 µJ and 169 µJ, respectively, sub-nanosecond single mode-locking pulses of the signal and idler waves were generated. The theoretical model was established using coupled rate equations with a Gaussian spatial distribution approximation. The numerical simulation results for generating sub-nanosecond single mode-locking pulses for the signal and idler waves within their respective Q-switched envelopes aligned fundamentally with the experimental results, proving that MoWS2 can be a potential nanomaterial for further optoelectronic applications.

Nasopharyngeal carcinoma (NPC) is a highly prevalent head and neck malignancy in southern China frequently diagnosed at advanced stages owing to subtle early symptoms and associated metastasis. Angiogenesis emerges as a pivotal factor in NPC progression, with numerous angiogenesis-related factors showing aberrant expression and contributing to increased neovascularization within NPC tumors. These abnormal vessels not only nourish tumor growth but also facilitate metastasis, culminating in unfavorable patient outcomes. Multiple studies have demonstrated the applicability of various imaging techniques for assessing angiogenesis in NPC tumors, thus serving as a foundation for personalized treatment strategies and prognostic assessments. Anti-angiogenic therapies have exhibited significant potential for inhibiting NPC angiogenesis and exerting anti-tumor effects. To enhance efficacy, anti-angiogenic drugs are frequently combined with other treatment modalities to synergistically enhance anti-tumor effects while mitigating the side effects associated with single-agent therapies, consequently improving patient prognosis. Identifying the potential mechanisms and key targets underlying NPC angiogenesis and exploring more effective detection and treatment approaches holds promise for shaping the future of NPC diagnosis, treatment, and prognosis, thereby offering new avenues and perspectives for research and clinical practice.

BackgroundThe most appropriate tool for estimating the pretest probability (PTP) of obstructive coronary artery disease (CAD) in patients with diabetes mellitus (DM) and stable chest pain (SCP) remains unknown. Therefore, we aimed to validate and compare two recent models, namely, the risk factor-weighted clinical likelihood (RF-CL) model and coronary artery calcium score (CACS)-weighted clinical likelihood (CACS-CL) model, in these patient populations.MethodsA total of 1,245 symptomatic patients with DM, who underwent CACS and coronary computed tomographic angiography (CCTA) scan, were identified and followed up. PTP of obstructive CAD for each patient was estimated using the RF-CL model and CACS-CL model, respectively. Area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to assess the performance of models. The associations of major adverse cardiovascular events (MACE) with risk groups were evaluated using Cox proportional hazards regression.ResultsCompared with the RF-CL model, the CACS-CL model revealed a larger AUC (0.856 vs. 0.782, p = 0.0016), positive IDI (12%, p

IntroductionAttentional enhancement has often been identified as the central cognitive mechanism underlying the benefits of mindfulness meditation. However, the extent to which this enhancement is observable in the neural processes underlying long-term meditation is unclear. This current study aimed to examine differences in attentional performance between meditators and controls (non-meditators) using a visual oddball task with concurrent electroencephalography (EEG) recordings.MethodsThirty-four participants were recruited, including 16 meditators and 18 healthy controls, who were non-meditators. The participants completed a visual oddball task, using visual stimuli, and EEG recording.ResultsSelf-reports revealed that meditators had higher mindful attention scores than did the control group. The behavioral results showed that the meditators demonstrated faster reaction times than the non-meditators did. Neural findings indicated a higher P2 amplitude in the meditators than in the controls. The meditators demonstrated a significantly higher P3 in the target trials than in the distractor trials, which was not observed in the controls. Additionally, the time-frequency analysis demonstrated that the delta and theta powers in the meditators were significantly higher than those in the controls.ConclusionsThe study suggests the meditators exhibited greater attentional performance than the controls did, as revealed by EEG and behavioral measures. This study extends previous research on the effects of mindfulness meditation on attention and adds to our understanding of the effects of long-term mindfulness meditation.

Abstract Memristors are regarded as promising candidates for breaking the problems including high off‐chip memory access delays and the hash rate cost of frequent data moving induced by algorithms for data‐intensive applications of existing computational systems. Recently, organic–inorganic halide perovskites (OIHPs) have been recognized as exceptionally favorable materials for memristors due to ease of preparation, excellent electrical conductivity, and structural flexibility. However, research on OIHP‐based memristors focuses on modulating resistive switching (RS) performance through electric fields, resulting in difficulties in moving away from complex external circuits and wire connections. Here, a multilayer memristor has been constructed with eutectic gallium and indium (EGaIn)/ MAPbI3/poly(3,4‐ethylenedioxythiophene): poly(4‐styrenesulphonate) (PEDOT: PSS)/indium tin oxide (ITO) structure, which exhibits reproducible and reliable bipolar RS with low SET/RESET voltages, stable endurance, ultrahigh average ON/OFF ratio, and excellent retention. Importantly, based on ion migration activated by sound‐driven piezoelectric effects, the device exhibits a stable acoustic response with an average ON/OFF ratio greater than 103, thus realizing non‐contact, multi‐signal, and far‐field control in RS modulation. This study provides a single‐structure multifunctional memristor as an integrated architecture for sensing, data storage, and computing.

Abstract Bleeding is as particularly a serious phenomenon in Actinidia arguta and has important effects on this plant’s growth and development. Here we used A. arguta to study the effects of bleeding on the growth and development of leaves and fruits after a bleeding episode. We detect and analyze physiological indices of leaves and fruit after bleeding. The result revealed that the relative electrical conductivity and malondialdehyde (MDA) of leaves increased in treatment. Nitro blue tetrazolium chloride (NBT) and 3,3-diaminobenzidine (DAB) staining revealed the accumulation of reactive oxygen species (ROS) in leaves after bleeding. The chlorophyll content and photosynthetic parameter of plants were also decreased. In fruits, pulp and seed water content decreased after the damage, as did fruit vitamin C (Vc), soluble sugar content, and soluble solids content (SSC); the titratable acid content did not change significantly. We therefore conclude that bleeding affects the physiological indices of A. arguta. Our study provides a theoretical basis for understanding the physiological changes of A. arguta after bleeding episodes and laying a timely foundation for advancing research on A. arguta bleeding and long-term field studies should be executed in order to gain insights into underlying mechanisms.

Abstract Supported metal clusters comprising of well-tailored low-nuclearity heteroatoms have great potentials in catalysis owing to the maximized exposure of active sites and metal synergy. However, atomically precise design of these architectures is still challenging for the lack of practical approaches. Here, we report a defect-driven nanostructuring strategy through combining defect engineering of nitrogen-doped carbons and sequential metal depositions to prepare a series of Pt and Mo ensembles ranging from single atoms to sub-nanoclusters. When applied in continuous gas-phase decomposition of formic acid, the low-nuclearity ensembles with unique Pt3Mo1N3 configuration deliver high-purity hydrogen at full conversion with unexpected high activity of 0.62 molHCOOH molPt −1 s−1 and remarkable stability, significantly outperforming the previously reported catalysts. The remarkable performance is rationalized by a joint operando dual-beam Fourier transformed infrared spectroscopy and density functional theory modeling study, pointing to the Pt-Mo synergy in creating a new reaction path for consecutive HCOOH dissociations.

Abstract Resistance training could counter hypertension and improve muscle quality (MQ), but current evidence about the correlation between MQ and hypertension is limited. The authors aimed to explore this correlation using the data of participants aged 20–59 from NHANES 2011–2014 via a cross‐sectional study. The MQ was quantified as handgrip strength (kg)/lean soft tissue mass (kg) of the dominant arm. Weighted multivariate logistic regression models were mainly utilized to investigate the MQ—hypertension association; linear trend tests and subgroup analysis were also conducted. Moreover, the authors employed weighted multivariate linear regression models to uncover the association between blood pressure (BP) and MQ. Four thousand four hundred and sixty‐nine individuals were enrolled, and 1167 were hypertensive. Hypertensive participants had a lower MQ than normotensive participants. In the totally adjusted model, each unit elevation in MQ was related to a 7% reduction in hypertension prevalence (p =.002). There was a decreasing trend in hypertension prevalence and in systolic BP as the MQ increased from the bottom to the top quartile across all three models (p for trend ≤.01), with a 28% difference (OR: 0.72, 95% CI: 0.54, 0.95) in hypertension prevalence and a 1.88 mm Hg (95% CI: −3.56, −0.20) difference in SBP between the top and bottom quartiles in the fully adjusted model. Subgroup analysis further confirmed the MQ—hypertension inverse association. In conclusions, the MQ was negatively associated with hypertension prevalence and systolic BP, which suggests the MQ may be a protective factor for hypertension and need to be improved.

Abstract Background Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) characterized by hepatocellular injury, inflammation, and fibrosis in various stages. More than 20% of patients with NASH will progress to cirrhosis. Currently, there is a lack of clinically effective drugs for treating NASH, as improving liver histology in NASH is difficult to achieve and maintain through weight loss alone. Hence, the present study aimed to investigate potential therapeutic drugs for NASH. Methods BMDMs and THP1 cells were used to construct an inflammasome activation model, and then we evaluated the effect of epalrestat on the NLRP3 inflammasome activation. Western blot, real-time qPCR, flow cytometry, and ELISA were used to evaluate the mechanism of epalrestat on NLRP3 inflammasome activation. Next, MCD-induced NASH models were used to evaluate the therapeutic effects of epalrestat in vivo. In addition, to evaluate the safety of epalrestat in vivo, mice were gavaged with epalrestat daily for 14 days. Results Epalrestat, a clinically effective and safe drug, inhibits NLRP3 inflammasome activation by acting upstream of caspase-1 and inducing ASC oligomerization. Importantly, epalrestat exerts its inhibitory effect on NLRP3 inflammasome activation by inhibiting the activation of aldose reductase. Further investigation revealed that the administration of epalrestat inhibited NLRP3 inflammasome activation in vivo, alleviating liver inflammation and improving NASH pathology. Conclusions Our study indicated that epalrestat, an aldose reductase inhibitor, effectively suppressed NLRP3 inflammasome activation in vivo and in vitro and might be a new therapeutic approach for NASH. Graphical Abstract

Abstract As the associated gas of tight reservoirs, natural gas is abundant and noncorrosive, which is more suitable for the development of tight oil reservoirs in China. However, the mechanism of gas injection development is unclear, and the gas channeling is serious in tight reservoirs after fracturing. The water-alternating-gas (WAG) flooding is an effective means to delay gas channeling and improve oil recovery. Therefore, it is significant to clarify the mechanism of preventing gas channeling and recovering oil by water-alternation-natural gas (WANG) flooding. The WANG flooding experiments with different water–gas slugs were conducted in non-fracture and fractured tight cores. Besides, the oil distribution of different pore spaces of cores before and after displacement and the main contribution spaces on oil recovery were quantitatively analyzed by using nuclear magnetic resonance and core mercury porosimetry techniques. The results indicate that compared with natural gas flooding, the WANG flooding can retard gas channeling, increase formation energy, and enhance oil recovery by up to 14.1%, especially in fractured cores. Under the resistance of water slugs, the gas was allowed to enter smaller pores and its swept volume was expanded. Oil is mainly stored in mesopores (0.1–1 μm) and small pores (0.01–0.1 μm), accounting for over 90% of the total volume. The oil recovered mainly comes from mesopores, which accounts for over 75% of the total amount. Moreover, the WANG flooding strengthens the recovery of oil in mesopores and macropores (1–10 μm), but it also squeezes oil into small pores and micropores (0.001–0.01 μm).

Abstract Background To achieve potential financial savings and avoid exposing the patients to unnecessary risk, an optimal diagnostic strategy to identify low risk individual who may derive minimal benefit from further cardiac imaging testing (CIT) is important for patients with stable chest pain (SCP) suggestive of chronic coronary syndrome (CCS). Although several diagnostic strategies have been recommended by the most recent guidelines, few randomized controlled trials (RCTs) have prospectively investigated the actual effect of applying these strategies in clinical practice. Methods OPERATE (OPtimal Evaluation of stable chest pain to Reduce unnecessAry utilization of cardiac imaging TEsting) trial is an investigator-initiated, multicenter, coronary computed tomography angiography (CCTA)-based, 2-arm parallel-group, double-blind, pragmatic and confirmative RCT planning to include 800 subjects with SCP suggestive of CCS. After enrollment, all subjects will be randomized to two arms (2016 U.K. National Institute of Health and Care Excellence guideline-determined and 2019 European Society of Cardiology guideline-determined diagnostic strategy) on a 1:1 basis. According to each strategy, CCTA should be referred and deferred for a subject in high and low risk group, respectively. The primary (effectiveness) endpoint is CCTA without obstructive coronary artery disease. Safety of each strategy will be mainly assessed by 1-year major adverse cardiovascular event rates. Discussion The OPERATE trial will provide comparative effectiveness and safety evidences for two different diagnostic strategies for patients with SCP suggestive of CCS, with the intension of improving the diagnostic yield of CCTA at no expense of safety. Clinical trial registration ClinicalTrial.org Identifier NCT05640752.

Rational design of catalytic sites to activate the C≡C bond is of paramount importance to advance acetylene hydrochlorination. Herein, Cu sites with electron-rich and electron-deficient states were constructed by controlling the impregnation solutions. The π electrons flowing from acetylene to Cu site are facilitated over the electron-deficient Cu sites, achieving high activation of C≡C bond. The contradiction between the increased activation of acetylene required for enhanced catalytic activity and the resistance of Cu site to reduction by acetylene required for maintaining catalytic stability can be balanced by establishing strong interactions of Cu site with pyrrolic-N species. The catalytic activity displays a volcano shape scaling relationship as a function of Cu particle size. Tribasic copper chloride is concomitantly generated with the construction of electron-deficient Cu sites. The H–Cl bond of HCl can be activated over the tribasic copper chloride, accelerating the surface reaction of vinyl chloride production. This strategy of inducing electron deficiency provides new insight into the rational design of catalysts for the synthesis of vinyl chloride with a high catalytic performance.

Objectives: This study aimed to explore the effects of the mini-clinical evaluation exercise (mini-CEX) teaching model based on nurse-faculty collaboration in Fundamentals of Nursing course. Methods: A quasi-experimental design was conducted. A total of 111 nursing students of two parallel classes were recruited from a nursing college in Guilin, China from February to December 2022, and allocated to the intervention group (n = 56) and control group (n = 55). The intervention group received a mini-CEX teaching model based on nurse-faculty collaboration, the teaching-learning process included scenario creation (10 min), inquiry-based learning (30 min), case report (30 min), scenario simulation exercise (40 min), and effectiveness evaluation (10 min). While the control group received conventional teaching method. All students were invited to complete the College Classroom Climate Assessment Scale (CCCA) and the Chinese version of the Competency Inventory for Nursing Students (CINS-CV) before and after the intervention. Course achievement of students was evaluated. After the intervention, the intervention group was asked an open-ended question to explore the difficulties or challenges they had encountered. Results: After intervention, the CCCA score (208.36 ± 23.25 vs. 190.60 ± 28.83), CINS-CV score(106.95 ± 14.48 vs. 99.55 ± 14.60), the oretical exam score (83.01 ± 4.27 vs. 79.75 ± 5.45), and scenario simulation exam score (89.23 ± 3.17 vs. 81.42 ± 7.19) of intervention group were higher than those of the control group (P＜0.01). The open-ended questionnaire survey revealed that the difficulties or challenges faced by the intervention group were mainly related to case analysis, group cooperation, learning material acquisition, and teacher guidance. Conclusion: Applying the mini-CEX teaching model based on nurse-faculty collaboration could cultivate nursing students’ competency, build a positive classroom climate, and improve the course achievement of students.

Abstract Background Abnormal activation of NLRP3 inflammasome is related to a series of inflammatory diseases, including type 2 diabetes, gouty arthritis, non-alcoholic steatohepatitis (NASH), and neurodegenerative disorders. Therefore, targeting NLRP3 inflammasome is regarded as a potential therapeutic strategy for many inflammatory diseases. A growing number of studies have identified tanshinone I (Tan I) as a potential anti-inflammatory agent because of its good anti-inflammatory activity. However, its specific anti-inflammatory mechanism and direct target are unclear and need further study. Methods IL-1β and caspase-1 were detected by immunoblotting and ELISA, and mtROS levels were measured by flow cytometry. Immunoprecipitation was used to explore the interaction between NLRP3, NEK7 and ASC. In a mouse model of LPS-induced septic shock, IL-1β levels in peritoneal lavage fluid and serum were measured by ELISA. Liver inflammation and fibrosis in the NASH model were analyzed by HE staining and immunohistochemistry. Results Tan I inhibited the activation of NLRP3 inflammasome in macrophages, but had no effect on the activation of AIM2 or NLRC4 inflammasome. Mechanistically, Tan I inhibited NLRP3 inflammasome assembly and activation by targeting NLRP3-ASC interaction. Furthermore, Tan I exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including septic shock and NASH. Conclusions Tan I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC, and exhibits protective effects in mouse models of LPS-induced septic shock and NASH. These findings suggest that Tan I is a specific NLRP3 inhibitor and may be a promising candidate for treating NLRP3 inflammasome-related diseases. Graphical Abstract

Abstract The generation of functional β-cells from human pluripotent stem cells (hPSCs) for cell replacement therapy and disease modeling of diabetes is being investigated by many groups. We have developed a protocol to harvest and aggregate hPSC-derived pancreatic progenitors generated using a commercially available kit into near uniform spheroids and to further differentiate the cells toward an endocrine cell fate in suspension culture. Using a static suspension culture platform, we could generate a high percentage of insulin-expressing, glucose-responsive cells. We identified FGF7 as a soluble factor promoting aggregate survival with no inhibitory effect on endocrine gene expression. Notch inhibition of pancreatic progenitor cells during aggregation improved endocrine cell induction in vitro and improved graft function following implantation and further differentiation in mice. Thus we provide an approach to promote endocrine formation from kit-derived pancreatic progenitors, either through extended culture or post implant.

Abstract TGF‐β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2‐SREBP‐1c mice and ob/ob mice, were used. TGF‐β pathway showed up‐regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF‐β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre‐administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild‐type levels in aP2‐SREBP‐1c mice. In contrast, TGF‐β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF‐β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF‐β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.

IntroductionProso millet, a high-quality fermentation material used for Chinese yellow wine production, can produce special flavored substances; however, its role in improving the flavor and altering microbial communities of light-flavored Baijiu during fermentation remain unknown. Thus, we aimed to investigate the effect of proso millet on improving the flavor of light-flavored Baijiu and altering microbial communities during different fermentation stages.MethodsThe dynamic changes in the microbial communities and flavor of proso millet (50%) + sorghum (50%) mixed fermentation samples were analyzed through intermittent sampling on days 7, 14, 21, and 28 of the fermentation process. Microbial high-throughput sequencing and the analysis of flavor characteristics were conducted through 16S DNA/ ITS amplicon sequencing and gas chromatography (multi-capillary column)-ion mobility spectrometry, respectively.ResultsProso millet significantly changed the core flavor compound composition of traditional light-flavored Baijiu from ethyl acetate, ethyl hexanoate, ethyl hexanoate dimer, ethyl butanoate, ethyl lactate, and butyl acetate to oct-2-ene, 2-butanol, propyl propanoate, 2-pentenal, and 4-methylpentanal. The amplicon sequencing analysis revealed that the alpha diversity parameters of bacterial and fungal communities, including the Chao1, Pielou_e, Shannon, and Simpson indices, for proso millet–sorghum mixed fermentation samples were significantly higher than those for sorghum fermentation samples (p

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer, and effective treatments are urgently needed owing to its poor prognosis. Surgery, radiotherapy, and chemotherapy, alone or in combination, are the leading choices for TNBC therapy. Although promising approaches and procedures have emerged, several challenges, such as off-target effects, drug resistance, and severe side effects, remain to be addressed. Recently, transient receptor potential channel mucolipin 1 (TRPML1) has attracted the attention of researchers because its expression has been implicated in numerous diseases, including cancer. TRPML1 regulates biological events and signaling pathways, including autophagic flux, exocytosis, ionic homeostasis, and lysosomal biogenesis, all contributing to tumorigenesis and cancer progression. TRPML1 also functions as a building block for cancer cell growth, mitogenic signaling, priming tissues for metastasis, and activation of transcriptional programs, processes involved in several malignant tumors. This review provides an overview of breast cancer epidemiology and diagnostic techniques and then discusses the existing therapeutics. Additionally, we elaborate on the development of, and associated challenges to, TNBC diagnostics and treatment and the feasibility of TRPML1 as a therapeutic target for TNBC.

Abstract Objectives This research aimed to explore the relationship between pre‐treatment inflammatory markers and other clinical characteristics and the survival of small‐cell lung cancer (SCLC) patients who received first‐line platinum‐based treatment and to construct nomograms for predicting overall survival (OS) and progression‐free survival (PFS). Methods A total of 612 patients diagnosed with SCLC between March 2008 and August 2021 were randomly divided into two cohorts: a training cohort (n = 459) and a validation cohort (n = 153). Inflammatory markers, clinicopathological factors, and follow‐up information of patients were collected for each case. Cox regression was used to conduct univariate and multivariate analyses and the independent prognostic factors were adopted to develop the nomograms. Harrell's concordance index (C‐index) and time‐dependent receiver operating characteristic curve were used to verify model differentiation, calibration curve was used to verify consistency, and decision curve analysis was used to verify the clinical application value. Results Our results showed that baseline C‐reactive protein/albumin ratio, neutrophil/lymphocyte ratio, NSE level, hyponatremia, the efficacy of first‐line chemotherapy, and stage were independent prognostic factors for both OS and PFS in SCLC. In the training cohort, the C‐index of PFS and OS was 0.698 and 0.666, respectively. In the validation cohort, the C‐index of PFS and OS was 0.727 and 0.747, respectively. The nomograms showed good predictability and high clinical value. Also, our new clinical models were superior to the US Veterans Administration Lung Study Group (VALG) staging for predicting the prognosis of SCLC. Conclusions The two prognostic nomograms of SCLC including inflammatory markers, VALG stage, and other clinicopathological factors had good predictive value and could individually assess the survival of patients.

Abstract Submergence stress represents a major obstacle limiting the application of direct seeding in rice cultivation. Under flooding conditions, coleoptile elongation can function as an escape strategy that contributes to submergence tolerance during seed germination in rice; however, the underlying molecular bases have yet to be fully determined. Herein, we report that natural variation of rice coleoptile length subjected to submergence is determined by the glucosyltransferase encoding gene OsUGT75A. OsUGT75A regulates coleoptile length via decreasing free abscisic acid (ABA) and jasmonic acid (JA) levels by promoting glycosylation of these two phytohormones under submergence. Moreover, we find that OsUGT75A accelerates coleoptile length through mediating the interactions between JASMONATE ZIMDOMAIN (OsJAZ) and ABSCISIC ACID-INSENSITIVE (OsABI) proteins. Last, we reveal the origin of the haplotype that contributes to coleoptile length in response to submergence and transferring this haplotype to indica rice can enhance coleoptile length in submergence conditions. Thus, we propose that OsUGT75A is a useful target in breeding of rice varieties suitable for direct seeding cultivation.

Abstract Objectives Neuroinflammation has been suggested that affects the processing of depression. There is renewed interest in berberine owing to its anti-inflammatory effects. Herein, we investigated whether berberine attenuate depressive-like behaviors via inhibiting NLRP3 inflammasome activation in mice model of depression. Methods Adult male C57BL/6N mice were administrated corticosterone (CORT, 20 mg/kg/day) for 35 days. Two doses (100 mg/kg/day and 200 mg/kg/day) of berberine were orally administrated from day 7 until day 35. Behavioral tests were performed to measure the depression-like behaviors alterations. Differentially expressed gene analysis was performed for RNA-sequencing data in the prefrontal cortex. NLRP3 inflammasome was measured by quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence labeling. The neuroplasticity and synaptic function were measured by immunofluorescence labeling, Golgi–Cox staining, transmission electron microscope, and whole-cell patch-clamp recordings. Results The results of behavioral tests demonstrated that berberine attenuated the depression-like behaviors induced by CORT. RNA-sequencing identified that NLRP3 was markedly upregulated after long-term CORT exposure. Berberine reversed the concentrations of peripheral and brain cytokines, NLRP3 inflammasome elicited by CORT in the prefrontal cortex and hippocampus were decreased by berberine. In addition, the lower frequency of neuronal excitation as well as the dendritic spine reduction were reversed by berberine treatment. Together, berberine increases hippocampal adult neurogenesis and synaptic plasticity induced by CORT. Conclusion The anti-depressants effects of berberine were accompanied by reduced the neuroinflammatory response via inhibiting the activation of NLRP3 inflammasome and rescued the neuronal deterioration via suppression of impairments in synaptic plasticity and neurogenesis.

An integrated optical isolator is a crucial part of photonic integrated circuits (PICs). Existing optical isolators, predominantly based on the silicon-on-insulator (SOI) platform, face challenges in integrating with active devices. We propose a broadband, compact TM mode Mach–Zehnder optical isolator based on InP-on-insulator platforms. We designed two distinct magneto-optical waveguide structures, employing different methods for bonding Ce:YIG and InP, namely O2 plasma surface activation direct wafer bonding and DVS-benzocyclobutene (BCB) adhesive bonding. Detailed calculations and optimizations were conducted to enhance their non-reciprocal phase shift (NRPS). At a wavelength of 1550 nm, the direct-bonded waveguide structure achieved a 30 dB bandwidth of 72 nm with a length difference of 0.256 µm. The effects of waveguide arm length, fabrication accuracy, and dimensional errors on the device performance are discussed. Additionally, manufacturing tolerances for three types of lithographic processes were calculated, serving as references for practical manufacturing purposes.

The calorie and taste choices of food have been shown to be related to the external environment, including music. Previous studies have mostly focused on manipulating basic auditory parameters, with few scholars exploring the impact of complex musical parameters on food selection. This study explored the effects of different kinds of music (classical, rock, jazz, and hip-hop) on food liking based on the calories (high and low) and taste (sweet and salty) using event-related potentials (ERPs). Twenty-four participants (8 males, 16 females) were recruited from Southwest University, China to participate in the food liking task using a Likert seven-point rating and simultaneously recording EEG signals (N2, P2, N3, and LPC). This study used repeated-measures analyses of covariances and found that the score of the high-calorie foods was greater than that of the low-calorie foods. Additionally, results revealed that the score in classical music was greatest for sweet foods, while there was no difference among music kinds in the salty foods. The ERP results showed that P2 amplitudes were greater for sweet foods than those for the salty foods. N2 amplitudes for the salty foods were greater than those for the sweet foods during rock music; in addition, N2 amplitudes during hip-hop music were greatest for sweet foods. However, N2 amplitudes during rock music were the greatest for salty foods. The results also revealed that N2 amplitudes during hip-hop music were greater than those during jazz music. This study provides unique operational insights for businesses.