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Abstract This paper proposes a method of impulse current generator modulated DC arc by combining the advantages of pulse and the RF to solve the low electron energy problem of direct current arc. Through experimental analyzing the electrical, spectral, and optical characteristics of the arc, the effect of impulse current generator (ICG) on improving electron energy is discussed. The results show that the ICG consumes more energy to enhance the strength of arc discharge, and therefore electron energy is increased in a microsecond scale. In addition, it is found that the electron energy of the arc discharge can be adjusted by varying inductance, capacitance, and discharge tube: increasing the inductance or capacitance can increase the electron energy firstly and then decrease it. In adjusting the three adjustable components, adjusting the inductor is the most effective method, followed by adjusting the capacitor, and adjusting the repetition frequency has the least effect. The reason is discussed, and it is believed that the results are related to leakage inductance and distributed capacitance.

Abstract Peptide‐based drugs hold great potential for cancer treatment, and their effectiveness is driven by mechanisms on how peptides target cancer cells and escape from potential lysosomal entrapment post‐endocytosis. Yet, the mechanisms remain elusive, which hinder the design of peptide‐based drugs. Here hendeca‐arginine peptides (R11) are synthesized for targeted delivery in bladder carcinoma (BC), investigated the targeting efficiency and elucidated the mechanism of peptide‐based delivery, with the aim of refining the design and efficacy of peptide‐based therapeutics. It is demonstrated that the over‐activated Piezo1/integrin β1 (ITGB1) signaling axis significantly facilitates tumor‐targeted delivery of R11 peptides via macropinocytosis. Furthermore, R11 peptides formed hydrogen bonds with integrin β1, facilitating targeting and penetration into tumor cells. Additionally, R11 peptides protected integrin β1 from lysosome degradation, promoting its recycling from cytoplasm to membrane. Moreover, this findings establish a positive feedback loop wherein R11 peptides activate Piezo1 by increasing membrane fusion, promoting Ca2+ releasing and resulting in enhanced integrin β1‐mediated endocytosis in both orthotopic models and clinical tissues, demonstrating effective tumor‐targeted delivery. Eventually, the Piezo1/integrin β1 signaling axis promoted cellular uptake and transport of peptides, establishing a positive feedback loop, promoting mechanical delivery to cancer and offering possibilities for drug modification in cancer therapy.

Abstract Tumor malignancy highly depends on the stiffness of tumor matrix, which mainly consists of collagen. Despite the destruction of tumor matrix is conducive to tumor therapy, it causes the risk of tumor metastasis. Here, metal‐anesthetic network‐coated dormant collagenase‐producing Clostridium is constructed to simultaneously destruct tumor matrix and inhibit tumor metastasis. By metal‐phenolic complexation and π–π stacking interactions, a Fe3+‐propofol network is formed on bacterial surface. Coated dormant Clostridium can selectively germinate and rapidly proliferate in tumor sites due to the ability of carried Fe3+ ions to promote bacterial multiplication. Intratumoral colonization of Clostridium produces sufficient collagenases to degrade tumor collagen mesh and the loaded propofol restrains tumor metastasis by inhibiting tumor cell migration and invasion. Meanwhile, the delivered Fe3+ ions are reduced to the Fe2+ form by intracellular glutathione, thereby inducing potent Fenton reaction to trigger lipid peroxidation and ultimate ferroptosis of tumor cells. In addition to a satisfactory safety, a single intratumoral injection of coated dormant Clostridium not only effectively retards the growth of established large primary tumors, but also significantly suppresses distal lung metastasis in two different orthotopic tumor models. This work proposes a strategy to develop advanced therapeutics for malignant tumor treatment and metastasis prevention.

Abstract The summer monsoon onset over the Bay of Bengal and South China Sea signals the beginning of the Asian summer monsoon, critical for local fisheries, agriculture and livelihoods, so communities are concerned about its potential changes under global warming. Previous projections have suggested a delay, but the extent of this delay remains uncertain, undermining the reliability of the projections. Here, we show a significant correlation between the projected shift in Bay of Bengal/South China Sea monsoon onset and present‐day sea surface temperature (SST) simulation over the western Pacific (WP). This emergent relationship arises from the spread of the precipitation response over the western‐central Pacific to WP SST, as more precipitation induces stronger tropical upper‐tropospheric warming, increasing westerly vertical shear near South Asia, and facilitating the onset delay. The rectified projections indicate that the delayed shift is almost halved compared to raw projections, and the intermodel uncertainty is reduced by 30%.

Abstract Asynchronous nuclear and cytoplasmic maturation in human oocytes is believed to cause morphological anomalies after controlled ovarian hyperstimulation. Vacuolar protein sorting 34 (VPS34) is renowned for its pivotal role in regulating autophagy and endocytic trafficking. To investigate its impact on oocyte development, oocyte‐specific knockout mice (ZcKO) are generated, and these mice are completely found infertile, with embryonic development halted at 2‐ to 4‐cell stage. This infertility is related with a disruption on autophagic/mitophagic flux in ZcKO oocytes, leading to subsequent failure of zygotic genome activation (ZGA) in derived 2‐cell embryos. The findings further elucidated the regulation of VPS34 on the activity and subcellular translocation of RAS‐related GTP‐binding protein 7 (RAB7), which is critical not only for the maturation of late endosomes and lysosomes, but also for initiating mitophagy via retrograde trafficking. VPS34 binds directly with RAB7 and facilitates its activity conversion through TBC1 domain family member 5 (TBC1D5). Consistent with the cytoplasmic vacuolation observed in ZcKO oocytes, defects in multiple vesicle trafficking systems are also identified in vacuolated human oocytes. Furthermore, activating VPS34 with corynoxin B (CB) treatment improved oocyte quality in aged mice. Hence, VPS34 activation may represent a novel approach to enhance oocyte quality in human artificial reproduction.

Abstract In this study, a novel bionic periosteum (BP)‐bioactive glass fiber membrane (BGFM) is designed. The introduction of magnesium ion (Mg2+) and zinc ion (Zn2+) change the phase separation during the electrospinning (ES) jet stretching process. The fiber's pore structure transitions from connected to closed pores, resulting in a decrease in the rapid release of metal ions while also improving degradation via reducing filling quality. Additionally, the introduction of magnesium (Mg) and zinc (Zn) lead to the formation of negative charged tetrahedral units (MgO42− and ZnO42−) in the glass network. These units effectively trap positive charged metal ions, further inhibiting ion release. In vitro experiments reveal that the deigned bionic periosteum regulates the polarization of macrophages toward M2 type, thereby establishing a conducive immune environment for osteogenic differentiation. Bioinformatics analysis indicate that BP enhanced bone repair via the JAK‐STAT signaling pathway. The slow release of metal ions from the bionic periosteum can directly enhance osteogenic differentiation and vascularization, thereby accelerating bone regeneration. Finally, the bionic periosteum exhibits remarkable capabilities in angiogenesis and osteogenesis, demonstrating its potential for bone repair in a rat calvarial defect model.

Abstract The development of acute respiratory distress syndrome (ARDS) in sepsis is associated with substantial morbidity and mortality. However, the molecular pathogenesis underlying sepsis‐induced ARDS remains elusive. Neutrophil heterogeneity and dysfunction contribute to uncontrolled inflammation in patients with ARDS. A specific subset of neutrophils undergoing reverse transendothelial migration (rTEM), which is characterized by an activated phenotype, is implicated in the systemic dissemination of inflammation. Using single‐cell RNA sequencing (scRNA‐seq), it identified functionally activated neutrophils exhibiting the rTEM phenotype in the lung of a sepsis mouse model using cecal ligation and puncture. The prevalence of neutrophils with the rTEM phenotype is elevated in the blood of patients with sepsis‐associated ARDS and is positively correlated with disease severity. Mechanically, scRNA‐seq and proteomic analys revealed that inflamed endothelial cell (EC) released extracellular vesicles (EVs) enriched in karyopherin subunit beta‐1 (KPNB1), promoting abluminal‐to‐luminal neutrophil rTEM. Additionally, EC‐derived EVs are elevated and positively correlated with the proportion of rTEM neutrophils in clinical sepsis. Collectively, EC‐derived EV is identified as a critical regulator of neutrophil rTEM, providing insights into the contribution of rTEM neutrophils to sepsis‐associated lung injury.

Abstract Peer‐to‐peer energy trading enhances distribution network resilience by reducing energy demand from central power plants and enabling distributed energy resources to support critical loads after extreme events. However, adequate reserves from main grids are still required to ensure real‐time energy balance in distribution networks due to the uncertainty in renewable generation. This paper introduces a novel two‐stage joint energy and reserve market for prosumers, wherein local flexible resources are fully utilized to manage renewable generation uncertainty. In contrast to cooperative optimization methods, the interactions between prosumers are modelled as a generalized Nash game, considering that prosumers are self‐interested and should follow distribution network constraints. Then, linear decision rules are employed to ensure a feasible market equilibrium and develop a privacy‐preserving algorithm to guide prosumers the market equilibrium with a proven convergence. Finally, the numerical study on a modified IEEE 33‐power system demonstrates that the designed market effectively manages renewable generation uncertainty, and that the algorithm converges to the market equilibrium.

Abstract Background The spleen plays an important role in systemic antitumor immune response, but whether spleen imaging features have predictive effect for prognosis and immune status was unknown. The aim of this study was to investigate computed tomography (CT)‐based spleen radiomics to predict the prognosis of patients with esophageal squamous cell carcinoma (ESCC) underwent definitive radiotherapy (dRT) and to try to find its association with systemic immunity. Methods This retrospective study included 201 ESCC patients who received dRT. Patients were randomly divided into training (n = 142) and validation (n = 59) groups. The pre‐ and delta‐radiomic features were extracted from enhanced CT images. LASSO‐Cox regression was used to select the radiomics signatures most associated with progression‐free survival (PFS) and overall survival (OS). Independent prognostic factors were identified by univariate and multivariate Cox analyses. The ROC curve and C‐index were used to evaluate the predictive performance. Finally, the correlation between spleen radiomics and immune‐related hematological parameters was analyzed by spearman correlation analysis. Results Independent prognostic factors involved TNM stage, treatment regimen, tumor location, pre‐ or delta‐Rad‐score. The AUC of the delta‐radiomics combined model was better than other models in the training and validation groups in predicting PFS (0.829 and 0.875, respectively) and OS (0.857 and 0.835, respectively). Furthermore, some spleen delta‐radiomic features are significantly correlated with delta‐ALC (absolute lymphocyte count) and delta‐NLR (neutrophil‐to‐lymphocyte ratio). Conclusions Spleen radiomics is expected to be a useful noninvasive tool for predicting the prognosis and evaluating systemic immune status for ESCC patients underwent dRT.

Abstract Background Uncontrolled inflammation caused by macrophages and monocytes plays a crucial role in worsening acute respiratory distress syndrome (ARDS). Previous studies have highlighted the importance of IFIH1 in regulating macrophage polarisation in ARDS triggered by pneumonia. However, the mechanisms by which IFIH1 is activated in ARDS remain unclear. Methods In this study, we utilised multiomics sequencing and molecular interaction experiments to explore the molecular mechanisms underlying IFIH1 activation in ARDS. Through the use of conditional gene knockout mice and primary cells, we demonstrated the significant role of these mechanisms in the development of ARDS. Additionally, we validated the associations between these mechanisms and ARDS by quantitative PCR analysis of CD14+ cells obtained from the peripheral blood of 140 ARDS patients. Results Our investigation revealed that lipopolysaccharide, a critical component derived from Gram‐negative bacteria, activated IFIH1 by upregulating a novel transcript known as IFIH1‐binding RNA1 (IBR1) in monocytes and macrophages. Specifically, as an endogenous double‐stranded RNA, IBR1 bind to the helicase domain of IFIH1 because of its unique double‐stranded structure. Deletion of IBR1 significantly reduced the activation of IFIH1, M1 polarisation of macrophages, and inflammatory lung injury in ARDS. Moreover, IBR1 directly induced M1 polarisation of macrophages and ARDS, whereas deletion of IFIH1 inhibited IBR1‐induced macrophage M1 polarisation and inflammatory lung injury. Importantly, we observed a notable increase in IBR1 expression in ARDS patients with pneumonia caused by Gram‐negative bacteria. Furthermore, we demonstrated that the delivery of IFIH1 mutants through exosomes effectively counteracted IBR1, thereby reducing pulmonary inflammation and alleviating lung injury. Conclusions This study revealed a novel mechanism involving IBR1, an endogenous double‐stranded RNA (dsRNA) that binds to IFIH1, shedding light on the complex process of macrophage polarisation in ARDS. The administration of IFIH1 variants has the potential to eliminate pulmonary dsRNA and alleviate inflammatory lung injury in ARDS. Highlights In monocytes and macrophages, the endogenous double‐stranded RNA, IFIH1‐binding RNA 1 (IBR1), binds to the helicase domain of IFIH1 because of its unique double‐stranded structure. IBR1 plays a significant role in macrophage polarisation and the development of acute respiratory distress syndrome (ARDS) induced by Gram‐negative bacteria or lipopolysaccharide (LPS). Administration of IFIH1 variants has potential for eliminating pulmonary IBR1 and reducing inflammatory lung injury in ARDS patients.

Abstract The “shuttle effect” issue severely hinders the practical application of lithium–sulfur (Li–S) batteries, which is primarily caused by the significant accumulation of lithium polysulfides in the electrolyte. Designing effective catalysts is highly desired for enhancing polysulfide conversion to address the above issue. Here, the one‐step flash‐Joule‐heating route is employed to synthesize a W‐W2C heterostructure on the graphene substrate (W‐W2C/G) as a catalytic interlayer for this purpose. Theoretical calculations reveal that the work function difference between W (5.08 eV) and W2C (6.31 eV) induces an internal electric field at the heterostructure interface, accelerating the movement of electrons and ions, thus promoting the sulfur reduction reaction (SRR) process. The high catalytic activity is also confirmed by the reduced activation energy and suppressed polysulfide shuttling by in situ Raman analyses. With the W‐W2C/G interlayer, the Li–S batteries exhibit an outstanding rate performance (665 mAh g−1 at 5.0 C) and cycle steadily with a low decay rate of 0.06% over 1000 cycles at a high rate of 3.0 C. Moreover, a high areal capacity of 10.9 mAh cm−2 (1381.4 mAh g−1) is obtained with a high area sulfur loading of 7.9 mg cm−2 but a low electrolyte/sulfur ratio of 9.0 µL mg−1.

Abstract Cardiac metabolism ensures a continuous ATP supply, primarily using fatty acids in a healthy state and favoring glucose in pathological conditions. Pyruvate kinase muscle (PKM) controls the final step of glycolysis, with PKM1 being the main isoform in the heart. PKM2, elevated in various heart diseases, has been suggested to play a protective role in cardiac stress, but its function in basal cardiac metabolism remains unclear. We examined hearts from global PKM2 knockout (PKM2−/−) mice and found reduced intracellular glucose. Isotopic tracing of U‐13C glucose revealed a shift to biosynthetic pathways in PKM2−/− cardiomyocytes. Total ATP content was two‐thirds lower in PKM2−/− hearts, and functional analysis indicated reduced mitochondrial oxygen consumption. Total reactive oxygen species (ROS) and mitochondrial superoxide were also increased in PKM2−/− cardiomyocytes. Intriguingly, PKM2−/− hearts had preserved ejection fraction compared to controls. Mechanistically, increased calcium/calmodulin‐dependent kinase II activity and phospholamban phosphorylation may contribute to higher sarcoendoplasmic reticulum calcium ATPase 2 pump activity in PKM2−/− hearts. Loss of PKM2 led to altered glucose metabolism, diminished mitochondrial function, and increased ROS in cardiomyocytes. These data suggest that cardiac PKM2 acts as an important rheostat to maintain ATP levels while limiting oxidative stress. Although loss of PKM2 did not impair baseline contractility, its absence may make hearts more sensitive to environmental stress or injury.

Abstract Objective This study aims to investigate the correlation between changes in bone mineral density (BMD) in postmenopausal women and circulating inflammatory markers. Methods This retrospective study focused on postmenopausal women admitted to the orthopedic department of Suzhou Benq Medical Center from June 2022 to December 2023, following predetermined inclusion and exclusion criteria. We retrospectively collected data on initial blood routine test results and bone density measurements for all study subjects upon admission, including parameters such as white blood cell count (WBC), C‐reactive protein, interleukin‐6 (IL‐6), and procalcitonin (PCT). Additionally, the systemic immune‐inflammation index (SII) was calculated using neutrophil count, lymphocyte count, and platelet count. Statistical analyses using SPSS and GraphPad software were performed to assess the correlation between bone density and inflammatory markers. Results Patients were classified into three groups based on BMD results, including 60 individuals in the osteoporosis (OP) group, 127 individuals in the osteopenia group, and 37 individuals in the Normal group, respectively. Principal component analysis analysis suggested that WBC, SII, and postmenopausal OP (PMOP) held significant feature values. Correlation analysis indicated a correlation between WBC (p = 0.021), IL‐6 (p = 0.044), SII (p = 0.034), and PMOP. One‐way ANOVA analysis revealed significant differences in IL‐6 (p = 0.0179), SII (p = 0.0210), and PCT (p = 0.0200) among the three groups. Finally, ROC curve analysis demonstrated that SII (area under the curve = 0.716) has predictive value for PMOP. Conclusion This study identified a certain predictive value for PMOP through the assessment of inflammatory markers in peripheral blood using routine blood tests.

Background Long noncoding RNA (lncRNA) and mRNA profiles in leukocytes have shown potential as biomarkers for acute ischemic stroke (AIS). This study aimed to identify altered lncRNA and target mRNA profiles in peripheral blood leukocytes as biomarkers and to assess the diagnostic value and association with AIS prognosis. Methods and Results Differentially expressed lncRNAs (DElncRNAs) and differentially expressed target mRNAs (DEmRNAs) were screened by RNA sequencing in the discovery set, which consisted of 10 patients with AIS and 20 controls. Validation sets consisted of a multicenter (311 AIS versus 303 controls) and a nested case–control study (351 AIS versus 352 controls). The discriminative value of DElncRNAs and DEmRNAs added to the traditional risk factors was estimated with the area under the curve. NAMPT‐AS, FARP1‐AS1, FTH1, and NAMPT were identified in the multicenter case–control study (P

Abstract Continental alkaline magmatism has been suggested to play a significant role in releasing deep mantle carbon into the atmosphere, which can greatly impact the global climate. However, the temporal variations of alkaline magmatism and their potential to modulate climate over geologic time remain poorly constrained. The detrital zircon record is a frequently used proxy for tracking secular variations in particular magmatism. Here, we use a novel machine‐learning technique to discriminate zircon from carbonatites, kimberlites, and other alkaline rocks. A global compilation of detrital zircon yields continental alkaline magmatic flare‐ups between 1,050−850, 650−500, 250−200, and 50−0 Ma. Our estimates indicate relatively elevated contributions of total magmatic carbon outgassing from alkaline magmatism during the aforementioned magmatic flare‐ups. We infer that anomalous alkaline magmatism may influence global warming during specific intervals of geologic time, but when they are not that voluminous or persistent extensive arc magmatism may drive warming conditions.

Background ELMSAN1 (ELM2‐SANT domain‐containing scaffolding protein 1) is a newly identified scaffolding protein of the MiDAC (mitotic deacetylase complex), playing a pivotal role in early embryonic development. Studies on Elmsan1 knockout mice showed that its absence results in embryo lethality and heart malformation. However, the precise function of ELMSAN1 in heart development and formation remains elusive. To study its potential role in cardiac lineage, we employed human‐induced pluripotent stem cells (hiPSCs) to model early cardiogenesis and investigated the function of ELMSAN1. Methods and Results We generated ELMSAN1‐deficient hiPSCs through knockdown and knockout techniques. During cardiac differentiation, ELMSAN1 depletion inhibited pluripotency deactivation, decreased the expression of cardiac‐specific markers, and reduced differentiation efficiency. The impaired expression of genes associated with contractile sarcomere structure, calcium handling, and ion channels was also noted in ELMSAN1‐deficient cardiomyocytes derived from hiPSCs. Additionally, through a series of structural and functional assessments, we found that ELMSAN1‐null hiPSC cardiomyocytes are immature, exhibiting incomplete sarcomere Z‐line structure, decreased calcium handling, and impaired electrophysiological properties. Of note, we found that the cardiac‐specific role of ELMSAN1 is likely associated with histone H3K27 acetylation level. The transcriptome analysis provided additional insights, indicating maturation reduction with the energy metabolism switch and restored cell proliferation in ELMSAN1 knockout cardiomyocytes. Conclusions In this study, we address the significance of the direct involvement of ELMSAN1 in the differentiation and maturation of hiPSC cardiomyocytes. We first report the impact of ELMSAN1 on multiple aspects of hiPSC cardiomyocyte generation, including cardiac differentiation, sarcomere formation, calcium handling, electrophysiological maturation, and proliferation.

Abstract Myocardial infarction (MI) is a critical global health challenge, with current treatments limited by the complex MI microenvironment, particularly the excessive oxidative stress and intense inflammatory responses that exacerbate cardiac dysfunction and MI progression. Herein, a mannan‐based nanomedicine, Que@MOF/Man, is developed to target the inflammatory infarcted heart and deliver the antioxidative and anti‐inflammatory agent quercetin (Que), thereby facilitating a beneficial myocardial microenvironment for cardiac repair. The presence of mannan on the nanoparticle surface enables selective internalization by macrophages rather than cardiomyocytes. Que@MOF/Man effectively neutralizes reactive oxygen species in macrophages to reduce oxidative stress and promote their differentiation into a reparative phenotype, reconciling the inflammatory response and enhancing cardiomyocyte survival through intercellular communication. Owing to the recruitment of macrophages into inflamed myocardium post‐MI, in vivo, administration of Que@MOF/Man in MI rats revealed the specific distribution into the injured myocardium compared to free Que. Furthermore, Que@MOF/Man exhibited favorable results in resolving inflammation and protecting cardiomyocytes, thereby preventing further myocardial remodeling and improving cardiac function in MI rats. These findings collectively validate the rational design of an inflammation‐targeted delivery strategy to mitigate oxidative stress and modulate the inflammation response in the injured heart, presenting a therapeutic avenue for MI treatment.

Abstract South China Karst faces the challenge of balancing ecological conservation and regional development, a task made more intricate by the geological limitations of carbonate formations. Large‐scale conservation and restoration initiatives have mitigated rocky desertification and positioned South China Karst as a global hotspot for vegetation regrowth over the past two decades. However, challenges stemming from geological constraints and oversights in recognizing the synergies within social‐ecological systems remain. Here, we propose a social‐ecological framework that integrates the extended timescale of both historical and recent human impacts with the corresponding processes of forest evolution. The framework elucidates the enduring and continuous progression of “forest‐deforestation‐reforestation,” offering applicability for optimizing ecological space across diverse social‐ecological contexts. Moreover, it serves to enhance the sustainability of reforestation efforts when faced with geological constraints.

Abstract Understanding historical soil moisture (SM) variations and their relationship with temperature in high‐latitude humid regions is essential for predicting hot droughts under widespread warming. This paper presents the first‐ever annual‐resolution summer surface SM reconstruction (1736–2006 CE) in Sweden, located in northern Europe (NE). The reconstruction utilizes the paleoclimate proxy, tree‐ring δ18O, which exhibits a strong correlation with reanalysis SM data during 1948–2007 CE (r = −0.67, p

Abstract The equivalence of absorption rates and extents between generic drugs and their reference formulations is crucial for ensuring therapeutic comparability. Bioequivalence (BE) studies are widely utilized and play a pivotal role in substantiating the approval and promotional efforts for generic drugs. Virtual BE simulation is a valuable tool for mitigating risks and guiding clinical BE studies, thereby minimizing redundant in vivo BE assessments. Herein, we successfully developed a physiologically based absorption model for virtual BE simulations, which precisely predicts the BE of the apixaban test and reference formulations. The modeling results confirm that the test and reference formulations were bioequivalent under both fasted and fed conditions, consistent with clinical studies. This highlights the efficacy of physiologically based absorption modeling as a powerful tool for formulation screening and can be adopted as a methodological and risk assessment strategy to detect potential clinical BE risks.

Abstract Owing to the highly parallel network structure of the biological neural network and its triggered processing mode, tactile sensory neurons can realize the perception of external signals and the functions of perception, memory, and data processing by adjusting the synaptic weight. In this paper, a piezoresistive pressure sensor is combined with a memristor to design an artificial tactile sensory neuron. The polyurethane sponge sensor has excellent sensitivity and can convert physical stimuli into electrical signals, and the chitosan‐based memristor has stable bipolar resistive switching characteristics, allowing further information to be memorized and processed. The neuron can respond to tactile stimuli of different degrees, durations, and frequencies; realize potentiation/depression modulation, paired‐pulse facilitation, and spike‐timing‐dependent plasticity; exhibit spike‐rate‐dependent plasticity; and store and erase tactile information through memistor state switching, which has great application potential in biological sensing systems.

Abstract The Tibetan Plateau (TP) is an area highly sensitive to climate change and is warming faster than the global average. The TP temperature change has a significant impact on the local ecological environment and the downstream weather and climate. The TP will undoubtedly warm in the future, but the warming extent is uncertain. Using the Coupled Model Inter‐comparison Project Phase 6 multi‐model ensemble, we found that models simulating smaller TP temperature increases in recent decades tend to project weaker warming in the future. This relationship is driven by the simulation of snowmelt response to greenhouse gas increases, as snow‐related albedo feedback dominates the TP temperature changes in both historical and future periods. Based on a two‐step emergent constraint approach, the rectified TP warming magnitude increases by about 0.3°C compared to the unconstrained result under both the medium and high emission scenarios, and the inter‐model uncertainty is reduced by about 60%.

Abstract Understanding the forest evolution is vital to answering the reforestation potential in karst areas. Here, we present the first‐ever pollen record in karst depression sediment, combined with comprehensive dating methods (137Cs, 210Pbex, and 14C) and historical documents, to reveal plant change history in southwest Guangxi, a severe rocky‐desertification region. We inferred three stages of “virgin forest–deforestation–sparse tree planting” over the past three centuries. Before the 1780s, the barren mountains used to be a lush mixed broadleaf forest probably. However, maize cultivation, along with explosive population growth and migration, accelerated mountain reclamation and deforestation, leading to severe rocky desertification since the 1780s, featured by the co‐occurrence of Zea pollen appearance and Dicranopteris spore surge from 0.92% to 12.18%. Since the 1930s, sparse tree planting began, as Cupressaceae/Taxodiaceae pollen abruptly increased by 32%. Our study is significant in understanding the rocky desertification causes and guiding ecological restoration in the region.

Abstract Asthenozoospermia (AZS) is a prevalent contributor to male infertility, characterized by a substantial decline in sperm motility. In recent years, large‐scale studies have explored the interplay between the male reproductive system's microecology and its implications for reproductive health. Nevertheless, the direct association between seminal microecology and male infertility pathogenesis remains inconclusive. This study used 16S rDNA sequencing and multi‐omics analysis to conduct a comprehensive investigation of the seminal microbial community and metabolites in AZS patients. Patients were categorized into four distinct groups: Normal, mild AZS (AZS‐I), moderate AZS (AZS‐II), and severe AZS (AZS‐III). Microbiome differential abundance analysis revealed significant differences in microbial composition and metabolite profiles within the seminal plasma of these groups. Subsequently, patients were classified into a control group (Normal and AZS‐I) and an AZS group (AZS‐II and AZS‐III). Correlation and cross‐reference analyses identified distinct microbial genera and metabolites. Notably, the AZS group exhibited a reduced abundance of bacterial genera such as Pseudomonas, Serratia, and Methylobacterium‐Methylorubrum in seminal plasma, positively correlating with core differential metabolite (hexadecanamide). Conversely, the AZS group displayed an increased abundance of bacterial genera such as Uruburuella, Vibrio, and Pseudoalteromonas, with a negative correlation with core differential metabolite (hexadecanamide). In vitro and in vivo experiments validated that hexadecanamide significantly enhanced sperm motility. Using predictive metabolite‐targeting gene analysis and single‐cell transcriptome sequencing, we profiled the gene expression of candidate target genes PAOX and CA2. Protein immunoblotting techniques validated the upregulation protein levels of PAOX and CA2 in sperm samples after hexadecanamide treatment, enhancing sperm motility. In conclusion, this study uncovered a significant correlation between six microbial genera in seminal plasma and the content of the metabolite hexadecanamide, which is related to AZS. Hexadecanamide notably enhances sperm motility, suggesting its potential integration into clinical strategies for managing AZS, providing a foundational framework for diagnostic and therapeutic advancements.

Abstract Senile plaque, composed of amyloid β protein (Aβ) aggregates, is a critical pathological feature in Alzheimer's disease (AD), leading to cognitive dysfunction. However, how Aβ aggregates exert age‐dependent toxicity and temporal cognitive dysfunction in APP/PS1 mice remains incompletely understood. In this study, we investigated AD pathogenesis and dynamic alterations in lysosomal pathways within the hippocampus of age‐gradient male mice using transcriptome sequencing, molecular biology assays, and histopathological analyses. We observed high levels of β‐amyloid precursor protein (APP) protein expression in the hippocampus at an early stage and age‐dependent Aβ deposition. Transcriptome sequencing revealed the enrichment of differential genes related to the lysosome pathway. Furthermore, the protein expression of ATP6V0d2 and CTSD associated with lysosomal functions exhibited dynamic changes with age, increasing in the early stage and decreasing later. Similar age‐dependent patterns were observed for the endosome function, autophagy pathway, and SGK1/FOXO3a pathway. Nissl and Golgi staining in the hippocampal region showed age‐dependent neuronal loss and synaptic damage, respectively. These findings clearly define the age‐gradient changes in the autophagy–lysosome system, the endosome/lysosome system, and the SGK1/FOXO3a pathway in the hippocampus of APP/PS1 mice, providing new perspectives and clues for understanding the possible mechanisms of AD, especially the transition from compensatory to decompensated state.

Abstract Radiotherapy (RT) can induce tumor regression outside the irradiation field, known as the abscopal effect. However, the detailed underlying mechanisms remain largely unknown. A tumor‐bearing mouse model is successfully constructed by inducing both subcutaneous tumors and lung metastases. Single‐cell RNA sequencing, immunofluorescence, and flow cytometry are performed to explore the regulation of tumor microenvironment (TME) by RT. A series of in vitro assays, including luciferase reporter, RNA Pulldown, and fluorescent in situ hybridization (FISH) assays, are performed to evaluate the detailed mechanism of the abscopal effect. In addition, in vivo assays are performed to investigate combination therapy strategies for enhancing the abscopal effect. The results showed that RT significantly inhibited localized tumor and lung metastasis progression and improved the TME. Mechanistically, RT promoted the release of tumor‐derived exosomes carrying circPIK3R3, which is taken up by macrophages. circPIK3R3 promoted Type I interferon (I‐IFN) secretion and M1 polarization via the miR‐872‐3p/IRF7 axis. Secreted I‐IFN activated the JAK/STAT signaling pathway in CD8+ T cells, and promoted IFN‐γ and GZMB secretion. Together, the study shows that tumor‐derived exosomes promote I‐IFN secretion via the circPIK3R3/miR‐872‐3p/IRF7 axis in macrophages and enhance the anti‐tumor immune response of CD8+ T cells.

AbstractMutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca2+ permeable nonselective cation channel, cause TRPV4‐related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4‐mediated Ca2+ deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain‐of‐function TRPV4 mutation, c.1855C > T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca2+ augmented AKT‐mediated α‐synuclein (α‐syn) induction, resulting in mitochondrial Ca2+ accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α‐syn knockdown, normalizes the mitochondrial Ca2+ levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca2+/AKT‐induced α‐syn in mitochondrial Ca2+ accumulation. Folic acid was effective in normalizing mitochondrial Ca2+ levels via the transcriptional repression of α‐syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4‐related disorders and related therapeutic strategies.

Abstract In vivo pharmacokinetic simulations and virtual bioequivalence (BE) evaluation of cilostazol have not yet been described for humans. Here, we successfully developed a physiologically based absorption model to simulate plasma concentrations of cilostazol. In addition, virtual population simulations integrating dissolution of 0.3% sodium dodecyl sulfate water media were executed to evaluate the BE of test and reference formulations. Simulation results show that test and reference formulations were bioequivalent among 28 subjects, but not nine subjects, consistent with clinical studies. The model proved to be an important tool to show potential BE for cilostazol. This finding may facilitate understanding of the potential risks during the development of generic products.

Abstract Keverprazan, a novel potassium‐competitive acid blocker, was approved for treating acid‐related diseases. This study aimed to analyze the safety, pharmacokinetics (PKs) and pharmacodynamics (PDs) of multiple doses of keverprazan. This was a randomized, positive‐/placebo‐controlled, phase Ic trial. Twenty‐six healthy adults were randomized to receive 20 mg/day keverprazan (n = 8), 40 mg/day keverprazan (n = 8), placebo (n = 6), or 20 mg/day vonoprazan (n = 4) for 7 days. Safety, PK and PD assessments were conducted. In the keverprazan, vonoprazan, and placebo groups, adverse events (AEs) were reported in nine (56.25%), two (50.00%), and three (50.00%) subjects, respectively. AEs were mild except a moderate abdominal pain leading to withdraw. No serious AEs occurred. The plasma concentration‐time profiles of keverprazan showed rapid absorption (median time to maximum plasma concentration of 1.25–3.0 h). The terminal half‐life was 6.23 and 7.01 h for keverprazan 20 and 40 mg groups on day 7. The maximum plasma concentration was 43.1 and 93.2 ng/mL, respectively. There was no apparent accumulation of keverprazan and the major metabolite after 7‐day administration. The intragastric pH greater than 5 holding time ratios (HTRs) over 24 h postdose increased from 79.1%, 84.4%, and 84.5% on day 1 to 99.0%, 97.4%, and 100.0% on day 7 in the vonoprazan 20 mg and keverprazan 20 and 40 mg groups, respectively. The intragastric pH greater than 5 HTR of keverprazan reached a plateau at 20 mg. Keverprazan is well‐tolerable. A steady‐state in exposure was generally reached after 7 days of treatment. A dose of 20 mg/day keverprazan can elicit a significant, stable, and long‐lasting gastric acid inhibition effect.

Abstract Herein, we present a rare case of acute myeloid leukemia (AML) with CBFA2T3‐rearrangement and the expression of megakaryocytic and lymphoid markers, highlighting the need for a high suspicion index in differential diagnosis and applying adequate workup to avoid misdiagnosing this entity. CBFA2T3::GLIS2‐positive AML is primarily found in infants with non‐down syndrome acute megakaryoblastic leukemia (non‐DSAMKL). Flow cytometry immunophenotyping plays an important role in recognizing the unique immunophenotype of bright CD56 expression with dim/negative expression of HLA‐DR, CD38, and CD45 termed the RAM immunophenotype in this entity. Still, CBFA2T3::GLIS2‐positive acute leukemia with T/megakaryocytic markers could be misdiagnosed as T‐lymphoblastic leukemia/lymphoma, early T‐cell precursor acute lymphoblastic leukemia/lymphoma, NK lymphoblastic leukemia, AML with minimal differentiation, or AML with myelodysplasia‐related changes.

Abstract This study aimed to evaluate [18F]GSK1482160 Positron emission tomography imaging for targeting P2X7R, a biomarker for neuroinflammation. Studies of acute neuroinflammation in rodents and transgenic mice with Alzheimer's disease (AD), as well as wild‐type (WT) controls, were conducted via PET‐CT‐MRI scans after tail vein injection of [18F]GSK1482160. Imaging was quantified based on the time‐activity curve, the standardized uptake value ratio, and the binding kinetics distribution volume ratio (DVR) to assess the expression of P2X7R. Tissues were collected post‐PET for immunofluorescence staining. Correlation analysis was performed between DVR and Morris water maze test results. Finally, dynamic Positron Emission Tomography‐Magnetic Resonance Imaging (PET‐MRI) scans were performed in healthy non‐human primates (NHPs). Our study demonstrated that AD mice had a significantly higher DVR than WT mice in the hippocampus (0.92 ± 0.06 vs. 0.79 ± 0.02, p

Abstract Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life‐threatening syndrome with no effective pharmacotherapy. Sepsis‐related ARDS is the main type of ARDS and is more fatal than other types. Extracellular vesicles (EVs) are considered novel mediators in the development of inflammatory diseases. Our previous research suggested that endothelial cell‐derived EVs (EC‐EVs) play a crucial role in ALI/ARDS development, but the mechanism remains largely unknown. Here, we demonstrated that the number of circulating EC‐EVs was increased in sepsis, exacerbating lung injury by targeting monocytes and reprogramming them towards proinflammatory macrophages. Bioinformatics analysis and further mechanistic studies revealed that vascular cell adhesion molecule 1 (VCAM1), overexpressed on EC‐EVs during sepsis, activated the NF‐κB pathway by interacting with integrin subunit alpha 4 (ITGA4) on the monocyte surface, rather than the tissue resident macrophage surface, thereby regulating monocyte differentiation. This effect could be attenuated by decreasing VCAM1 levels in EC‐EVs or blocking ITGA4 on monocytes. Furthermore, the number of VCAM1+ EC‐EVs was significantly increased in patients with sepsis‐related ARDS. These findings not only shed light on a previously unidentified mechanism underling sepsis‐related ALI/ARDS, but also provide potential novel targets and strategies for its precise treatment.

Abstract Sex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid‐beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.

Abstract The desert ecosystem of the Qinghai–Tibet Plateau (QTP) is an important component of China's desert ecosystem. Studying the mechanisms shaping the taxonomic, phylogenetic, and functional beta diversity of plant communities in the QTP desert will help us to promote scientific conservation and management of the region's biodiversity. This study investigated the effects of environmental (including altitude, climate factors, and soil factors) and geographic distances on three facets of beta diversity as well as their turnover and nestedness components based on field survey data. The results showed that turnover components dominate the three facets of beta diversity. However, the turnover contributions to phylogenetic and functional beta diversity were lower than for taxonomic beta diversity. Environmental distance had a greater influence than geographic distance, with the former uniquely explaining 15.2%–22.8% of beta diversity and the latter explaining only 1.7%–2.4%. Additionally, the explanatory power of different factors for beta diversity differed between herbs and shrubs, with environmental distance being more important for the latter. Distance‐based redundancy analysis suggested that soil total potassium content had a substantial impact on the beta diversity of three dimensions, with mean temperature of the coldest month and soil total phosphorus content having a substantial impact on taxonomic and functional beta diversity as well. Our results support that environmental sorting plays a predominant role in shaping plant community composition across QTP desert ecosystems. To maintain the plant diversity of this region, it is crucial to prioritize the conservation of its diverse environmental conditions and actively mitigate its degradation by anthropogenic pressures.

Abstract Background and Objective Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by ineffective hematopoiesis due to stem cell abnormalities. Monosomy 7q aberrations are a common cytogenetic abnormality in MDS. Specifically, an unbalanced translocation der(1;7)(q10;p10) [der(1;7)] has been identified in MDS patients, which is a monosomy 7q aberration variant like −7/del(7q). However, knowledge of der(1;7)'s features remains limited. Existing studies have compared the clinical and genetic characteristics of der(1;7) to those of −7/del(7q) but yielded inconsistent findings. Accordingly, we conducted meta‐analyses comparing der(1;7) to −7/del(7q). Methods Publications were searched from the following databases up to January 10, 2023: Pubmed, Web of Science, Embase, Cochrane, and ClinicalTrials.gov. Eligible studies were assessed for risks of bias. Relevant data were extracted from included studies and analyzed using random‐effects models. Publication bias was evaluated and sensitivity analyses were performed. Results The comparative meta‐analyses included 405 MDS patients with der(1;7) from nine studies. The analysis revealed that der(1;7) was associated with a greater male preponderance (86.1% vs. 68.3%, Odds Ratios (ORs) 2.007, p

Abstract Background Myeloid‐derived suppressor cells (MDSCs) played an essential role in tumor microenvironment to suppress host antitumor immunity and help cancer cells escape immune surveillance. However, the molecular mechanism behind tumor evasion mediated by MDSCs is not fully understood. Glycoprotein nonmetastatic melanoma protein B (GPNMB) is considered to associate with tumor initiation, metastasis and angiogenesis. Blocking GPNMB function is a potentially valuable therapy for cancer by eliminating GPNMB+MDSCs. Our previous study has proved that blockage the MyD88 signaling with the MyD88 inhibitor, TJ‐M2010‐5, may completely prevent the development of CAC in mice, accompanying with downregulation of GPNMB mRNA in the inhibitor‐treated mice of CAC. Methods We here focus on the underlying the relationship between GPNMB function and MyD88 signaling pathway activation in MDSCs' antitumor activity in CAC. Results CAC development in the mouse model is associated with expanded GPNMB+MDSCs by a MyD88‐dependent pathway. The GPNMB expression on MDSCs is associated with MyD88 signaling activation. The inhibitory effect of MDSCs on T cell proliferation, activation and antitumor cytotoxicity in CAC is mediated by GPNMB in a MyD8‐dependent manner. Conclusion MyD88 signaling pathway plays an essential role in GPNMB+MDSC‐mediated tumor immune escape during CAC development and is a promising focus for revealing the mechanisms of MDSC that facilitate immunosuppression and tumor progression.

Objective This study aimed to explore decision‐making impulsivity and its neural mechanisms in patients with episodic migraine without aura (EMoA). Background Previous evidence indicates increased impulsivity and altered reward processing in patients with chronic migraine and medication overuse; however, whether the same holds true for those with EMoA is unclear. Methods Patients newly diagnosed with EMoA (n = 51) and healthy controls (HC, n = 45) were recruited. All participants completed delay discounting task, cognitive assessments, a questionnaire for headache profile, and resting‐state function magnetic resonance imaging scans. Resting‐state functional connectivity (RSFC) between the regions of interest and the entire brain was explored. Results Patients with EMoA showed a steeper subjective discount rate than HCs (F = 4.74, p = .032), which was positively related to a history of migraines (r = .742, p

Abstract The essential branched‐chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs’ full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence‐associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation‐related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age‐related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age‐related and inflammatory diseases.