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Abstract An innovative Chardonnay wine flavored with black tea was prepared under optimal ultrasound conditions at 450.0 W for 22.6 min, and its physicochemical features, antioxidant power, total phenolic content, and volatile composition were systematically examined. A total of 165 phenolic and non-phenolic substances were characterized, including 27 newly formed phenolic substances and 10 non-phenolic substances that were not found in both black tea and Chardonnay wine. Catechin was found to be the phenolic compound with the largest amount detected, which was responsible for the potentiated antioxidant activities. The wine exhibited a profile of 44 volatile compounds, with 13 volatiles as odor-active compounds. Black tea infusion resulted in a decline in fruity, fermented and spicy aromas, but an increase in green and citrus odors, while ultrasound processing further intensified these odors. This study anticipated that ultrasound technology could hold promise for crafting flavored wines with heightened functionalities and appealing flavor profiles. Graphical Abstract Ultrasound-assisted infusion of black tea potentiated the antioxidant activity and enriched the volatile and phenolic profiles of Chardonnay wine.

Developing new high-entropy rare-earth zirconate (HE-RE2Zr2O7) ceramics with low thermal conductivity is essential for thermal barrier coating materials. In this work, the average atomic spacings, interatomic forces, and average atomic masses of 16 rare-earth elements occupying the A site of the cubic A2B2O7 crystal structure were calculated by density functional theory. These three physical qualities, as vectors, characterize the corresponding rare-earth elements. The distance between two vectors quantitatively describes the difference between two rare-earth elements. For greater differences between two rare-earth elements, the disorder degree of HE-RE2Zr2O7 is greater, and therefore, the thermal conductivity is lower. According to the theoretical calculations, the thermal conductivity of the ceramics gradually increases in the order of (Sc0.2Y0.2La0.2Ho0.2Yb0.2)2Zr2O7, (Sc0.2Ce0.2Nd0.2Eu0.2Gd0.2)2Zr2O7, (Sc0.2Y0.2Tm0.2Yb0.2Lu0.2)2Zr2O7, and (Sc0.2Er0.2Tm0.2Yb0.2Lu0.2)2Zr2O7. Using the solution precursor plasma spray method and pressureless sintering method, four types of HE-RE2Zr2O7 powder and bulk samples were prepared. The samples all showed a single defective fluorite structure with a uniform distribution of the elements and a stable phase structure. The thermal conductivities of the sintered HE-RE2Zr2O7 bulk samples ranged from 1.30 to 1.45 W·m−1·K−1 at 1400 °C, and their differences were consistent with the theoretical calculation results. Among the ceramics, (Sc0.2Y0.2La0.2Ho0.2Yb0.2)2Zr2O7 had the lowest thermal conductivity (1.30 W∙m−1∙K−1, 1400 °C), highest thermal expansion coefficient (10.19×10−6 K−1, 200–1400 °C), highest fracture toughness (1.69±0.28 MPa∙m1/2), and smallest brittleness index (3.03 μm−1/2). Therefore, (Sc0.2Y0.2La0.2Ho0.2Yb0.2)2Zr2O7 is considered to be an ideal candidate material for next-generation thermal barrier coating applications.

Abstract Background Gastric cancer (GC) encompasses many different histological and molecular subtypes. It is a major driver of cancer mortality because of poor survival and limited treatment options. Personalised medicine in the form of patient-derived organoids (PDOs) represents a promising approach for improving therapeutic outcomes. The goal of this study was to overcome the limitations of current models by ameliorating organoid cultivation. Methods Organoids derived from cancer tissue were evaluated by haematoxylin and eosin staining, immunohistochemistry, mRNA, and whole-exome sequencing. Three representative chemotherapy drugs, 5-fluorouracil, docetaxel, and oxaliplatin, were compared for their efficacy against different subtypes of gastric organoids by ATP assay and apoptosis staining. In addition, drug sensitivity screening results from two publicly available databases, the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopaedia, were pooled and applied to organoid lines. Once key targeting genes were confirmed, chemotherapy was used in combination with poly (ADP ribose) polymerase (PARP)-targeted therapy. Results We successfully constructed GC PDOs surgically resected from GC patient tissue. PDOs closely reflected the histopathological and genomic features of the corresponding primary tumours. Whole-exosome sequencing and mRNA analysis revealed that changes to the original tumour genome were maintained during long-term culture. The drugs caused divergent responses in intestinal, poorly differentiated intestinal, and diffuse gastric cancer organoids, which were confirmed in organoid lines. Poorly differentiated intestinal GC patients benefited from a combination of 5-fluorouracil and veliparib. Conclusion The present study demonstrates that combining chemotherapy with PARP targeting may improve the treatment of chemotherapy-resistant tumours.

Several mitochondrial dysfunctions in obesity and diabetes include impaired mitochondrial membrane potential, excessive mitochondrial reactive oxygen species generation, reduced mitochondrial DNA, increased mitochondrial Ca2+ flux, and mitochondrial dynamics disorders. Mitophagy, specialized autophagy, is responsible for clearing dysfunctional mitochondria in physiological and pathological conditions. As a paradox, inhibition and activation of mitophagy have been observed in obesity and diabetes-related heart disorders, with both exerting bidirectional effects. Suppressed mitophagy is beneficial to mitochondrial homeostasis, also known as benign mitophagy. On the contrary, in most cases, excessive mitophagy is harmful to dysfunctional mitochondria elimination and thus is defined as detrimental mitophagy. In obesity and diabetes, two classical pathways appear to regulate mitophagy, including PTEN-induced putative kinase 1 (PINK1)/Parkin-dependent mitophagy and receptors/adapters-dependent mitophagy. After the pharmacologic interventions of mitophagy, mitochondrial morphology and function have been restored, and cell viability has been further improved. Herein, we summarize the mitochondrial dysfunction and mitophagy alterations in obesity and diabetes, as well as the underlying upstream mechanisms, in order to provide novel therapeutic strategies for the obesity and diabetes-related heart disorders.

Abstract Background Ice and snow sports, which are inherently high risk due to their physically demanding nature, pose significant challenges in terms of participant safety. These activities increase the likelihood of injuries, largely due to reduced bodily agility and responsiveness in cold, often unpredictable winter environments. The critical need for effective injury prevention in these sports is emphasized by the considerable impact injuries have on the health of participants, alongside the economic and social costs associated with medical and rehabilitative care. In the context of ice and snow sports environments, applying the E principles of injury prevention to evaluate intervention measures can guide the implementation of future sports safety and other health promotion intervention measures in this field. When well executed, this approach can substantially reduce both the frequency and severity of injuries, thereby significantly enhancing the safety and long-term viability of these challenging sports. Objective The objective of this study was to rigorously assess and statistically substantiate the efficacy of diverse injury prevention strategies in ice and snow sports, aiming to bolster future safety measures with solid empirical evidence. Design Systematic review and meta-analysis. Methods The overarching aim of this research was to meticulously aggregate and scrutinize a broad spectrum of scholarly literature, focusing on the quantifiable efficacy of diverse, multicomponent intervention strategies in mitigating the incidence of injuries within the realm of ice and snow sports. This endeavour entailed an exhaustive extraction of data from esteemed academic databases, encompassing publications up to September 30, 2023. In pursuit of methodological excellence and analytical rigor, the study employed advanced bias assessment methodologies, notably the AMSTAR 2 and GRADE approaches, alongside sophisticated random-effects statistical modelling. This comprehensive approach was designed to ensure the utmost validity, reliability, and scholarly integrity of the study’s findings. Results Fifteen papers, including 9 randomized controlled trials, 3 case‒control studies, and 3 cohort studies with 26,123 participants and 4,382 injuries, were analysed. The findings showed a significant reduction in injury rates through various interventions: overall injury prevention (RR = 0.50, 95% CI 0.42–0.63), educational training (RR = 0.50, 95% CI 0.34–0.73), educational videos (RR = 0.53, 95% CI 0.34–0.81), protective equipment (RR = 0.64, 95% CI 0.46–0.87), and policy changes (RR = 0.28, 95% CI 0.16–0.49). Subgroup analysis revealed potential heterogeneity in compliance (p = 0.347). Compared to controls, multicomponent interventions effectively reduced injury rates. Conclusion This systematic review and meta-analysis demonstrated that multicomponent interventions significantly prevent injuries in ice and snow sports. By applying the E principles of injury prevention and constructing a framework for practical injury prevention research in ice and snow sports, we can gradually shift towards a systemic paradigm for a better understanding of the development and prevention of sports injuries. Moreover, sports injury prevention is a complex and dynamic process. Therefore, high-quality experiments in different scenarios are needed in future research to provide more reliable evidence, offer valuable and relevant prevention information for practitioners and participants, and help formulate more effective preventive measures in practice.

Abstract The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

Articular cartilage defects often involve damage to both the cartilage and subchondral bone, requiring a scaffold that can meet the unique needs of each tissue type and establish an effective barrier between the bone and cartilage. In this study, we used 3D printing technology to fabricate a tri-phasic scaffold composed of PLA/PCL-PLGA/Mg(OH)₂, which includes a cartilage layer, an osteochondral interface, and a bone layer. The scaffold was filled with Velvet antler polypeptides (VAP), and its characterization was assessed using compression testing, XRD, FTIR, SEM, fluorescence microscopy, and EDS. In vitro investigation demonstrated that the scaffold not only supported osteogenesis but also promoted chondrogenic differentiation of fibrocartilage stem cells (FCSCs). n vivo experiments showed that the tri-phasic PLA/PCL-PLGA/Mg(OH)2-VAP scaffold together with FCSC, when transplanted to animal models, increased the recovery of osteochondral defects. Those results demonstrate the promising future of illustrated tri-phasic PLA/PCL-PLGA/Mg(OH)2-VAP scaffold loaded with FCSCs as a new bone and cartilage tissue engineering approach for osteochondral defects treatment.

Abstract Mutations of the human leucine-rich repeat kinase 2 (LRRK2) have been associated with both, idiopathic and familial Parkinson’s disease (PD). Most of these pathogenic mutations are located in the kinase domain (KD) or GTPase domain of LRRK2. In this study we describe a mechanism in which protein kinase activity can be modulated by reversible oxidation or reduction, involving a unique pair of adjacent cysteines, the “CC” motif. Among all human protein kinases, only LRRK2 contains this “CC” motif (C2024 and C2025) in the Activation Segment (AS) of the kinase domain. In an approach combining site-directed mutagenesis, biochemical analyses, cell-based assays, and Gaussian accelerated Molecular Dynamics (GaMD) simulations we could attribute a role for each of those cysteines. We employed reducing and oxidizing agents with potential clinical relevance to investigate effects on kinase activity and microtubule docking. We find that each cysteine gives a distinct contribution: the first cysteine, C2024, is essential for LRRK2 protein kinase activity, while the adjacent cysteine, C2025, contributes significantly to redox sensitivity. Implementing thiolates (R-S-) in GaMD simulations allowed us to analyse how each of the cysteines in the “CC” motif interacts with its surrounding residues depending on its oxidation state. From our studies we conclude that oxidizing agents can downregulate kinase activity of hyperactive LRRK2 PD mutations and may provide promising tools for therapeutic strategies.

Ischemic stroke, a significant threat to human life and health, refers to a class of conditions where brain tissue damage is induced following decreased cerebral blood flow. The incidence of ischemic stroke has been steadily increasing globally, and its disease mechanisms are highly complex and involve a multitude of biological mechanisms at various scales from genes all the way to the human body system that can affect the stroke onset, progression, treatment, and prognosis. To complement conventional experimental research methods, computational systems biology modeling can integrate and describe the pathogenic mechanisms of ischemic stroke across multiple biological scales and help identify emergent modulatory principles that drive disease progression and recovery. In addition, by running virtual experiments and trials in computers, these models can efficiently predict and evaluate outcomes of different treatment methods and thereby assist clinical decision-making. In this review, we summarize the current research and application of systems-level computational modeling in the field of ischemic stroke from the multiscale mechanism-based, physics-based and omics-based perspectives and discuss how modeling-driven research frameworks can deliver insights for future stroke research and drug development.

Parkinson’s disease (PD) is neurodegenerative disease in middle-aged and elderly people with some pathological mechanisms including immune disorder, neuroinflammation, white matter injury and abnormal aggregation of alpha-synuclein, etc. New research suggests that white matter injury may be important in the development of PD, but how inflammation, the immune system, and white matter damage interact to harm dopamine neurons is not yet understood. Therefore, it is particularly important to delve into the crosstalk between immune cells in the central and peripheral nervous system based on the study of white matter damage in PD. This crosstalk could not only exacerbate the pathological process of PD but may also reveal new therapeutic targets. By understanding how immune cells penetrate through the blood–brain barrier and activate inflammatory responses within the central nervous system, we can better grasp the impact of structural destruction of white matter in PD and explore how this process can be modulated to mitigate or combat disease progression. Microglia, astrocytes, oligodendrocytes and peripheral immune cells (especially T cells) play a central role in its pathological process where these immune cells produce and respond to pro-inflammatory cytokines such as tumor necrosis factor (TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6), and white matter injury causes microglia to become pro-inflammatory and release inflammatory mediators, which attract more immune cells to the damaged area, increasing the inflammatory response. Moreover, white matter damage also causes dysfunction of blood–brain barrier, allows peripheral immune cells and inflammatory factors to invade the brain further, and enhances microglia activation forming a vicious circle that intensifies neuroinflammation. And these factors collectively promote the neuroinflammatory environment and neurodegeneration changes of PD. Overall, these findings not only deepen our understanding of the complexity of PD, but also provide new targets for the development of therapeutic strategies focused on inflammation and immune regulation mechanisms. In summary, this review provided the theoretical basis for clarifying the pathogenesis of PD, summarized the association between white matter damage and the immune cells in the central and peripheral nervous systems, and then emphasized their potential specific mechanisms of achieving crosstalk with further aggravating the pathological process of PD.

Abstract LRRK2 is one of the most promising drug targets for Parkinson’s disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2–inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2–inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2–inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design.

Abstract Background The benefits of combining benzoic acid and essential oils (BAO) to mitigate intestinal impairment during the weaning process have been well established, while the detailed underlying mechanism has not been fully elucidated. Previous research has primarily focused on the reparative effects of BAO on intestinal injury, while neglecting its potential in enhancing intestinal stress resistance. Methods In this study, we investigated the pre-protective effect of BAO against LPS-induced stress using a modified experimental procedure. Piglets were pre-supplemented with BAO for 14 d, followed by a challenge with LPS or saline to collect blood and intestinal samples. Results Our findings demonstrated that BAO supplementation led to significant improvements in piglets' final weight, average daily gain, and feed intake/body gain ratio. Additionally, BAO supplementation positively influenced the composition of intestinal microbiota, increasing beneficial Actinobacteriota and Alloprevotella while reducing harmful Desulfobacterota, Prevotella and Oscillospira. Furthermore, BAO supplementation effectively mitigated oxidative disturbances and inflammatory responses induced by acute LPS challenge. This was evidenced by elevated levels of T-AOC, SOD, and GSH, as well as decreased levels of MDA, TNF-α, and IL-6 in the plasma. Moreover, piglets subjected to LPS challenge and pre-supplemented with BAO exhibited significant improvements in intestinal morphological structure and enhanced integrity, as indicated by restored expression levels of Occludin and Claudin-1 compared to the non-supplemented counterparts. Further analysis revealed that BAO supplementation enhanced the jejunal antioxidative capacity by increasing GSH-Px levels and decreasing MDA levels under the LPS challenge and stimulated the activation of the Nrf2 signaling pathway. Additionally, the reduction of TLR4/NF-κB/MAPK signaling pathways activation and proinflammatory factor were also observed in the jejunal of those piglets fed with BAO. Conclusions In summary, our study demonstrates that pre-supplementation of BAO enhances the anti-stress capacity of weaned piglets by improving intestinal microbiota composition, reinforcing the intestinal barrier, and enhancing antioxidative and anti-inflammatory capabilities. These effects are closely associated with the activation of Nrf2 and TLR4/NF-κB/MAPK signaling pathways.

Abstract In clinical trials involving patients with HER2 (ERBB2 receptor tyrosine kinase 2) positive gastric cancer, the efficacy of the HER2-targeted drug lapatinib has proven to be disappointingly poor. Under the persistent pressure exerted by targeted drug therapy, a subset of tumor cells exhibit acquired drug resistance through the activation of novel survival signaling cascades, alongside the proliferation of tumor cells that previously harbored mutations conferring resistance to the drug. This study was undertaken with the aim of elucidating in comprehensive detail the intricate mechanisms behind adaptive resistance and identifying novel therapeutic targets that hold promise in the development of effective lapatinib-based therapies for the specific subset of patients afflicted with gastric cancer. We have successfully established a gastric cancer cell line with acquired lapatinib resistance, designated as HGC-27-LR cells. Utilizing comprehensive coding and noncoding transcriptome sequencing analysis, we have identified key factors that regulate lapatinib resistance in HGC-27 cells. We have compellingly validated that among all the lncRNAs identified in HGC-27-LR cells, a novel lncRNA (long noncoding RNA) named NONHSAT160169.1 was found to be most notably upregulated following exposure to lapatinib treatment. The upregulation of NONHSAT160169.1 significantly augmented the migratory, invasive, and stemness capabilities of HGC-27-LR cells. Furthermore, we have delved into the mechanism by which NONHSAT160169.1 regulates lapatinib resistance. The findings have revealed that NONHSAT160169.1, which is induced by the p-STAT3 (signal transducer and activator of transcription 3) nuclear transport pathway, functions as a decoy that competitively interacts with hsa-let-7c-3p and thereby abrogates the inhibitory effect of hsa-let-7c-3p on SOX2 (SRY-box transcription factor 2) expression. Hence, our study has unveiled the NONHSAT160169.1/hsa-let-7c-3p/SOX2 signaling pathway as a novel and pivotal axis for comprehending and surmounting lapatinib resistance in the treatment of HER2-positive gastric cancer.

Abstract Background Seed aging is a critical factor contributing to vigor loss, leading to delayed forage seed germination and seedling growth. Numerous studies have revealed the regulatory role of WRKY transcription factors in seed development, germination, and seed vigor. However, a comprehensive genome-wide analysis of WRKY genes in Zhongmu No.1 alfalfa has not yet been conducted. Results In this study, a total of 91 MsWRKY genes were identified from the genome of alfalfa. Phylogenetic analysis revealed that these MsWRKY genes could be categorized into seven distinct subgroups. Furthermore, 88 MsWRKY genes were unevenly mapped on eight chromosomes in alfalfa. Gene duplication analysis revealed segmental duplication as the principal driving force for the expansion of this gene family during the course of evolution. Expression analysis of the 91 MsWRKY genes across various tissues and during seed germination exhibited differential expression patterns. Subsequent RT-qPCR analysis highlighted significant induction of nine selected MsWRKY genes in response to seed aging treatment, suggesting their potential roles in regulating seed vigor. Conclusion This study investigated WRKY genes in alfalfa and identified nine candidate WRKY transcription factors involved in the regulation of seed vigor. While this finding provides valuable insights into understanding the molecular mechanisms underlying vigor loss and developing new strategies to enhance alfalfa seed germinability, further research is required to comprehensively elucidate the precise pathways through which the MsWRKY genes modulate seed vigor.

Soil salinization is a significant global threat to sustainable agricultural development, with soil salinity serving as a crucial indicator for evaluating soil salinization. Remote sensing technology enables large-scale inversion of soil salinity, facilitating the monitoring and assessment of soil salinization levels, thus supporting the prevention and management of soil salinization. This study employs multi-source remote sensing data, selecting 8 radar polarization combinations, 10 spectral indices, and 3 topographic factors to form a feature variable dataset. By applying a normalized weighted variable optimization method, highly important feature variables are identified. AdaBoost, LightGBM, and CatBoost machine learning methods are then used to develop soil salinity inversion models and evaluate their performance. The results indicate the following: (1) There is generally a strong correlation between radar polarization combinations and vegetation indices, and a very high correlation between various vegetation indices and the salinity index S3. (2) The top five feature variables, in order of importance, are Aspect, VH2, Normalized Difference Moisture Index (NDMI), VH, and Vegetation Moisture Index (VMI). (3) The method of normalized weighted importance scoring effectively screens important variables, reducing the number of input feature variables while enhancing the model’s inversion accuracy. (4) Among the three machine learning models, CatBoost performs best overall in soil salt content (SSC) prediction. Combined with the top five feature variables, CatBoost achieves the highest prediction accuracy (R2 = 0.831, RMSE = 2.653, MAE = 1.034) in the prediction phase. This study provides insights for the further development and application of methods for collaborative inversion of soil salinity using multi-source remote sensing data.

Resistant starch (RS) has the advantage of reshaping gut microbiota for human metabolism and health, like glycemic control, weight loss, etc. Among them, RS3 prepared from pure starch is green and safe, but it is hard to achieve structural control. Here, we regulate the crystal structure of starch with different chain-length distributions (CLDs) via extrusion at low/high shearing levels. The change in CLDs in extruded starch was obtained, and their effects on the fine structure (Dm, dBragg, dLorentz, degree of order and double helix, degree of crystal) of RS and its physicochemical properties were investigated by SAXS, FTIR, XRD and 13C NMR analyses. The results showed that the RS content under a 250 r/min extrusion condition was the highest at 61.52%. Furthermore, the crystalline system induced by high amylopectin (amylose ≤ 4.78%) and a small amount of amylose (amylose ≥ 27.97%) was favorable for obtaining a high content of RS3-modified products under the extruding environment. The control of the moderate proportion of the A chains (DP 6–12) in the starch matrix was beneficial to the formation of RS.

ABSTRACT: Background: To investigate the clinical distribution and changing trend of antibiotic resistance profiles of multidrug-resistant organisms (MDROs), a retrospective study was undertaken. Methods: The characteristics of MDROs isolated from 2016 to March 2023 were retrospectively analysed. The detection rate of these MDROs was compared prior to COVID-19 (Period 1, 2016–2019), during the COVID-19 pandemic with restrictions (Period 2, 2020–2022), and after the end of zero-policy (Period 3, Jan-March, 2023). Antibiotic-resistant genes were detected. Results: The overall detection rates of CRPA, CRAB, CREC, CRKP, MRSA, and VREfm were 22.6%, 22.6%, 1.3%, 4.0%, 19.5%, and 3.1%, respectively. The detection rate of CRAB was significantly lower in Period 2 and 3 compared with Period 1 (P < 0.0001). The detection rate of CRPA and VREfm was significantly increased in Period 3 compared with Period 1 and 2 (P < 0.0001). The resistance rate to ticarcillin/clavulanic acid (TIM) and piperacillin/tazobactam (TZP) has gradually increased in CRPA since 2018. NDM and KPC were the most common carbapenemase genes identified in CREC (60.0%) and CRKP isolates (47.8%), respectively. All the 10 VREfm isolates carried the vanA gene. Conclusions: The detection rate of CRAB has decreased since 2018, but a significantly increased prevalence of CRPA and VREfm was seen after the end of zero-policy. An increasing resistance rate to TIM and TZP was seen in CRPA. NDM, KPC, and vanA were the common genes harboured by CREC, CRKP, and VREfm, respectively. Ongoing surveillance after the COVID-19 era is suggested.

Abstract Background COVID‐19 has caused severe morbidity and mortality worldwide. After the end of the dynamic zero‐COVID policy in China in December, 2022, concerns regarding reinfection were raised while little was known due to the lack of surveillance data in this country. Aims This study reviews the probability, risk factors, and severity of severe acute respiratory syndrome coronavirus 2 Omicron variant reinfection, as well as the interval between infections, risk of onward transmission by reinfected cases, and the role of booster vaccination against reinfection. Sources References for this review were identified through searches of PubMed and Web of Science up to September 24, 2023. Results The rate of reinfection ranges from 3.1% to 13.0%. Factors associated with a higher risk of reinfection include being female, having comorbidities, and being unvaccinated. Reinfection with the BA.4 or BA.5 variant occurs approximately 180 days after the initial infection. Reinfections are less clinically severe than primary infections, and there is evidence of lower transmissibility. The debate surrounding the effectiveness and feasibility of booster vaccinations in preventing reinfection continues. Conclusions The reinfection rate during the Omicron epidemic is significantly higher than in previous epidemic periods. However, the symptoms and infectivity of reinfection were weaker than those of the prior infection. Medical staff and individuals at high risk of reinfection should be vigilant. The efficacy of booster vaccinations in reducing reinfection is currently under debate.

Studies on the crosstalk between muscle and adipose tissue can provide beneficial help in elucidating the pathogenesis and treatment of obesity-related diseases [1]. In this data article, we performed RNA sequence analysis of mRNA isolated from epididymal adipose tissue and gastrocnemius muscle tissue in obese rats. Twenty-two samples were selected for gene expression analysis. Raw data from the Illumina Hiseq™ platform sequencer was used for differential gene expression analysis using DESeq and deposited in the GEO public repository under accession number GSE237950. With the economic development and the change of people's lifestyle, obesity has become a major public health problem that endangers global health. Obesity is a metabolic disorder caused by excessive accumulation of white adipose tissue, which can further induce metabolic syndrome such as insulin resistance, type 2 diabetes, and cardiovascular and cerebrovascular diseases. Studies have shown that altitude hypoxic exercise can not only improve muscle buffering capacity and body performance, but also reduce body weight and body fat more significantly. In many countries, it has been used as a treatment program for obesity diseases [2]. Hypoxic exercise can improve lipid metabolism, reduce blood lipid levels, inhibit fatty acid synthesis, and promote fatty acid decomposition and oxidation, which is the mechanism of hypoxic exercise to significantly reduce weight and fat. However, the mechanism of the cross-talk between muscle and fat tissue is not well understood under hypoxia exercise and normoxia exercise conditions. The data contained rat's four different states: normoxia quiet, normoxia exercise, hypoxic quiet, and hypoxic exercise. RNA-seq data will provide insights into the cross-talk between muscle and fat, and the mechanisms of fat metabolism. The data of this study have not been published and are hereby published on this platform to study the cross talk between muscle tissue and adipose tissue in rats under different oxygen content and exercise environment.

BackgroundHER2-positive molecular breast cancer subtypes are characterized by high aggressiveness and malignancy, and their metastasis and mortality rates are among the highest of all types of breast cancer. The use of anti-HER2-targeted agents in neoadjuvant therapy has significantly improved the prognosis of patients with HER2-positive breast cancer. In this study, we investigated the efficacy and safety of a neoadjuvant Chinese THP regimen (docetaxel, trastuzumab biosimilar TQB211 plus the pertuzumab biosimilar TQB2440 or pertuzumab) for ER/PR-negative and HER2-positive breast cancer in China.MethodAll enrolled patients received the THP regimen (T: docetaxel 75 mg/m2 per cycle; H: trastuzumab biosimilar TQB211 8 mg/kg in the first cycle and 6 mg/kg maintenance dose in cycles 2 to 4; P: pertuzumab biosimilar TQB2440 or pertuzumab 840 mg in the first cycle, maintenance dose 420 mg in cycles 2 to 4) every 3 weeks for 4 cycles. The biosimilar TQB2440 pertuzumab and pertuzumab were randomly assigned to patients. Docetaxel, TQB211, and TQB2440 were all developed by Chiatai Tianqing. The primary endpoint was the complete pathological response (pCR) in the breast, and the secondary endpoint was cardiac safety. ResultsOf the 28 eligible patients, 19 (67.9%) achieved tpCR. The tpCR rate was higher than in the NeoSphere trial (pCR63.2%) and the PEONY study (tpCR52.5%). The adverse events that occurred most frequently were leukopenia and neutropenia, with incidence rates of 82.1% and 75.0%, respectively. Of these, grade 3 leukopenia and neutropenia occupied 46.4% and 35.7%. Other grade 3 or higher adverse events were bone marrow suppression (7.1%), lymphopenia (3.6%), and anemia (3.6%). There were no events of heart failure in patients and no patient died during the neoadjuvant phase. ConclusionDomestic dual-target HP has a more satisfactory efficacy and safety in the neoadjuvant phase of treatment.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05985187, NCT05985187.

Background/purpose: With the development of computer-assisted surgery, digital guide plate was widely used in vascularized bone flap grafts for mandibular reconstruction. The purpose of this study was to design and manufacture a digital guide plate with drill-hole sharing for mandibular reconstruction and assess for surgical accuracy. Materials and methods: 17 patients that required mandibular reconstruction using fibula free flap or iliac crest free flap were included in the study. The computed tomography (CT) data of the patient's mandible and pelvis or fibula were acquired preoperatively. A surgical simulation was then performed using computer-aided surgical simulation (CASS) technology based on above date, which allowed the design of two cutting guide and a repositioning guide for mandibular reconstruction. After surgery, the accuracy of reconstruction was evaluated by superimposing the postoperative image onto the preoperative image of mandible, recording the linear and angular deviation of landmarks, measuring the differences between the planned and actual outcomes. Results: The osteotomy and repositioning of fibula or iliac crest segments were successfully performed as planned using surgical guides. The digital guide plate with drill-hole sharing showed excellent accuracy, When the iliac crest or the fibula free flap were used for mandibular reconstruction, the largest mean differences between the preoperative and postoperative were 1.11 mm and 2.8° or 1.3 mm and 3.87°. Conclusion: The digital guide plate with drill-hole sharing designed preoperatively provides a reliable method of for the mandibular reconstruction. This can assist surgeons in accurately performing osteotomy and repositioning fibula or iliac crest segments during the mandibular reconstruction.

Abstract Mannoproteins (MPs) originate from yeast cells and can play important roles in maintaining wine stability and modulating wine organoleptic properties. Due to their natural presence in wines, MP products are allowed to be used as enological additives in wine industry. To guarantee an appropriate application of these products during winemaking, it is necessary for both researchers and winemakers to understand the mechanisms of MPs as multifunctional organoleptic modulators. This review has introduced the current state of knowledge of the researches focus on the application of different MP products in red wines and also the interactions between MPs and wine sensory active components (polyphenols, aroma compounds) in model wine solutions. We have summarized the possible mechanisms of MPs that affect the color, astringency, and aroma of red wines and the relationship between the physicochemical characteristics and functionalities of MPs. Besides, development trends of MP products are also discussed. It seems that yeast biomass, especially those from non‐Saccharomyces yeasts show good potential in producing large quantities of MPs, an appropriate combination of yeast cultivation and preservation methods with extraction and purification techniques may obtain MPs of ideal production, purity, and functionality in an industrial scale, which should be put more efforts by both scientists and manufacturers in the future.

Abstract Adipose tissue is essential for maintaining systemic metabolic homeostasis through traditional metabolic regulation, endocrine crosstalk, and extracellular vesicle production. Adipose dysfunction is a risk factor for cardiovascular diseases. The heart is a traditional pump organ. However, it has recently been recognized to coordinate interorgan cross-talk by providing peripheral signals known as cardiokines. These molecules include specific peptides, proteins, microRNAs and novel extracellular vesicle-carried cargoes. Current studies have shown that generalized cardiokine-mediated adipose regulation affects systemic metabolism. Cardiokines regulate lipolysis, adipogenesis, energy expenditure, thermogenesis during cold exposure and adipokine production. Moreover, cardiokines participate in pathological processes such as obesity, diabetes and ischemic heart injury. The underlying mechanisms of the cardiac-to-adipose axis mediated by cardiokines will be further discussed to provide potential therapeutic targets for metabolic diseases and support a new perspective on the need to correct adipose dysfunction after ischemic heart injury.

Abstract Background We evaluated the prognostic value of m6A-related long noncoding RNAs (lncRNAs) in lung adenocarcinoma (LUAD). Methods The expression levels of lncRNAs and mRNAs in LUAD and normal adjacent tissues from The Cancer Genome Atlas dataset were analyzed using the limma package. m6A enzyme-related differentially expressed lncRNAs and mRNAs were identified and used to construct a regulatory network. Survival analysis was performed and the correlation between lncRNAs, m6A regulators, and mRNAs was analyzed; followed by functional enrichment analysis. Results A comparison of LUAD samples and normal tissues identified numerous differentially expressed lncRNAs and mRNAs, demonstrating that a comprehensive network was established. Two lncRNAs and six mRNAs were selected as prognosis related factors including SH3PXD2A-AS1, MAD2L1, CCNA2, and CDC25C. The pathological stage and recurrence status were identified as independent clinical factors (P

Despite mounting evidence for dietary protease benefits, the mechanisms beyond enhanced protein degradation are poorly understood. This study aims to thoroughly investigate the impact of protease addition on the growth performance, intestinal function, and microbial composition of weaned piglets. Ninety 28-day-old weaned pigs were randomly assigned to the following three experimental diets based on their initial body weight for a 28-day experiment: (1) control (CC), a basic diet with composite enzymes without protease; (2) negative control (NC), a diet with no enzymes; and (3) dietary protease (PR), a control diet with protease. The results show that dietary proteases significantly enhanced growth performance and boosted antioxidant capacity, increasing the total antioxidant capacity (T-AOC) levels (p < 0.05) while reducing malonaldehyde levels (p < 0.05). Additionally, protease addition reduced serum levels of inflammatory markers TNF-α, IL-1β, and IL-6 (p < 0.05), suppressed mRNA expression of pro-inflammatory factors in the jejunum (p < 0.01), and inhibited MAPK and NF-κB signaling pathways. Moreover, protease-supplemented diets improved intestinal morphology and barrier integrity, including zonula occludens protein 1(ZO-1), Occludin, and Claudin-1 (p < 0.05). Microbiota compositions were also significantly altered by protease addition with increased abundance of beneficial bacteria (Lachnospiraceae_AC2044_group and Prevotellaceae_UCG-001) (p < 0.05) and reduced harmful Terrisporobacter (p < 0.05). Further correlation analysis revealed a positive link between beneficial bacteria and growth performance and a negative association with inflammatory factors and intestinal permeability. In summary, dietary protease addition enhanced growth performance in weaned piglets, beneficial effects which were associated with improved intestinal barrier integrity, immunological response, and microbiota composition.

Road transport and traffic congestion significantly contribute to dust pollution, which negatively impacts the growth of roadside plants in urban areas. This study aims to quantify the air pollution tolerance index (APTI) and analyze the impacts of dust deposition on different plant species and trees planted along a busy urban roadside in Lahore, Pakistan by considering seasonal variations. The APTI of each species is determined based on inputs of various biochemical parameters (leaf extract pH, ascorbic acid content, relative water content, and total chlorophyll levels), including dust deposition. In this study, laboratory analysis techniques are employed to assess these factors in selected plant species such as Mangifera indica, Saraca asoca, Cassia fistula, and Syzygium cumini. A statistical analysis is conducted to understand the pairwise correlation between various parameters and the APTI at significant and non-significant levels. Additionally, uncertainties in the inputs and APTI are addressed through a probabilistic analysis using the Monte Carlo simulation method. This study unveils seasonal variations in key parameters among selected plant species. Almost all biochemical parameters exhibit higher averages during the rainy season, followed by the summer and winter. Conversely, dust deposition on plants follows an inverse trend, with values ranging from 0.19 to 4.8 g/cm2, peaking during winter, notably in Mangifera indica. APTI values, ranging from 9.39 to 14.75, indicate varying sensitivity levels across species, from sensitive (Syzygium cumini) to intermediate tolerance (Mangifera indica). Interestingly, plants display increased tolerance during regular traffic hours, reflecting a 0.9 to 5% difference between the APTI at peak and regular traffic hours. Moreover, a significant negative correlation (−0.86 at p < 0.05 level) between APTI values and dust deposition suggests a heightened sensitivity to pollutants during the winter. These insights into the relationship between dust pollution and plant susceptibility will help decision makers in the selection of resilient plants for urban areas and improve air quality.

Abstract Vertebrate embryogenesis is a remarkable process, during which numerous cell types of different lineages arise within a short time frame. An overwhelming challenge to understand this process is the lack of dynamic chromatin accessibility information to correlate cis-regulatory elements (CREs) and gene expression within the hierarchy of cell fate decisions. Here, we employed single-nucleus ATAC-seq to generate a chromatin accessibility dataset on the first day of zebrafish embryogenesis, including 3.3 hpf, 5.25 hpf, 6 hpf, 10 hpf, 12 hpf, 18 hpf and 24 hpf, obtained 51,620 high-quality nuclei and 23 clusters. Furthermore, by integrating snATAC-seq data with single-cell RNA-seq data, we described the dynamics of chromatin accessibility and gene expression across developmental time points, which validates the accuracy of the chromatin landscape data. Together, our data could serve as a fundamental resource for revealing the epigenetic regulatory mechanisms of zebrafish embryogenesis.

This study used Tweedie-GAM to evaluate the distribution characteristics of Japanese scad (Decapterus maruadsi) in spring, summer, and autumn (from 2015 to 2020) and its relationship with marine environmental factors. The fishery resources data from the southern Zhejiang coastal waters were combined with the hydrological environment survey data collected simultaneously. The results showed significant differences in the Japanese scad spatial distribution in different seasons. Japanese scad is mainly concentrated in the nearshore waters in spring and concentrated primarily on the south and north regions of the Zhejiang southern waters in summer, showing a "high on both sides, low in the middle" pattern. The distribution pattern in autumn is opposite to that in spring, wherein the Japanese scad mainly concentrated in open waters. There are some differences in the key influencing factors of Japanese scad in different seasons. In spring, with a range of 19.5~25.0 ℃, the resource density firstly showed an increasing trend and then decreased with the rise in water temperature, peaking at 22.7 ℃. During summer, the water temperature reached 28.0~30.3 ℃, and the resource density showed the maximum value when the salinity was 32.3. In autumn, the resource density showed a decreasing trend and later increased with the increment in the water salinity, with a minimum value of 29.8. The relationship between resource density and water depth remained stable, showing a multi-wavy nonlinear relationship, with an overall increasing trend and later stable pattern. This study revealed the relationship between the Japanese scad's temporal and spatial distribution characteristics and environmental factors. It provides a research reference for the conservation, management, and sustainable utilization of Japanese scad in the coastal waters of southern Zhejiang.

T cells play a pivotal role in the immune system by distinguishing between various harmful pathogens and cancerous cells within the human body and initiating an immune response. Within the tumor microenvironment (TME), immune effector T cells encounter both immunosuppressive cells and factors that hinder their functionality. Additionally, they endure robust and persistent antigenic stimulation, often leading to exhaustion and apoptosis. However, the stemness of T cells, characterized by their ability to survive and self-renew over extended periods, represents a primary target in immune checkpoint therapies such as anti-PD-1 therapy. T cell stemness encompasses specific memory T cell subsets and progenitor-exhausted T cells with stem cell-like properties. Therefore, understanding the impact of the TME on T cell stemness, including factors like K+, lactate, and H+, holds significant importance and can facilitate the mitigation of terminal T-cell depletion, the identification of potential resilient biomarkers or therapeutic targets resistant to immune checkpoint therapies, and ultimately lead to sustained anti-tumor effects. Thus, it offers a novel perspective for advancing tumor immunotherapy.

Background The role of nonalcoholic fatty liver disease (NAFLD) as a mediator in the association between various unhealthy lifestyles and major adverse cardiovascular events and all‐cause death remains unclear. Methods and Results This study used data from the UK Biobank, with follow‐up until the end of 2021. It involved the calculation of unweighted and weighted lifestyle scores using the Cox model to classify participants on the basis of these scores. Additionally, the research assessed the mediation effect proportion of NAFLD using the difference method and examined the interaction and joint effects of lifestyle and NAFLD on health outcomes. Among the 134 616 enrolled participants, 4024 had records of major adverse cardiovascular events, while among the 130 144 participants included in the analysis of all‐cause death, 6697 deaths occurred. The proportions of the association between overall lifestyle and major adverse cardiovascular events mediated by NAFLD were 19.4% and 21.7% (95% CI, 16.2–22.6 and 17.8–25.7) for scores 1 and 2, respectively, and those for all‐cause death were 14.1% and 10.1% (95% CI, 11.3–17.1 and 7.9–12.2). After fully adjusting for traditional cardiovascular risk factors, the mediating effects declined across both outcomes. The associations between overall lifestyle and outcomes were stronger among those of the non‐NAFLD group, and significant interactions were observed between overall lifestyle and NAFLD status. The joint analysis revealed that patients with NAFLD with unhealthy lifestyle had the highest risk of major adverse cardiovascular events and all‐cause death. Conclusions Improving lifestyle and addressing metabolic risk factors are essential for cardiovascular risk management in patients with NAFLD.

Previous studies have revealed the miR164 family and the miR164-targeted NAC transcription factor genes in rice (Oryza sativa) and Arabidopsis that play versatile roles in developmental processes and stress responses. In wheat (Triticum aestivum L.), we found nine genetic loci of tae-miR164 (tae-MIR164 a to i) producing two mature sequences that down-regulate the expression of three newly identified target genes of TaNACs (TaNAC1, TaNAC11, and TaNAC14) by the cleavage of the respective mRNAs. Overexpression of tae-miR164 or one of its target genes (TaNAC14) demonstrated that the miR164-TaNAC14 module greatly affects root growth and development and stress (drought and salinity) tolerance in wheat seedlings, and TaNAC14 promotes root growth and development in wheat seedlings and enhances drought tolerance, while tae-miR164 inhibits root development and reduces drought and salinity tolerance by down-regulating the expression of TaNAC14. These findings identify the miR164-TaNAC14 module as well as other tae-miR164-regulated genes which can serve as new genetic resources for stress-resistance wheat breeding.

Abstract It is difficult to accurately estimate the incidence rate of intimate partner violence (IPV) using traditional social survey methods because IPV victims are often reluctant to disclose their experiences, leading to an underestimation of the incidence rate. To address this issue, we applied machine learning algorithms to predict the incidence rate of IPV in China based on data from the Third Wave Survey on the Social Status of Women in China (TWSSSCW 2010). Specifically, we examined five unbalanced sample-processing methods and six machine learning algorithms, choosing the random under-sampling ensemble method and the random forest algorithm to impute the missing data. Analysis of the complete data showed that the incidence rates of physical violence, verbal violence, and cold violence were 7.10%, 13.74%, and 21.35%, respectively, which were higher than the incidence rates in the original dataset (4.05%, 11.21%, and 17.95%, respectively). The robustness of our findings was further confirmed by analysis using different training sets. Overall, this study demonstrates that better tools need to be developed to accurately estimate the incidence rates of IPV. It also serves as a useful guide for future research that imputes missing data using machine learning.

Yellow light-emitting diodes (LEDs) as soft light have attracted abundant attention in lithography room, museum and art gallery. However, the development of efficient yellow LEDs lags behind green and blue LEDs, and the available perovskites yellow LEDs suffer from the instability. Herein, a pressure-assisted cooling method is proposed to grow lead-free CsCu2I3 single crystals, which possess uniform surface morphology and enhanced photoluminescence quantum yield (PLQY) stability, with only 10% PLQY losses after being stored in air after 5000 ​h. Then, the single crystals used for yellow LEDs without encapsulation exhibit a decent Correlated Color Temperature (CCT) of 4290 ​K, a Commission Internationale de l'Eclairage (CIE) coordinate of (0.38, 0.41), and an excellent 570-h operating stability under heating temperature of 100 ​°C. Finally, the yellow LEDs facilitate the application in wireless visible light communication (VLC), which show a −3 dB bandwidth of 21.5 ​MHz and a high achievable data rate of 219.2 Mbps by using orthogonal frequency division multiplexing (OFDM) modulation with adaptive bit loading. The present work not only promotes the development of lead-free single crystals, but also inspires the potential of CsCu2I3 in the field of yellow illumination and wireless VLC.

Multispectral thermometry is based on the law of blackbody radiation and is widely used in engineering practice today. Temperature values can be inferred from radiation intensity and multiple sets of wavelengths. Multispectral thermometry eliminates the requirements for single-spectral and spectral similarity, which are associated with two-colour thermometry. In the process of multispectral temperature inversion, the solution of spectral emissivity and multispectral data processing can be seen as the keys to accurate thermometry. At present, spectral emissivity is most commonly estimated using assumption models. When an assumption model closely matches an actual situation, the inversion of the temperature and the accuracy of spectral emissivity are both very high; however, when the two are not closely matched, the inversion result is very different from the actual situation. Assumption models of spectral emissivity exhibit drawbacks when used for thermometry of a complex material, or any material whose properties dynamically change during a combustion process. To address the above problems, in the present study, we developed a multispectral thermometry method based on optimisation ideas. This method involves analysing connections between measured temperatures of each channel in a multispectral temperature inversion process; it also makes use of correlations between multispectral signals at different temperatures. In short, we established a multivariate temperature difference correlation function based on the principles of multispectral radiometric thermometry, using information correlations between data for each channel in a temperature inversion process. We then established a high-precision thermometry model by optimising the correlation function and correcting any measurement errors. This method simplifies the modelling process so that it becomes an optimisation problem of the temperature difference function. This also removes the need to assume the relationships between spectral emissivity and other physical quantities, simplifying the process of multispectral thermometry. Finally, this involves correction of the spectral data so that any impact of measurement error on the thermometry is reduced. In order to verify the feasibility and reliability of the method, a simple eight-channel multispectral thermometry device was used for experimental validation, in which the temperature emitted from a blackbody furnace was identified as the standard value. In addition, spectral data from the 468–603 nm band were calibrated within a temperature range of 1923.15–2273.15 K, resulting in multispectral thermometry based on optimisation principles with an error rate of around 0.3% and a temperature calculation time of less than 3 s. The achieved level of inversion accuracy was better than that obtained using either a secondary measurement method (SMM) or a neural network method, and the calculation speed achieved was considerably faster than that obtained using the SMM method.

Biomedical and food analysis has always been an important topic that closely relates to health [...]

Smooth bromegrass (Bromus inermis) is a perennial, high-quality forage grass. However, its seed yield is influenced by agronomic practices, climatic conditions, and the growing year. The rapid and effective prediction of seed yield can assist growers in making informed production decisions and reducing agricultural risks. Our field trial design followed a completely randomized block design with four blocks and three nitrogen levels (0, 100, and 200 kg·N·ha−1) during 2022 and 2023. Data on the remote vegetation index (RVI), the normalized difference vegetation index (NDVI), the leaf nitrogen content (LNC), and the leaf area index (LAI) were collected at heading, anthesis, and milk stages. Multiple linear regression (MLR), support vector machine (SVM), and random forest (RF) regression models were utilized to predict seed yield. In 2022, the results indicated that nitrogen application provided a sufficiently large range of variation of seed yield (ranging from 45.79 to 379.45 kg ha⁻¹). Correlation analysis showed that the indices of the RVI, the NDVI, the LNC, and the LAI in 2022 presented significant positive correlation with seed yield, and the highest correlation coefficient was observed at the heading stage. The data from 2022 were utilized to formulate a predictive model for seed yield. The results suggested that utilizing data from the heading stage produced the best prediction performance. SVM and RF outperformed MLR in prediction, with RF demonstrating the highest performance (R2 = 0.75, RMSE = 51.93 kg ha−1, MAE = 29.43 kg ha−1, and MAPE = 0.17). Notably, the accuracy of predicting seed yield for the year 2023 using this model had decreased. Feature importance analysis of the RF model revealed that LNC was a crucial indicator for predicting smooth bromegrass seed yield. Further studies with an expanded dataset and integration of weather data are needed to improve the accuracy and generalizability of the model and adaptability for the growing year.

Background: Trace elements such as copper are essential for human health. Recently the journal Nat Rev Cancer has put forward the concept of Cuproplasia, a way of promoting tumor growth through reliance on copper. We attempted to conduct a comprehensive analysis of Cuproplasia-related genes in lung adenocarcinoma (LUAD) to explore the mechanism of action of Cuproplasia-related genes in LUAD.Method: Transcriptome data and clinical information of LUAD were obtained from TCGA-LUAD and GSE31210, and prognostic models of Cuproplasia-related genes were constructed and verified by regression analysis of GSVA, WGCNA, univariate COX and lasso. The signal pathways affected by Cuproplasia-related genes were analyzed by GO, KEGG and hallmarK pathway enrichment methods. Five immunocell infiltration algorithms and IMVIGOR210 data were used to analyze immune cell content and immunotherapy outcomes in the high-low risk group.Results: In the results of WGCNA, BROWN and TURQUOISE were identified as modules closely related to Cuproplasia score. In the end, lasso regression analysis established a Cuproplasia-related signature (CRS) based on 24 genes, and the prognosis of high-risk populations was worse in TCGA-LUAD and GSE31210 datasets. The enrichment analysis showed that copper proliferation was mainly through chromosome, cell cycle, dna replication, g2m checkpoint and other pathways. Immunoinfiltration analysis showed that there were differences in the content of macrophages among the four algorithms. And IMVIGOR210 found that the lower the score, the more effective the immunotherapy was.Conclusion: The Cuproplasia related gene can be used to predict the prognosis and immunotherapy outcome of LUAD patients, and may exert its effect by affecting chromosome-related pathways and macrophages.

IntroductionTumor immunotherapy targeting PD-L1 has emerged as one of the powerful tools for tumor therapy. Numerous studies indicate that tumor-targeted drugs critically have an influence on the interaction between the immune system and tumors by changing the expression of PD-L1, which is beneficial for immunotherapy. Our study provided novel evidence for improving the drug regimen in tumor targeted therapy and immunotherapy.MethodsThe expression of PD-L1 on SKBR3, MDA-MB-231, MCF7, 4T1, MC38 and B16 cells was evaluated by flow cytometry after treatment with six preclinical targeted drugs (ARN-509, AZD3514, Galeterone, Neratinib, MLN8237 and LGK974). AURKA was knockdowned by using the specific siRNA or CRISPR-Cas9 technology. In the 4T1-breast tumor and colorectal cancer xenograft tumor models, we determined the number of infiltrated CD3+ and CD8+ T cells in tumor tissues by IHC.ResultsWe found that AURKA inhibitor MLN8237 promoted the expression of PD-L1 in a time- and concentration-dependent manner while exerted its antitumor effect. Knockdown of AURKA could induce the upregulation of PD-L1 on SKBR3 cells. MLN8237-induced PD-L1 upregulation was mainly associated with the phosphorylation of STAT3. In the 4T1-breast tumor xenograft model, the infiltrated CD3+ and CD8+ T cells decreased after treatment with MLN8237. When treated with MLN8237 in combination with anti-PD-L1 antibody, the volumes of tumor were significantly reduced and accompanied by increasing the infiltration of CD3+ and CD8+ T cells in colorectal cancer xenograft tumor model.DiscussionOur data demonstrated that MLN8237 improved the effect of immunology-related therapy on tumor cells by interacting with anti-PD-L1 antibody, which contributed to producing creative sparks for exploring the possible solutions to overcoming drug resistance to tumor targeted therapy.

There are defects including peak stacking and large load fluctuations in existing multi-tube combined structures. To overcome these defects, a differentiated combination design based on the idea of peak load dislocation superposition is undertaken for the height configuration and diaphragm spacing configuration of each tube. The influence of time to peak load is revealed by combining experiment, theory, and simulation. The results show that the height difference only induces a difference in the time to initial peak loads of tubes, while the subsequent peak loads remain stacked, which cannot reduce the load fluctuations. The variations of the diaphragm spacing can prolong or shorten the duration of deformation of folds in a designated area, thus changing the formation timings of subsequent peak loads, which is a feasible method for controlling the time to formation of the peaks. By optimally setting heights and distributing diaphragm spacings of tubes, peak loads of multi-tube structures can be fully separated, thus reducing the initial peak and load fluctuations. The initial peak load and the fluctuations of the 6-4GT-ΔJ-ΔH 2-Adj combined tube constructed based on the configuration differentiated design idea are reduced by 45.33% and 76.62% respectively, while maintaining the high energy absorption of the system.

Owing to their outstanding optoelectronic properties, all-inorganic CsPbBr3 perovskite nanocrystals (NCs) are regarded as excellent materials for various optoelectronic applications. Unfortunately, their practical applications are limited by poor stability against water, heat, and polar solvents. Here, we propose a facile synthesis strategy for CsPbBr3@Cs4PbBr6 NCs via tetraoctylammonium bromide ligand induction at room temperature. The resulting CsPbBr3@Cs4PbBr6 NCs show a high photoluminescence quantum yield of 94%. In order to prevent Cs4PbBr6 from being converted back to CsPbBr3 NCs when exposed to water, a second coating layer of SiO2 is formed on the surface of the CsPbBr3@Cs4PbBr6 NCs by the facile hydrolysis of tetramethoxysilane. The resulting CsPbBr3@Cs4PbBr6/SiO2 NCs with their double coating structure have outstanding stability against not only a polar solvent (ethanol) but also water and heat. The as-prepared CsPbBr3@Cs4PbBr6/SiO2 NCs serve as green emitters in efficient white light-emitting diodes (WLEDs) with a high color rendering index (CRI) of 91 and a high power efficiency 59.87 lm W−1. Furthermore, the use of these WLEDs in visible light communication (VLC) results in a maximum rate of 44.53 Mbps, suggesting the great potential of the reported methods and materials for solid-state illumination and VLC.

Abstract Background Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is one of the most frequent gastrointestinal disorders worldwide. Although the actual etiology of IBD remains unclear, growing evidence suggests that CD4+ T cells-associated cytokines, including interferon (IFN)-γ, interleukin (IL)-10 and IL-17A, are crucial for the occurrence of IBD. It has been reported that there is a positive association between miRNAs and IBD development. In this study, we investigated the roles of hsa-miRNA-374b-5p(miRNA-374b-5p) and hsa-miRNA-106a-5p(miRNA-106a-5p) in regulating IBD development. Methods Serum was obtained from vein blood of IBD patients and healthy controls, qRT-PCR was performed to study the expression of miRNA-374b-5p and miRNA-106a-5p. Furthermore, we investigate the effects of overexpression or inhibition of miRNA-374b-5p on naïve CD4 + T cell subsets differentiation from vein blood of healthy controls by RT-qPCR, flow cytometry and western blot. And more the prediction and confirmation of the targeting genes of miRNA-374b-5p and miRNA-106a-5p were performed by bioinformatics softwares and dual-luciferase reporter assay. Results The results showed that miRNA-106a-5p and miRNA-374b-5p were significantly overexpressed in IBD patients. MiRNA-374b-5p could enhance Th1/Th17 cell differentiation and was related to IBD pathogenesis. MiRNA-374b-5p overexpression induced the mRNA expression of IL-17A and IFN-γ, and suppressed that of IL-10 in T cells. MiRNA-374b-5p inhibition decreased the mRNA expression of IL-17A and IFN-γ, while upregulated that of IL-10 in T cells. These qPCR data were further verified at protein level by western blotting and flow cytometry. In addition, dual-luciferase reporter (DLR) assay indicated that miRNA-374b-5p was directly targeted by IL-10, a key anti-inflammatory cytokine for preventing the occurrence of IBD. Meanwhile, STAT3 was identified as a target gene of miRNA-106a-5p by DLR assays. Further analysis revealed that miRNA-374b-5p regulated JAK1 and STAT3 pathways in CD4+ T cells via IL-10/STAT3 axis. MiRNA-374b-5p overexpression remarkably decreased the mRNA expression and phosphorylated (ser-727) protein levels of STAT3, while miRNA-374b-5p inhibition had the opposite effects. Conclusion MiRNA-374b-5p and miRNA-106a-5p may contribute to IBD development by regulating IL-10/STAT3 signal transduction.

It is an urgent demand worldwide to control the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) are key targets to discover SARS-CoV-2 inhibitors. After screening 12 Chinese herbal medicines and 125 compounds from licorice, we found that a popular natural product schaftoside inhibited 3CLpro and PLpro with IC50 values of 1.73 ± 0.22 and 3.91 ± 0.19 μmol/L, respectively, and inhibited SARS-CoV-2 virus in Vero E6 cells with EC50 of 11.83 ± 3.23 μmol/L. Hydrogen–deuterium exchange mass spectrometry analysis, quantum mechanics/molecular mechanics calculations, together with site-directed mutagenesis indicated the antiviral activities of schaftoside were related with non-covalent interactions with H41, G143 and R188 of 3CLpro, and K157, E167 and A246 of PLpro. Moreover, proteomics analysis and cytokine assay revealed that schaftoside also regulated immune response and inflammation of the host cells. The anti-inflammatory activities of schaftoside were confirmed on lipopolysaccharide-induced acute lung injury mice. Schaftoside showed good safety and pharmacokinetic property, and could be a promising drug candidate for the prevention and treatment of COVID-19.

PCR is an essential method for the amplification and manipulation of nucleic acids, but the requirement for a thermocycler limits access. Here, authors engineer a helicase to replace the heating step of PCR with enzymatic unwinding, allowing the isothermal amplification of fragments up to 6 kb.

Abstract Background The association between body mass index (BMI) and Alzheimer's disease (AD) remains controversial. Genetic and environmental factors are now considered contributors to AD risk. However, little is known about the potential interaction between genetic risk and BMI on AD risk. Objective To study the causal relationship between BMI and AD, and the potential interaction between AD genetic risk and BMI on AD risk. Methods and Results Using the UK Biobank database, 475,813 participants were selected for an average follow-up time of more than 10 years. Main findings: 1) there was a nonlinear relationship between BMI and AD risk in participants aged 60 years or older (p for non-linear 30 kg/m2) group was associated with a lower AD risk (HR = 0.741; 95% CI 0.618–0.888, p

Abstract Background Alzheimer's disease (AD) is the most frequently occurring type of dementia. Concurrently, inadequate sleep has been recognized as a public health epidemic. Notably, genetic and environmental factors are now considered contributors to AD progression. Objective To assess the association between sleep duration, genetic susceptibility, and AD. Methods and results Based on 483,507 participants from the UK Biobank (UKB) with an average follow-up of 11.3 years, there was a non-linear relationship between AD incidence and sleep duration (P for non-linear 9 h/night). No statistically significant interaction was identified between sleep duration and the AD-GRS (Alzheimer's disease genetic risk score, P for interaction = 0.45) using Cox proportional risk model. Compared with the participants who had a low AD-GRS and normal sleep duration, there was associated with a higher risk of AD in participants with a low AD-GRS and long sleep duration (HR = 3.4806; 95% CI 2.0011–6.054, p 9 h/night) was significantly associated with a higher risk of AD, regardless of high, intermediate or low AD-GRS. Prolonged sleep duration may be one of the clinical predictors of a higher risk of AD.

An intelligent lithology identification method is proposed based on deep learning of the rock microscopic images. Based on the characteristics of rock images in the dataset, we used Xception, MobileNet_v2, Inception_ResNet_v2, Inception_v3, Densenet121, ResNet101_v2, and ResNet-101 to develop microscopic image classification models, and then the network structures of seven different convolutional neural networks (CNNs) were compared. It shows that the multi-layer representation of rock features can be represented through convolution structures, thus better feature robustness can be achieved. For the loss function, cross-entropy is used to back propagate the weight parameters layer by layer, and the accuracy of the network is improved by frequent iterative training. We expanded a self-built dataset by using transfer learning and data augmentation. Next, accuracy (acc) and frames per second (fps) were used as the evaluation indexes to assess the accuracy and speed of model identification. The results show that the Xception-based model has the optimum performance, with an accuracy of 97.66% in the training dataset and 98.65% in the testing dataset. Furthermore, the fps of the model is 50.76, and the model is feasible to deploy under different hardware conditions and meets the requirements of rapid lithology identification. This proposed method is proved to be robust and versatile in generalization performance, and it is suitable for both geologists and engineers to identify lithology quickly.

In mammals, early organogenesis begins soon after gastrulation, accompanied by specification of various type of progenitor/precusor cells. In order to reveal dynamic chromatin landscape of precursor cells and decipher the underlying molecular mechanism driving early mouse organogenesis, we performed single-cell ATAC-seq of E8.5-E10.5 mouse embryos. We profiled a total of 101,599 single cells and identified 41 specific cell types at these stages. Besides, by performing integrated analysis of scATAC-seq and public scRNA-seq data, we identified the critical cis-regulatory elements and key transcription factors which drving development of spinal cord and somitogenesis. Furthermore, we intersected accessible peaks with human diseases/traits-related loci and found potential clinical associated single nucleotide variants (SNPs). Overall, our work provides a fundamental source for understanding cell fate determination and revealing the underlying mechanism during postimplantation embryonic development, and expand our knowledge of pathology for human developmental malformations.

Abstract Fluorescent probes for detection of CN− still have many limitations, such as small Stokes shift, irreversible, and background interference, which hamper their applications for on‐site detection and bioimaging of CN−. In this work, we design a new CN−‐activatable fluorescent probe (named AHMM) containing an ESIPT (excited‐state intramolecular proton transfer) and hydrogen bond features, which show a large Stokes shift (225 nm) and molecular structural reversible detection. The probe AHMM exhibits an excellent selectivity for CN− without any interference from other anions in aqueous DMSO system. Furthermore, the mechanism of the interaction of AHMM with CN− is concluded by various experiments. The limit of detection of AHMM for CN− is calculated as low as 4.47 × 10−8 M, lower than the concentration of CN− deemed acceptable by WHO (World Health Organization). AHMM can recognize CN− in tap water quantitatively and on‐site by a smartphone APP. Moreover, food samples such as almond and cassava including CN− are visualized by fluorescence imaging. In addition, the probe shows practical applications of CN− imaging in cells and mice. This concept can be applied for designing multifunctional fluorescent probes with ESIPT and reversible characteristics for detection of CN−.

Abiotic stresses have deleterious effects on seed germination and seedling establishment, leading to significant crop yield losses. Adverse environmental conditions can cause the accumulation of methylglyoxal (MG) within plant cells, which can negatively impact plant growth and development. The glyoxalase system, which consists of the glutathione (GSH)-dependent enzymes glyoxalase I (GLX1) and glyoxalase II (GLX2), as well as the GSH-independent glyoxalase III (GLX3 or DJ-1), plays a crucial role in detoxifying MG. However, genome-wide analysis of glyoxalase genes has not been performed for one of the agricultural important species, oat (Avena sativa). This study identified a total of 26 AsGLX1 genes, including 8 genes encoding Ni2+-dependent GLX1s and 2 genes encoding Zn2+-dependent GLX1s. Additionally, 14 AsGLX2 genes were identified, of which 3 genes encoded proteins with both lactamase B and hydroxyacylglutathione hydrolase C-terminal domains and potential catalytic activity, and 15 AsGLX3 genes encoding proteins containing double DJ-1 domains. The domain architecture of the three gene families strongly correlates with the clades observed in the phylogenetic trees. The AsGLX1, AsGLX2, and AsGLX3 genes were evenly distributed in the A, C, and D subgenomes, and gene duplication of AsGLX1 and AsGLX3 genes resulted from tandem duplications. Besides the core cis-elements, hormone responsive elements dominated the promoter regions of the glyoxalase genes, and stress responsive elements were also frequently observed. The subcellular localization of glyoxalases was predicted to be primarily in the cytoplasm, chloroplasts, and mitochondria, with a few presents in the nucleus, which is consistent with their tissue-specific expression. The highest expression levels were observed in leaves and seeds, indicating that these genes may play important roles in maintaining leaf function and ensuring seed vigor. Moreover, based on in silico predication and expression pattern analysis, AsGLX1-7A, AsGLX2-5D, AsDJ-1-5D, AsGLX1-3D2, and AsGLX1-2A were suggested as promising candidate genes for improving stress resistance or seed vigor in oat. Overall, the identification and analysis of the glyoxalase gene families in this study can provide new strategies for improving oat stress resistance and seed vigor.