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Abstract Artificial Intelligence (AI) is currently experiencing a bloom driven by deep learning (DL) techniques, which rely on networks of connected simple computing units operating in parallel. The low communication bandwidth between memory and processing units in conventional von Neumann machines does not support the requirements of emerging applications that rely extensively on large sets of data. More recent computing paradigms, such as high parallelization and near-memory computing, help alleviate the data communication bottleneck to some extent, but paradigm- shifting concepts are required. Memristors, a novel beyond-complementary metal-oxide-semiconductor (CMOS) technology, are a promising choice for memory devices due to their unique intrinsic device-level properties, enabling both storing and computing with a small, massively-parallel footprint at low power. Theoretically, this directly translates to a major boost in energy efficiency and computational throughput, but various practical challenges remain. In this work we review the latest efforts for achieving hardware-based memristive artificial neural networks (ANNs), describing with detail the working principia of each block and the different design alternatives with their own advantages and disadvantages, as well as the tools required for accurate estimation of performance metrics. Ultimately, we aim to provide a comprehensive protocol of the materials and methods involved in memristive neural networks to those aiming to start working in this field and the experts looking for a holistic approach.

Traditional hot-dip galvanized coatings, typically single-silver in color, present increasing aesthetic challenges in diverse applications, while prevailing organic coating methods involve complex processes with high energy consumption and pollution emissions. In this study, a novel hot-dip process for in-situ synthesis of color coating on steel was proposed, capable of producing various uniform color coating. The microstructure of color coatings on steel was systematically examined, and an assessment of their corrosion and weather resistance was conducted. The results demonstrate the sequence of typical color variation is gold, purple, blue, cyan, red, green, and grey. By controlling the immersion temperature range, and regulating the final stable color of the oxide film. The coloration mechanism mainly is attributed to the light interference on the Mn oxide film. The cyan and brown coatings mainly consist of the dense rod-like ζ-FeZn13 phases which provide a structural foundation for corrosion resistance. Furthermore, the brown coating exhibited excellent weather resistance.

Abstract Background Yaks (Bos grunniens), prized for their ability to thrive in high-altitude environments, are indispensable livestock in the plateau region. Modifying their feeding systems holds significant promise for improving their growth and meat quality. Tenderness, a key determinant of yak meat quality and consumer appeal, is demonstrably influenced by dietary regimen. Indoor feeding regimes have been shown to enhance tenderness by lowering shear stress and optimizing pH values. CircRNAs, well-known modulators of circulatory function, also play a crucial role in skeletal muscle development across various animal species. However, their functional significance in yak skeletal muscle remains largely unexplored. Results In this study, we identified a total of 5,534 circRNAs within the longissimus dorsi muscle, and we found 51 differentially expressed circRNAs (20 up-regulated and 31 down-regulated) between the two feeding groups. Constructing a comprehensive ceRNA network illuminated intricate regulatory mechanisms, with PGP and circRNA_0617 converging on bta-miR-2285q, mirrored by KLF15/circRNA_0345/bta-miR-20b and CTSF/circRNA_0348/bta-miR-146a. These findings shed light on the potential of circRNAs to influence yak muscle development and meat quality, offering valuable insights for future research. Conclusions This investigation unraveled a complex interaction network between circRNAs、mRNAs and miRNAs in yak skeletal muscle. We further elucidated the target genes regulated by these target genes within the network, offering valuable insights into the potential regulatory mechanisms governing muscle development and meat quality-related traits in yaks.

Background: The Klebsiella oxytoca complex is an opportunistic pathogen that has been recently identified as an actual complex. However, the characteristics of each species remain largely unknown. We aimed to study the clinical prevalence, antimicrobial profiles, genetic differences, and interaction with the host of each species of this complex. Methods: One hundred and three clinical isolates of the K. oxytoca complex were collected from 33 hospitals belonging to 19 areas in China from 2020 to 2021. Species were identified using whole genome sequencing based on average nucleotide identity. Clinical infection characteristics of the species were analyzed. Comparative genomics and pan-genome analyses were performed on these isolates and an augmented dataset, including 622 assemblies from the National Center for Biotechnology Information. In vitro assays evaluating the adhesion ability of human respiratory epithelial cells and survivability against macrophages were performed on randomly selected isolates. Results: Klebsiella michiganensis (46.6%, 48/103) and K. oxytoca (35.92%, 37/103) were the major species of the complex causing human infections. K. michiganensis had a higher genomic diversity and larger pan-genome size than did K. oxytoca. K. michiganensis isolates with blaoxy-5 had a higher resistance rate to various antibiotics, antimicrobial gene carriage rate, adhesion ability to human respiratory epithelial cells, and survival rate against macrophages than isolates of other species. Conclusion: Our study revealed the genetic diversity of K. michiganensis and firstly identified the highly antimicrobial-resistant profile of K. michiganensis carrying blaoxy-5.

The role of the intratumoral microbiome in gastric cancer (GC) has not been comprehensively assessed. Here, we explored the relationship between the microbial community and GC prognosis and therapy efficacy. Several cancer-associated microbial characteristics were identified, including increased α-diversity, differential β-diversity, and decreased Helicobacter pylori abundance. After adjusting for clinical features, prognostic analysis revealed 2 phyla, 14 genera, and 5 species associated with the overall survival of patients with GC. Additionally, 2 phyla, 14 genera, and 6 species were associated with adjuvant chemotherapy (ACT) efficacy in patients with stage II – III GC. Furthermore, we classified GC microbiome structures into three microbial subtypes (MS1, MS2 and MS3) with distinguishing features. The MS1 subtype exhibited high immune activity and enrichment of microbiota related to immunotherapy and butyric acid-producing, as well as potential benefits in immunotherapy. MS2 featured the highest α-diversity and activation of the TFF pathway, MS3 was characterized by epithelial-mesenchymal transition and was associated with poor prognosis and reduced ACT efficacy. Collectively, the results of this study provide valuable insights into the microbial characteristics associated with GC prognosis and therapy efficacy.

ABSTRACT Morganella morganii, encompassing two subspecies, subsp. morganii and subsp. sibonii, is a common opportunistic pathogen, notable for intrinsic resistance to multiple antimicrobial agents. Despite its clinical significance, research into the potential evolutionary dynamics of M. morganii remains limited. This study involved the analysis of genome sequences from 431 M. morganii isolates, comprising 206 isolates that cause host infections, obtained from this study and 225 from the NCBI genome data sets. A diverse array of antimicrobial resistance genes (ARGs) was identified in M. morganii isolates, including mcr-1, tet(X4), tmexCD-toprJ, and various carbapenemase genes. In addition, a novel blaKPC-2-bearing plasmid with demonstrated conjugative capability was discovered in M. morganii. The majority of virulence-related genes (VRGs), except for the hlyCABD gene cluster, were found in almost all M. morganii. Three novel genospecies of M. morganii were identified, designated as M. chanii, M. variant1, and M. variant2. Compared to M. sibonii, M. chanii genospecies possessed a greater number of flagellar-related genes, typically located within mobile genetic elements (MGEs), suggesting potential for better environmental adaptability. Phylogenetic analysis further disclosed that M. morganii was divided into 12 sequence clusters (SCs). Particularly, SC9 harbored an elevated abundance of ARGs and VRGs, mainly toxin-related genes, and was associated with a higher presence of MGEs compared to non-SC9 strains. The collective findings suggest that M. morganii undergoes evolution driven by the influence of MGEs, thereby significantly enhancing its adaptability to selective pressures of environmental changes and clinical antimicrobial agents.IMPORTANCEThe growing clinical significance of Morganella morganii arises from its abundant virulence factors and antimicrobial resistance genes, resulting in elevated infection rates and increased clinical scrutiny. However, research on the molecular epidemiology and evolutionary trends of M. morganii has been scarce. Our study established a list of virulence-related genes (VRGs) for M. morganii and conducted a large-scale epidemiological investigation into these VRGs. Based on genomic classification, three novel genotypes of M. morganii were identified, representing evolutionary adaptations and responses to environmental challenges. Furthermore, we discovered the emergence of a sequence cluster enriched with antimicrobial resistance genes, VRGs, and mobile genetic elements, attributed to the selective pressure of antimicrobial agents. In addition, we identified a novel conjugative plasmid harboring the blaKPC-2 gene. These findings hold significance in monitoring and comprehending the epidemiology of M. morganii.

Soil copper (Cu) pollution is a serious environmental risk in the Panax notoginseng planting area. However, the effect of Cu on soil microbial metabolism and nutrient cycling in this area remains unknown. Therefore, Biolog ECO-plate and enzyme stoichiometry methods were utilized in this study to investigate the impact of exogenous Cu (control: 0 mg·kg−1; Cu100: 100 mg·kg−1; Cu400: 400 mg·kg−1; and Cu600: 600 mg·kg−1) on the metabolic function of soil microbial and nutrient limitation in the P. notoginseng soil. The results indicated that Cu100 significantly increased soil organic carbon (SOC), total phosphorus (TP), soil C:N, microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) 9.89%, 15.65%, 17.91%, 61.87%, and 90.56% higher than the control, respectively. Moreover, the carbon source utilization ratio of carbohydrates, amino acids, and amphiphilic compounds of Cu100 also increased by 7.16%, 25.47%, and 84.68%, respectively, compared with the control. The activities of β-1,4-glucosidase, cellobiohyrolase, leucine amino peptidase, β-1,4-N-acetylglucosaminidase, and phosphatase significantly decreased with increasing Cu concentration. Soil enzyme stoichiometry showed that all treatments were limited by nitrogen (vector angle < 45°; 19.045–22.081). Cu600 led to the lowest carbon limitation (1.798) and highest carbon use efficiency (CUE:0.267). The PLS-SEM model also showed that MBC, MBN, MBP, and microbial diversity positively affected carbon and nitrogen limitation (0.654 and 0.424). Soil carbon, nitrogen, phosphorus, stoichiometric ratio, MBC, MBN, and MBP positively affected CUE (0.527 and 0.589). The microbial diversity index significantly negatively affected CUE (−1.490). Multiple linear stepwise regression analyses showed that CUE was mainly influenced by MBC, AP, C:P, and LAP. Thus, P. notoginseng soil can benefit soil microbial carbon and nitrogen limitations at low Cu concentrations. Clarifying the metabolic activity and nutritional status of microorganisms under Cu stress can provide some theoretical basis for realizing China's comprehensive and effective management and control policies for environmental risks from metals by 2035.

Background: Hypertrophic scar (HS) is a common fibrotic skin disease that occurs secondary to burns or injuries. The activation of the TGF-β signaling pathway contributes immensely to HS formation. Isorhamnetin (ISO) is a type of flavonoid compound that exerts an antifibrotic effect via TGF-β signaling suppression. However, whether ISO can inhibit HS formation via TGF-β signaling is yet to be elucidated. This study aimed to examine the influence of ISO on HS pathogenesis and TGF-β signaling, especially the downstream molecules and networks of TGF-β signaling that facilitate HS formation. Methods: Hypertrophic scar fibroblasts (HSFBs) were isolated from human HS tissues. The in vitro proliferation, migration, contractile ability, cell cycle, and apoptosis of HSFBs after ISO treatment were determined using cell viability assay, EdU staining, wound healing assay, collagen gel contraction assay, and flow cytometry. The expressions of genes and proteins involved in TGF-β signaling and its downstream molecules in ISO-treated HSFBs were determined using quantitative PCR (qPCR), immunofluorescence, and western blotting. In vivo, a rabbit HS model was established, and the effects of ISO on rabbit HS formation were investigated using histological analysis, immunohistochemical staining, and qPCR. Results: In vitro studies indicated that ISO treatment suppressed the proliferation, migration, and contractile ability of HSFBs; attenuated the expressions of COL Ⅰ, COL Ⅲ, and α-SMA; and inhibited TGF-β1 signaling-induced activation of HSFBs by decreasing the levels of phosphorylated Smad2/3 and cleaved CREB3L1 in a dose-dependent manner. Furthermore, ISO augmented apoptosis and G2 phase cell cycle arrest of HSFBs by upregulating the expressions of the proapoptotic proteins Bax and cleaved caspase-3 and downregulating the expression of the antiapoptotic protein Bcl-2. In vivo studies revealed that ISO ameliorated HS formation in the rabbit ear by lowering the scar elevation index, attenuating the collagen density, facilitating the regular arrangement of collagen fibers, and downregulating the expressions of TGF-β1, CREB3L1, COL Ⅰ, COL Ⅲ, and α-SMA. Conclusions: ISO suppressed HS pathogenesis by dampening TGF-β1/Smad and TGF-β1/CREB3L1 signaling pathways, which suggests that it may serve as a candidate inhibitor of TGF-β1 signaling and a promising anti-HS drug with a high therapeutic potential.

Background: Pay-it-forward is when an individual receives a gift and is offered the opportunity to donate a gift to another person. This prosocial behavior has been used to develop health interventions, including strategies to increase sexually transmitted disease (STD) testing among men who have sex with men (MSM). Although pay-it-forward has improved service uptake across several settings, the underlying mechanism is unclear. This study aims to assess the participant experience to provide a theoretical basis for how pay-it-forward works among MSM in China. Methods: MSM participants of a pay-it-forward intervention were recruited from two STD clinics in Guangzhou, China, and underwent semi-structured interviews. Responses were translated verbatim into English. Transcripts were analyzed thematically. Results: Twenty-four MSM were interviewed. Despite many men feeling detached from other MSM, pay-it-forward engendered hope and solidarity among many participants. From an emotional perspective, reading handwritten postcards from other MSM induced gratitude, warmth, and support. From the perspective of the collective, receiving a free test and donating to other MSM solidified men's connection with the MSM community, even among men not yet out. Donation gave men an opportunity to pass on their gratitude and provide for MSM in need. Conclusions: Our data suggest that upstream reciprocity and warm glow explained pay-it-forward for some men, but this pathway was often complemented by a pathway aligned with principles of mutual aid. Further qualitative and mixed-methods research is needed to understand the basis for MSM decision-making about donating to support others.

Polyvinylidene fluoride (PVDF) membranes, widely used for their stability, face limitations due to the hardly adjustable pore size in nanoscale and inherent hydrophobicity. To address this, we proposed a co-deposition method incorporating dopamine (DA), polyethyleneimine (PEI), and silicon dioxide (SiO2) nanoparticles with glutaraldehyde cross-linking for precise regulation of pore size and hydrophilicity in PVDF hollow fiber membranes. Notably, the pore diameter reduced from 119.0 ± 3.55 nm to 18.4 ± 0.36 nm, while the contact angle decreased from 107.7° to 40.9°. This simultaneous regulation led to a high-performance PDA/PEI/SiO2-PVDF hydrophilic ultrafiltration membrane with a rejection rate exceeding 99% for 20 nm nanoparticles in a long-term simulated separation experiment while achieving a significant protein permeability of 97% in BSA permeation experiments. Additionally, the membrane demonstrated exceptional long-term stability, offering a novel approach for tuning the performance of ultrafiltration/microfiltration membranes.

Abstract Forest plantations most likely promote exotic plant invasion. Using an in situ monitoring method, this study investigated the traits correlated with growth and reproduction of an understory invader, Phytolacca americana L., and ecological factors including understory irradiance, soil stoichiometry and microbial patterns associated with these traits in different exotic plantations of Robinia pseudoacacia L. and Pinus thunbergii Parl. at Mount Lao, Qingdao, China. We found that the traits of P. americana underneath the R. pseudoacacia stand might be situated at the fast side of the trait economic spectrum. The R. pseudoacacia stand appeared to “nurse” P. americana. Furthermore, we intended to explain the nurse effects of R. pseudoacacia stands by examining their ecological factors. First, the R. pseudoacacia stand created understory light attenuation, which matched the sciophilous feature of P. americana. Second, the soil beneath the R. pseudoacacia stand might benefit P. americana more since the soil has greater resource availability. Third, a higher microbial diversity was found in the soil derived from P. americana underneath the R. pseudoacacia stand. A greater abundance of plant pathogens was detected in the soil derived from P. americana in the R. pseudoacacia stand, while more abundant mycorrhizal fungi were detected in the P. thunbergii stand. We speculate that plant pathogens can defend P. americana from aggression from other understory competitors. The mycorrhizal fungi in the P. thunbergii stand might benefit P. americana while simultaneously benefiting other understory plants. Intensive competition from other plants might interfere with P. americana. The potential relationships between plant performance and ecological factors may explain the invasion mechanism of P. americana. The present study provides a novel insight on the facilitative effects of exotic tree plantation on an exotic herb through the modification of soil biota, with implications for the biocontrol of invasive species and forest management and conservation.

BackgroundFrailty correlates with adverse outcomes in many cardiovascular diseases and is prevalent in individuals with heart failure (HF). The Hospital Frailty Risk Score (HFRS) offers an integrated, validated solution for frailty assessment in acute care settings, but its application in critically ill patients with congestive HF lacks exploration. This study aimed to identify the association between frailty assessed by the HFRS and in-hospital mortality in critically ill patients with congestive HF.MethodsThis observational study retrospectively enrolled 12,179 critically ill patients with congestive HF. Data from the Medical Information Mart for Intensive Care IV database was used. The HFRS was calculated to assess frailty. Patients were categorized into three groups: non-frailty (HFRS

Traditional environmental epidemiology has consistently focused on studying the impact of single exposures on specific health outcomes, considering concurrent exposures as variables to be controlled. However, with the continuous changes in environment, humans are increasingly facing more complex exposures to multi-pollutant mixtures. In this context, accurately assessing the impact of multi-pollutant mixtures on health has become a central concern in current environmental research. Simultaneously, the continuous development and optimization of statistical methods offer robust support for handling large datasets, strengthening the capability to conduct in-depth research on the effects of multiple exposures on health. In order to examine complicated exposure mixtures, we introduce commonly used statistical methods and their developments, such as weighted quantile sum, bayesian kernel machine regression, toxic equivalency analysis, and others. Delineating their applications, advantages, weaknesses, and interpretability of results. It also provides guidance for researchers involved in studying multi-pollutant mixtures, aiding them in selecting appropriate statistical methods and utilizing R software for more accurate and comprehensive assessments of the impact of multi-pollutant mixtures on human health.

BackgroundWith increased life expectancy, cognitive decline has emerged as a prevalent neurodegenerative disorder.ObjectiveThis study aimed to examine the correlation between concentrations of Plasma long-chain n-3 polyunsaturated fatty acids (LCPUFAs) and cognitive performance in elderly Americans.MethodsData were analyzed from older adults enrolled in two NHANES cycles. Participants completed four cognitive assessments, including the Immediate Recall Test (IRT), Delayed Recall Test (DRT), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Linear regression and restricted cubic spline modeling examined associations between plasma LCPUFAs levels and cognitive test outcomes.ResultsThe cohort included 610 adults aged 69 years on average, 300 (49.2%) males and 310 (50.8%) females. The median LCPUFAs concentration was 309.4 μmol/L, with an interquartile range of 244.7–418.9 μmol/L. In unadjusted and adjusted generalized linear regression model analyses, circulating LCPUFAs exhibited significant positive correlations with DRT performance. No relationships were detected among those with chronic conditions (chronic heart failure, stroke, diabetes). A significant association between LCPUFAs levels and DRT scores was evident in males but not females.ConclusionPlasma LCPUFAs concentrations were significantly associated with DRT performance in males free of chronic illnesses, including heart failure, stroke, and diabetes.

Nano porous silicon (PS) is a strong candidate for thermoelectric application, but it shows low structural stability and is prone to collapse. To enhance the structural stability of PS and offer a new way to improve its electrical conductivity, PS was prepared by electrochemical etching and Bi nanowires were fabricated in the pores of PS by electrodeposition. In addition, for studying the effect of structures on the properties of Bi-filled PS composites, aperiodic single-layer (SL) structure, and periodic rugate (Rgt) structure and Bragg structure PS samples were prepared by changing the etching current waveform and etching time. The results show that the initial Bi deposition position and filling fraction of Bi nanowires in PS templates can be precisely controlled. Since Bi nanowires have significantly different continuity in Rgt and Bragg structures compared with SL structures, we proposed two growth mechanisms of Bi nanowires, including the axis-growth mechanism and transverse-axis-growth mechanism, with the supports of the experimental results of XRD, SEM, and EDS.The room temperature thermal conductivities of pristine and Bi-filled PS layers are in the ranges of 4.5 ∼ 5.0 and 4.2 ∼ 6.0 W･m−1K−1, respectively, about 1/10 of the original unetched silicon wafer. No apparent increase of thermal conductivity was observed in any Bi-filled composites. In addition, the thermal conductivities of PS layers with Bragg structure, including pristine and Bi-filled PS composites, are significantly lower than those of the other two structures.SEM images also demonstrates that Bi greatly improved the mechanical property of PS composites, especially the periodic structures composites. This study firmly demonstrates that Bi-filling in PS with periodic Bragg structure is practical to obtain nanocomposites with low thermal conductivity and improved structural stability. It offers a new dimension to optimize the property of PS for thermoelectric application by pore configuration design and controllable nanowire Bi filling.

The residue remaining after oil extraction from grape seed contain abundant procyanidins. An ultrasonic-assisted enzyme method was performed to achieve a high extraction efficiency of procyanidins when the optimal extraction conditions were 8 U/g of cellulase, ultrasound power of 200 W, ultrasonic temperature of 50 ℃, and ultrasonic reaction time of 40 min. The effects of free procyanidins on both radical scavenging activity and thermal stability at 40, 60, and 80 ℃ of the procyanidins-loaded liposomal systems prepared by the ultrasonic-assisted method were discussed. The presence of procyanidins at concentrations ranging from 0.02 to 0.10 mg/mL was observed to be effective at inhibiting lipid oxidation by 15.15 % to 69.70 % in a linoleic acid model system during reaction for 168 h, as measured using the ferric thiocyanate method. The procyanidins-loaded liposomal systems prepared by the ultrasonic-assisted method were characterized by measuring the mean particle size and encapsulation efficiency. Moreover, the holographic plots showed that the effect–response points of procyanidins combined with α-tocopherol in liposomes were lower than the addition line and 95 % confidence interval limits. At the same time, there were significant differences between the theoretical IC50add value and the experimental IC50mix value. The interaction index (γ) of all combinations was observed to be less than 1. These results indicated that there was a synergistic antioxidant effect between procyanidins combined with α-tocopherol, which will show promising prospects in practical applications. In addition, particle size differentiation and morphology agglomeration were observed at different time points of antioxidant activity determination (0, 48, 96 h).

We consider a Multi-UAV multicarrier non-orthogonal multiple access (MC-NOMA) downlink network in which each UAV serves a group of ground users within its designated cell. Our goal is to maximize the total downlink rate for each cell by simultaneously optimizing the subcarrier assignment and power control. However, the need to maximize the downlink rate for each individual UAV cell introduces conflicts because the optimization objectives for different cells are inherently at odds with each other, making this a Multi-Objective Optimization Problem (MOOP). We applied the weighted Tchebycheff method to convert the MOOP into a Single-Objective Optimization Problem (SOOP). The resulting SOOP remains a Mixed-Integer Nonlinear Programming (MINLP) problem. To address this, we first relax the combinatorial subcarrier assignment variables into continuous variables and then apply a penalty method to enforce binary constraints. To handle the nonconvexity of the objective function and constraints, we utilize the Big-M method and Successive Convex Approximation (SCA) to decouple the product terms and deal with nonconvexity. We then employed an iterative approach to obtain a suboptimal solution and continued the process until convergence was achieved. Simulations demonstrate that this method effectively balances the trade-offs among different cells, achieves significant performance improvements and successfully approximates Pareto optimal solutions.

Abstract Background Renal cell carcinoma (RCC) is one of the most common malignant tumor worldwide. Metastasis is a leading case of cancer-related deaths of RCC. Circular RNAs (circRNAs), a class of noncoding RNAs, have emerged as important regulators in cancer metastasis. However, the functional effects and regulatory mechanisms of circRNAs on RCC metastasis remain largely unknown. Methods High-throughput RNA sequencing techniques were performed to analyze the expression profiles of circRNAs and mRNAs in highly and poorly invasive clear cell renal cell carcinoma (ccRCC) cell lines. Functional experiments were performed to unveil the regulatory role of circPPAP2B in the proliferation and metastatic capabilities of ccRCC cells. RNA pulldown, Mass spectrometry analysis, RNA methylation immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), co-immunoprecipitation (CoIP), next-generation RNA-sequencing and double luciferase experiments were employed to clarify the molecular mechanisms by which circPPAP2B promotes ccRCC metastasis. Results In this study, we describe a newly identified circular RNA called circPPAP2B, which is overexpressed in highly invasive ccRCC cells, as determined through advanced high-throughput RNA sequencing techniques. Furthermore, we observed elevated circPPAP2B in ccRCC tissues, particularly in metastatic ccRCC tissues, and found it to be associated with poor prognosis. Functional experiments unveiled that circPPAP2B actively stimulates the proliferation and metastatic capabilities of ccRCC cells. Mechanistically, circPPAP2B interacts with HNRNPC in a m6A-dependent manner to facilitate HNRNPC nuclear translocation. Subcellular relocalization was dependent upon nondegradable ubiquitination of HNRNPC and stabilization of an HNRNPC/Vimentin/Importin α7 ternary complex. Moreover, we found that circPPAP2B modulates the interaction between HNRNPC and splicing factors, PTBP1 and HNPNPK, and regulates pre-mRNA alternative splicing. Finally, our studies demonstrate that circPPAP2B functions as a miRNA sponge to directly bind to miR-182-5p and increase CYP1B1 expression in ccRCC. Conclusions Collectively, our study provides comprehensive evidence that circPPAP2B promotes proliferation and metastasis of ccRCC via HNRNPC-dependent alternative splicing and miR-182-5p/CYP1B1 axis and highlights circPPAP2B as a potential therapeutic target for ccRCC intervention.

Abstract Geometric deep learning has been revolutionizing the molecular modeling field. Despite the state-of-the-art neural network models are approaching ab initio accuracy for molecular property prediction, their applications, such as drug discovery and molecular dynamics (MD) simulation, have been hindered by insufficient utilization of geometric information and high computational costs. Here we propose an equivariant geometry-enhanced graph neural network called ViSNet, which elegantly extracts geometric features and efficiently models molecular structures with low computational costs. Our proposed ViSNet outperforms state-of-the-art approaches on multiple MD benchmarks, including MD17, revised MD17 and MD22, and achieves excellent chemical property prediction on QM9 and Molecule3D datasets. Furthermore, through a series of simulations and case studies, ViSNet can efficiently explore the conformational space and provide reasonable interpretability to map geometric representations to molecular structures.

Random phase interference is the main factor leading to uneven optical power distribution, which will affect the positioning accuracy of the four-quadrant detector. This paper uses the power spectrum inversion method to simulate the light spot power distribution affected by random phase interference, and studies the subdivision capability characteristics of the four-quadrant detector under different random phase interference. The simulation experiment results show that when the radius of the light spot received by the detector is 1/2 the radius of the detector, both detection range and positioning accuracy can be taken into account. When the random phase interference is enhanced, the detector's subdivision capability decreases. When the random phase interference is small, the detector can achieve more than 100 subdivisions. When the random phase interference is large, the light spot can only achieve 3 subdivision at the edge of the detector target surface. An experimental system was built to test the subdivision capability of the four-quadrant detector, the experimental test results were basically consistent with the simulation results. The research results provide a technical reference for the application of four-quadrant detector. in free space environments.

Unmanned Aerial Vehicle (UAV)-assisted Mobile Edge Computing (MEC) systems have emerged as promising solutions for enhancing the computational capabilities and reducing latency in next-generation wireless networks. However, the finite energy capacity of UAVs presents a significant challenge. In this study, we formulate a joint user association, computing resource allocation, and task offloading problem, called User Association and Computation Offloading (UACO), to minimize the energy consumption of both mobile devices and UAVs by considering the computational resource limitations of UAVs and the minimum user offloading data rate requirements. The UACO problem is a mixed-integer linear programming (MILP) problem that makes it NP-hard. We transform UACO into an Offload Exact Constrained Potential Game (OFECPG) based on game theory, which facilitates distributed execution. We propose the Best Response dynamics based on Local Decomposition (BR-LD) and Better Response dynamics based on the Local Switch operator (BR-LS) to enhance computational efficiency. We prove the existence of a pure strategy Nash Equilibrium (NE) and the convergence of the proposed algorithms. Extensive simulations demonstrated the effectiveness of the OFECPG, BR-LD, and BR-LS, showing significant improvements in system energy consumption compared to the baseline schemes. Our approach offers valuable insights into the design of efficient association and offloading schemes for multi-UAV MEC networks.

The rapid deployment of large-scale UAV-assisted cellular networks has emerged as an effective solution for delivering high-speed data services to ground users in areas where terrestrial base station (BS) infrastructure is inadequate. In this paper, we address a crucial problem in these networks by aiming to maximize the uplink total rate through joint optimization of Unmanned Aerial Vehicle (UAV) association and Orthogonal Frequency Division Multiple Access (OFDMA) subcarrier assignment. However, due to the mobility of pedestrians, fixed association and subcarrier assignments lack adaptation, and centralized optimization does not scale well, especially in large-scale UAV settings. To overcome these challenges, we formulate the joint optimization problem as an exact Constrained Potential Game, called the Subcarrier Assignment and UAV Association Game (SAUAG), based on game theory. In SAUAG, each user selfishness selects the most appropriate strategy with the objective of maximizing their own utility while still fulfilling the system’s Quality of Service (QoS) constraints. We analyze the conditions under which a Nash Equilibrium (NE) exists and provide rigorous proof of its existence.To mitigate the computational complexity typically associated with Best Response Dynamics (BRD), we introduce the Two-Step Better Response (TS-BR) algorithm, which significantly reduces the computational load while ensuring convergence to an NE. Furthermore, we proposed a distributed algorithm based on sequential play and demonstrated its effectiveness in achieving NE convergence. Through comprehensive simulations, the superiority of the proposed SAUAG and TS-BR algorithms was demonstrated, showing their potential in enhancing network performance and adaptability in UAV-assisted OFDMA networks with mobile ground users.

Enhancing power system resilience against extreme events is becoming increasingly critical. This paper discusses a unified framework for preventive control of power systems to enhance system resilience, which includes three parts: resilience assessment, resilience grading, and resilience enhancement. First, the resilience assessment contains facility-level and system-level resilience assessment. The concept of fragility curve is used in the facility-level resilience assessment. Various resilience indices are developed in system-level resilience assessment to roundly depict the impacts of extreme events on power systems and determine the system resilience. On this basis, the resilience is divided into different levels by resilience grading strategy, which can efficiently quantify the severity of the impact of extreme events and provide decision-making for the resilience enhancement strategies. Then, control strategies for enhancing power system resilience are also divided according to different resilience levels. A controlled islanding based preventive control is proposed to enhance system resilience, which aims to strengthen the first defensive line of power systems to deal with extreme events. Finally, taking the typhoon disaster in extreme events as an example, two tests carried out with two typhoons demonstrate the efficiency of the proposed method.

Abstract We conducted a retrospective study to evaluate the efficacy of immune checkpoint inhibitor (ICI) rechallenge in patients with advanced non-small cell lung cancer (NSCLC). The study included 111 patients who had previously received ICI therapy and experienced disease progression. The primary endpoints assessed were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Our findings revealed that the ICI rechallenge showed promising results in improving patient outcomes. OS (r) is the time from rechallenging with immune checkpoint inhibitors to the last follow-up or death from any cause. The median OS (r) was 14.3 months (95% CI 11.3–17.3 months), with a median PFS (r) of 5.9 months (95% CI 4.1–7.7 months). The ORR was 17.1%; the DCR was 82.3%. Subgroup analysis demonstrated that patients without brain or liver metastases had a longer OS (r) compared to those with metastases (21.6 vs. 13.8 months, χ2 = 3.873, P = 0.046; 20.8 vs. 9.1 months, χ2 = 10.733, P = 0.001, respectively). Moreover, patients without driver gene mutations exhibited significantly longer OS than those with mutations or wild-type patients (22.9 vs. 16.1 vs. 7.5 months, χ2 = 10.710, P = 0.005). Notably, patients who switched to a different ICI during the rechallenge had shorter OS than those who did not change medications (10.4 vs. 21.1 months, χ2 = 9.014, P = 0.003). The incidence of immune-related adverse events did not significantly differ between the two treatment phases. These findings suggest that ICI rechallenge may be a viable therapeutic strategy for select NSCLC patients. Further prospective studies are needed to validate these results and guide treatment decisions for advanced NSCLC.

Abstract Emerging evidence reveals associations between metabolic syndrome (MetS) and psychiatric disorders (PDs), although causality remains uncertain. Consequently, we conducted Mendelian randomization (MR) to systematically evaluate the causality between MetS and PDs. Linkage disequilibrium score regression estimated the heritability of PDs and their genetic correlations with MetS. In primary analyses, the main model employed inverse variance weighting method, with sensitivity analyses using various MR models to ensure robustness. Replication MR analyses, involving cohorts distinct from those in the primary analyses, were performed to validate the generalizability of the findings. Multivariable MR analyses were carried out to account for genetically predicted body mass index (BMI). As a result, genetic correlations of MetS with attention-deficit/hyperactivity disorder(ADHD), anorexia nervosa(ANO), major depressive disorder(MDD), and schizophrenia were identified. Causal effects of MetS on ADHD (OR: 1.59 [95% CI:1.45–1.74]), ANO (OR: 1.42 [95% CI:1.25–1.61]), MDD(OR: 1.23 [95% CI: 1.13–1.33]), and the effects of ADHD (OR: 1.03 [95% CI: 1.02–1.04]) and ANO (OR: 1.01 [95% CI: 1.01–1.02]) on MetS were observed in primary analyses. Results from sensitivity analyses and replication analyses were generally consistent with the primary analyses, confirming the robustness and generalizability of the findings. Associations between MetS and ADHD, as well as ANO persisted after adjusting for BMI, whereas the statistical significance of the association between MetS and MDD was no longer observable. These results contribute to a deeper understanding of the mechanisms underlying PDs, suggesting potential modifiable targets for public prevention and clinical intervention in specific PDs related to metabolic pathways.

AIM: To investigate the effects of Sonic hedgehog (Shh) gene-modified bone marrow mesenchymal stem cells (MSCs) on graft-induced retinal gliosis and retinal ganglion cells (RGCs) survival in diabetic mice. METHODS: Bone marrow-derived MSCs were genetically modified with the Shh gene to generate a stably transfected cell line of Shh-modified MSCs (MSC-Shh). Intravitreal injections of MSC-Shh and green fluorescent protein-modified MSCs (MSC-Gfp; control) were administered in diabetic mice. After 4wk, the effects of MSC-Shh on retinal gliosis were evaluated using fundus photography, and markers of gliosis were examined by immunofluorescence and Western blotting. The neurotrophic factors expression and RGCs survival in the host retina were evaluated using Western blotting and immunofluorescence. The mechanisms underlying the effects of MSC-Shh was investigated. RESULTS: A significant reduction of proliferative vitreoretinopathy (PVR) was observed after intravitreal injection of MSC-Shh compared to MSC-Gfp. Significant downregulation of glial fibrillary acidic protein (GFAP) was demonstrated in the host retina after MSC-Shh administration compared to MSC-Gfp. The extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase B (AKT) and phosphatidylin-ositol-3-kinase (PI3K) pathways were significantly downregulated after MSC-Shh administration compared to MSC-Gfp. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) levels were significantly increased in the host retina, and RGCs loss was significantly prevented after MSC-Shh administration. CONCLUSION: MSC-Shh administration reduces graft-induced reactive gliosis following intravitreal injection in diabetic mice. The ERK1/2, AKT and PI3K pathways are involved in this process. MSC-Shh also increases the levels of neurotrophic factors in the host retina and promoted RGCs survival in diabetic mice.

Abstract Background In 2022, Omicron outbreaks occurred at multiple sites in China. It is of great importance to track the incidence trends and transmission dynamics of coronavirus disease 2019 (COVID-19) to guide further interventions. Methods Given the population size, economic level and transport level similarities, two groups of outbreaks (Shanghai vs. Chengdu and Sanya vs. Beihai) were selected for analysis. We developed the SEAIQRD, ARIMA, and LSTM models to seek optimal modeling techniques for waves associated with the Omicron variant regarding data predictive performance and mechanism transmission dynamics, respectively. In addition, we quantitatively modeled the impacts of different combinations of more stringent interventions on the course of the epidemic through scenario analyses. Results The best-performing LSTM model showed better prediction accuracy than the best-performing SEAIQRD and ARIMA models in most cases studied. The SEAIQRD model had an absolute advantage in exploring the transmission dynamics of the outbreaks. Regardless of the time to inflection point or the time to R t curve below 1.0, Shanghai was later than Chengdu (day 46 vs. day 12/day 54 vs. day 14), and Sanya was later than Beihai (day 16 vs. day 12/day 20 vs. day 16). Regardless of the number of peak cases or the cumulative number of infections, Shanghai was higher than Chengdu (34,350 vs. 188/623,870 vs. 2,181), and Sanya was higher than Beihai (1,105 vs. 203/16,289 vs. 3,184). Scenario analyses suggested that upgrading control level in advance, while increasing the index decline rate and quarantine rate, were of great significance for shortening the time to peak and R t below 1.0, as well as reducing the number of peak cases and final affected population. Conclusions The LSTM model has great potential for predicting the prevalence of Omicron outbreaks, whereas the SEAIQRD model is highly effective in revealing their internal transmission mechanisms. We recommended the use of joint interventions to contain the spread of the virus.

Abstract Background Breast cancer is the leading cause of cancer death for women worldwide. Most of the breast cancer death are due to disease recurrence and metastasis. Increasingly accumulating evidence indicates that mitochondria play key roles in cancer progression and metastasis. Our recent study revealed that transmembrane protein PRRG4 promotes the metastasis of breast cancer. However, it is not clear whether PRRG4 can affect the migration and invasion of breast cancer cells through regulating mitochondria function. Methods RNA-seq analyses were performed on breast cancer cells expressing control and PRRG4 shRNAs. Quantitative PCR analysis and measurements of mitochondrial ATP content and oxygen consumption were carried out to explore the roles of PRRG4 in regulating mitochondrial function. Luciferase reporter plasmids containing different lengths of promoter fragments were constructed. Luciferase activities in breast cancer cells transiently transfected with these reporter plasmids were analyzed to examine the effects of PRRG4 overexpression on promoter activity. Transwell assays were performed to determine the effects of PRRG4-regulated pathway on migratory behaviors of breast cancer cells. Results Analysis of the RNA-seq data revealed that PRRG4 knockdown decreased the transcript levels of all the mitochondrial protein-encoding genes. Subsequently, studies with PRRG4 knockdown and overexpression showed that PRRG4 expression increased mitochondrial DNA (mtDNA) content. Mechanistically, PRRG4 via Src activated STAT3 in breast cancer cells. Activated STAT3 in turn promoted the transcription of mtDNA polymerase POLG through a STAT3 DNA binding site present in the POLG promoter region, and increased mtDNA content as well as mitochondrial ATP production and oxygen consumption. In addition, PRRG4-mediated activation of STAT3 also enhanced filopodia formation, migration, and invasion of breast cancer cells. Moreover, PRRG4 elevated migratory behaviors and mitochondrial function of breast cancer cells through POLG. Conclusion Our results indicate that PRRG4 via the Src-STAT3-POLG axis enhances mitochondrial function and promotes migratory behaviors of breast cancer cells.

Abstract Cultured meat production has emerged as a breakthrough technology for the global food industry with the potential to reduce challenges associated with environmental sustainability, global public health, animal welfare, and competition for food between humans and animals. The muscle stem cell lines currently used for cultured meat cannot be passaged in vitro for extended periods of time. Here, we develop a directional differentiation system of porcine pre-gastrulation epiblast stem cells (pgEpiSCs) with stable cellular features and achieve serum-free myogenic differentiation of the pgEpiSCs. We show that the pgEpiSCs-derived skeletal muscle progenitor cells and skeletal muscle fibers have typical muscle cell characteristics and display skeletal muscle transcriptional features during myogenic differentiation. Importantly, we establish a three-dimensional differentiation system for shaping cultured tissue by screening plant-based edible scaffolds of non-animal origin, followed by the generation of pgEpiSCs-derived cultured meat. These advances provide a technical approach for the development of cultured meat.

The novel weapon hypothesis suggests that allelopathy is an important mechanism for exotic plants to successfully invade native plant communities. Allelochemicals from exotic plants affect both native plants and arbuscular mycorrhizal fungi (AMF) in soil. To explore these effects, we conducted pot experiments using a native plant community comprising of Chenopodium album L., Vitex negundo L., Rhus chinensis Mill., and Acer truncatum Bunge. We incorporated AMF strains (Funneliformis mosseae, Glomus versiforme, and Rhizophagus intraradices in a 1:1:1 volume ratio) into a soil mixture comprising equal volumes of autoclaved field soil and grass ash at five concentrations (0 g L–1, CK; 10 g L–1, LRE; 20 g L–1, NRE; 30 g L–1, MRE; and 40 g L–1, HRE) to investigate the allelopathy of Rhus typhina L. root and its interactions with AMF on the native plant community. Our results indicated that low concentrations of allelochemicals promoted the relative growth rate and leaf nitrogen content in the native plant community, which was attributed to the increased environmental stress that improved the degree of leaf photosynthetic capacity and organic synthesis rate in the native communities. Moreover, allelochemicals with toxicity decreased the colonization rates of AMF. Meanwhile, the presence of allelopathic effects induced a decrease in leaf nitrogen, and allelopathy altered the effects of AMF on the native community. Specifically, the high concentration of allelochemicals altered the positive effect of AMF on the total aboveground biomass of the native plant community to a negative effect, likely by decreasing colonization rates or affecting soil physicochemical properties and the composition of the mycorrhizal communities. Consequently, it is necessary to consider the effects of AMF when testing the roles of allelopathy or the novel weapons hypothesis in biological invasions. Graphical abstract

Abstract Recent advances in next-generation sequencing (NGS) technology have greatly accelerated the need for efficient annotation to accurately interpret clinically relevant genetic variants in human diseases. Therefore, it is crucial to develop appropriate analytical tools to improve the interpretation of disease variants. Given the unique genetic characteristics of mitochondria, including haplogroup, heteroplasmy, and maternal inheritance, we developed a suite of variant analysis toolkits specifically designed for primary mitochondrial diseases: the Mitochondrial Missense Variant Annotation Tool (MmisAT) and the Mitochondrial Missense Variant Pathogenicity Predictor (MmisP). MmisAT can handle protein-coding variants from both nuclear DNA and mtDNA and generate 349 annotation types across six categories. It processes 4.78 million variant data in 76 min, making it a valuable resource for clinical and research applications. Additionally, MmisP provides pathogenicity scores to predict the pathogenicity of genetic variations in mitochondrial disease. It has been validated using cross-validation and external datasets and demonstrated higher overall discriminant accuracy with a receiver operating characteristic (ROC) curve area under the curve (AUC) of 0.94, outperforming existing pathogenicity predictors. In conclusion, the MmisAT is an efficient tool that greatly facilitates the process of variant annotation, expanding the scope of variant annotation information. Furthermore, the development of MmisP provides valuable insights into the creation of disease-specific, phenotype-specific, and even gene-specific predictors of pathogenicity, further advancing our understanding of specific fields.

Chemical fungicides can cause drug resistance of plant pathogenic fungi, environmental pollution, and potential threats to humans and animals. Therefore, developing low-toxicity, high-efficient and environment-friendly biological control products is critical for green prevention, controlling plant fungal diseases, and maintaining ecological balance. Biocontrol research mainly includes the following aspects: antagonistic microorganisms, fungicidal proteins, RNA interference techniques and botanical fungicides. Significantly, natural products extracted from medicinal plants are valuable repertoire for inhibiting plant fungal diseases. This review systematically reviewed the research advances of using natural products from medicinal plants to inhibit plant pathogenic fungi, including the types of natural products, extraction methods, and antifungal mechanisms. The further prospects for the study and application, which provide the reference for botanical fungicide development and practical application in preventing and controlling plant fungal disease, were also discussed.

Abstract Influenza A viruses (IAV) are a prevalent respiratory pathogen that can cause seasonal flu and global pandemics, posing a significant global public health threat. Emerging research suggests that IAV infections may disrupt the balance of gut microbiota, while gut dysbiosis can affect disease progression in IAV patients. Therefore, restoring gut microbiota balance may represent a promising therapeutic target for IAV infections. Traditional Chinese medicine, with its ability to regulate gut microbiota, offers significant potential in preventing and treating IAV. This article provides a comprehensive review of the relationship between IAV and gut microbiota, highlighting the impact of gut microbiota on IAV infections. It also explores the mechanisms and role of traditional Chinese medicine in regulating gut microbiota for the prevention and treatment of IAV, presenting novel research avenues for traditional Chinese medicine-based IAV treatments.

Abstract Background Lignocellulose, the most abundant non-edible feedstock on Earth, holds substantial potential for eco-friendly chemicals, fuels, and pharmaceuticals production. Glucose, xylose, and arabinose are primary components in lignocellulose, and their efficient conversion into high-value products is vital for economic viability. While glucose and xylose have been explored for such purpose, arabinose has been relatively overlooked. Results This study demonstrates a microbial platform for producing 1,2,4-butanetriol (BTO) from arabinose, a versatile compound with diverse applications in military, polymer, rubber and pharmaceutical industries. The screening of the key pathway enzyme, keto acids decarboxylase, facilitated the production of 276.7 mg/L of BTO from arabinose in Escherichia coli. Through protein engineering of the rate-limiting enzyme KivD, which involved reducing the size of the binding pocket to accommodate a smaller substrate, its activity improved threefold, resulting in an increase in the BTO titer to 475.1 mg/L. Additionally, modular optimization was employed to adjust the expression levels of pathway genes, further enhancing BTO production to 705.1 mg/L. Conclusion The present study showcases a promising microbial platform for sustainable BTO production from arabinose. These works widen the spectrum of potential lignocellulosic products and lays the foundation for comprehensive utilization of lignocellulosic components.

The low Earth orbit (LEO) satellite internet network (LEO-SIN) has become a heated issue for the next generation of mobile communications, serving as a crucial means to achieve global wide-area broadband coverage and, especially, mobile phone directly to satellite cell (MPDTSC) communication. The ultra-high-speed movement of LEO satellites relative to the Earth results in serious Doppler effects, leading to signal de-synchronization at the user end (UE), and relative high-speed motion leading to frequent satellite handovers. Satellite ephemeris, which indicates the satellite’s position, has the potential to determine the position of the transmit (Tx) within the LEO-SIN, thereby enhancing the reliability and efficiency of satellite communication. The adoption of ephemeris in the LEO-SIN has met some new challenges: (1) how UEs can acquire ephemerides before signal synchronization is complete, (2) how to minimize the frequency of ephemeris broadcasting, and (3) how to decrease the overhead of ephemeris broadcasting. To address the above challenges, this paper proposes a method for extrapolating the LEO-SIN orbit based on multi-satellite ephemeris coordination (MSEC) and the multi-stream fractional autoregressive integrated moving average (MS-FARIMA). First, a multi-factor global error analysis model for ephemeris-extrapolation error is established, which decomposes it into three types; namely, random error (RE), trending error (TE), and periodic error (PE), with a focus on increasing the extrapolation accuracy by improving RE and TE. Second, RE is eliminated by utilizing the ephemerides from multiple satellites received at the same UE at the same time, as well as multiple ephemerides from the same satellite at different times. Subsequently, we propose a new FARIMA algorithm with the innovation of a multi-stream data time-series forecast (TSF), which effectively improves ephemeris extrapolation errors. Finally, the simulation results show that the proposed method reduces ephemeris extrapolation errors by 33.5% compared to existing methods, which also contributes to a performance enhancement in the Doppler frequency offset (DFO) estimation of MPDTSC.

This study explored the polymorphism of the leucine aminopeptidase (LAP3) gene and its relationship with milk quality characteristics in Gannan yak. A cohort of 162 Gannan yak was genotyped utilizing the Illumina Yak cGPS 7K BeadChip, and the identified single nucleotide polymorphisms (SNPs) were evaluated for their association with milk protein, casein, lactose, and fat concentrations. The results showed that four SNPs (g.4494G > A, g.5919A > G, g.8033G > C, and g.15,615A > G) in the LAP3 gene exhibited polymorphism with information content values of 0.267, 0.267, 0.293, and 0.114, respectively. All four SNPs were in Hardy–Weinberg equilibrium (p > 0.05). The g.4494G > A and g.5919A > G SNPs were significantly associated with protein content (p < 0.05), with homozygous genotypes showing significantly higher protein content than heterozygous genotypes (p < 0.05). The g.8033G > C SNP was significantly associated with casein content, protein content, non-fat solids, and acidity (p < 0.05), with the CC genotype having significantly higher casein, protein, and non-fat solids content than the GG and GC genotypes (p < 0.05). The g.15,615A > G SNP was significantly associated with average fat globule diameter (p < 0.05). In general, the mutations within the LAP3 gene demonstrated a positive impact on milk quality traits in Gannan yak, with mutated genotypes correlating with enhanced milk quality. These results indicate that the LAP3 gene could be a significant or candidate gene affecting milk quality traits in Gannan yak and offer potential genetic markers for molecular breeding programs in this species.

Onychomycosis is a recalcitrant fungal infection of the nail unit that can lead to secondary infections and foot complications. Accurate pathogen identification by confirmatory testing is recommended to improve treatment outcomes. In this study, we reviewed the records of 710,541 patients whose nail specimens were sent to a single molecular diagnostic laboratory between 2015 and 2024. PCR testing revealed a more comprehensive spectrum of pathogens than previously reported, which was corroborated by the demonstration of fungal invasion on histopathology. Consistent with our current understanding, the T. rubrum complex (54.3%) are among the most common pathogens; however, a significant portion of mycology-confirmed diagnoses were caused by the T. mentagrophytes complex (6.5%), Aspergillus (7.0%) and Fusarium (4.5%). Females were significantly more likely to be infected with non-dermatophytes molds (NDMs; OR: 2.0), including Aspergillus (OR: 3.3) and Fusarium (OR: 2.0), and yeasts (OR: 1.5), including Candida albicans (OR: 2.0) and C. parapsilosis (OR 1.6), than males. The T. mentagrophytes complex became more prevalent with age, and conversely the T. rubrum complex became less prevalent with age. Patients aged ≥65 years also demonstrated a higher likelihood of contracting onychomycosis caused by NDMs (OR: 1.6), including Aspergillus (OR: 2.2), Acremonium (OR: 3.5), Scopulariopsis (OR: 2.9), Neoscytalidium (OR: 3.8), and yeasts (OR: 1.8), including C. albicans (OR: 1.9) and C. parapsilosis (OR: 1.7), than young adults. NDMs (e.g., Aspergillus and Fusarium) and yeasts were, overall, more likely to cause superficial onychomycosis and less likely to cause dystrophic onychomycosis than dermatophytes. With regards to subungual onychomycosis, Aspergillus, Scopulariopsis and Neoscytalidium had a similar likelihood as dermatophytes. The advent of molecular diagnostics enabling a timely and accurate pathogen identification can better inform healthcare providers of appropriate treatment selections and develop evidence-based recommendations.

With the increasingly serious problems of energy shortage and environmental degradation, countries around the world are actively developing safe, environmentally friendly, and renewable energy. Biomass energy has become an ideal substitute for fossil fuels due to its abundant reserves, good renewable performance, and zero carbon emissions. This paper discusses the importance and potential of biomass energy as a renewable energy source for China’s energy development, mainly including the three biomass conversion methods of physics, chemistry, and biology, seven utilization technologies, such as direct combustion, gasification, and pyrolysis, and five application approaches, such as biomass power generation, biomass gas fuel, biomass liquid fuel, and bio-based materials. This review systematically analyzes the challenges faced by China’s development of biomass energy and discusses the future development direction of biomass. The utilization of biomass resources should take a comprehensive and high-value path. China is actively looking for new energy utilization paths, and biomass energy has become a key measure to cope with carbon emission reduction, climate change, and ecological environment protection.

Selenium (Se) is an essential trace element known for its significant role in maintaining human health and mitigating disease progression. Selenium and its compounds exhibit high selective cytotoxicity against tumor cells. However, their anti-cervical cancer (CC) effects and underlying mechanisms have not been fully explored. This study found that sodium selenite (SS) inhibits the viability of HeLa and SiHa cells in a dose- and time-dependent manner. Intraperitoneal injection of 3 and 6 mg/kg SS for 14 days in female nude mice significantly inhibited the growth of HeLa cell xenografts without evident hepatotoxicity or nephrotoxicity. RNA sequencing results indicated that the AMP-activated protein kinase (AMPK), Forkhead box protein O (FOXO), and apoptosis signaling pathways are key regulatory pathways in SS’s anti-CC effects, and SS’s inhibition of HeLa cell proliferation may be related to autophagy and ROS-induced apoptosis. Further research has revealed that SS induces cell autophagy and apoptosis through the AMPK/mTOR/FOXO3a pathway, characterized by the upregulation of p-AMPK/AMPK, FOXO3a, LC3-II, cleaved-caspase3, and cleaved-PARP and the downregulation of p-mTOR/mTOR and p62. Additionally, SS impaired mitochondrial function, including decreased mitochondrial membrane potential, mitochondrial Ca2+ overload, and accumulation of mitochondrial reactive oxygen species (mtROS). Pretreatment with Mitoquinone mesylate (Mito Q) and compound C partially reversed SS-induced apoptosis, autophagy, and proliferation inhibition. Pretreatment with 3-methyladenine (3-MA) enhances SS-induced apoptosis and proliferation inhibition in HeLa cells but reverses these effects in SiHa cells. In summary, SS induces apoptosis, autophagy, and proliferation inhibition in HeLa and SiHa cells through the activation of the AMPK/mTOR/FOXO3a signaling pathway via mtROS. Autophagy activation may be a major risk factor for SS-induced apoptosis in SiHa cells but can protect HeLa cells from SS-induced apoptosis. These findings provide new evidence for understanding the molecular mechanisms underlying SS in potential new drug development for CC.

Diabetic nephropathy (DN) is one of the common complications of diabetes and the main cause of end-stage renal disease (ESRD) in clinical practice. Schisandrin A (Sch A) has multiple pharmacological activities, including inhibiting fibrosis, reducing apoptosis and oxidative stress, and regulating immunity, but its pharmacological mechanism for the treatment of DN is still unclear. In vivo, streptozotocin (STZ) and a high-fat diet were used to induce type 2 diabetic rats, and Sch A was administered for 4 weeks. At the same time, protein–protein interaction (PPI) networks were established to analyze the overlapping genes of DN and Sch A. Subsequently, the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were performed to determine the hub pathway. In addition, molecular docking was used to preliminarily verify the affinity of hub proteins and Sch A. Further, H&E staining, Sirius red staining, immunohistochemistry, immunofluorescence, and western blot analysis were used to detect the location and expression of related proteins in DN. This study revealed the multi-target and multi-pathway characteristics of Sch A in the treatment of DN. First, Sch A could effectively improve glucose tolerance, reduce urine microprotein and urine creatinine levels, and alleviate renal pathological damage in DN rats. Second, EGFR was the hub gene screened in overlapping genes (43) of Sch A (100) and DN (2524). Finally, it was revealed that Sch A could inhibit the protein expression levels of EGFR and PTRF and reduced the expression of apoptosis-related proteins, and this effect was related to the modulation of the AKT/GSK-3β signaling pathway. In summary, Sch A has a protective effect in DN rats, EGFR may be a potential therapeutic target, throughout modulating AKT/GSK-3β pathway.

Abstract Fast screening strategies that enable high‐throughput evaluation and identification of desired variants from diversified enzyme libraries are crucial to tailoring biocatalysts for the synthesis of D‐allulose, which is currently limited by the poor catalytic performance of ketose 3‐epimerases (KEases). Here, the study designs a minimally equipment‐dependent, high‐throughput, and growth‐coupled in vivo screening platform founded on a redesigned D‐allulose‐dependent biosensor system. The genetic elements modulating regulator PsiR expression levels undergo systematic optimization to improve the growth‐responsive dynamic range of the biosensor, which presents ≈30‐fold facilitated growth optical density with a high signal‐to‐noise ratio (1.52 to 0.05) toward D‐allulose concentrations from 0 to 100 mm. Structural analysis and evolutionary conservation analysis of Agrobacterium sp. SUL3 D‐allulose 3‐epimerase (ADAE) reveal a highly conserved catalytic active site and variable hydrophobic pocket, which together regulate substrate recognition. Structure‐guided rational design and directed evolution are implemented using the growth‐coupled in vivo screening platform to reprogram ADAE, in which a mutant M42 (P38N/V102A/Y201L/S207N/I251R) is identified with a 6.28‐fold enhancement of catalytic activity and significantly improved thermostability with a 2.5‐fold increase of the half‐life at 60 °C. The research demonstrates that biosensor‐assisted growth‐coupled evolutionary pressure combined with structure‐guided rational design provides a universal route for engineering KEases.

Background: In the realm of tumor-targeted therapeutics, Polo-like kinases (PLKs) are a significant group of protein kinases that were found recently as being related to tumors. However, the significance of PLKs in pan-cancer remains systematically studied. Methods and materials: We integrated multi-omics data to comprehensively investigate the expression patterns of the PLK family across various cancer types. Subsequently, study examined the associations between tumor mutation burden (TMB), microsatellite instability (MSI), immune subtype classification, immune infiltration, tumor microenvironment scores, immune checkpoint gene expression, and the PLKs expression profiles within various tumor types. Furthermore, using our mRNA sequencing data (TRUCE01) and four bladder cancer (BLCA) cohorts (GSE111636, GSE176307, and IMvigor210), We examined the correlation between the expression level of PLK and immunotherapy effectiveness. Next, Gene set enrichment analysis (GSEA) was evaluated to find that potentially enriched PLK signaling pathways. Utilizing TIMER 2.0, we conducted an immune infiltration analysis underlying transcriptome expression, copy number variations (CNV), or somatic mutations of PLKs in BLCA. Finally, mRNA expression validation of PLK1/3/4 by real-time PCR within 10 paired BLCA tissues, protein expression verification through the Human Protein Atlas (HPA), and PLK4 in vitro cytological studies have been employed in BLCA. Results: The expression of most of the PLK family members exhibits variation between cancerous tissues and adjacent normal tissues across various cancer species. Furthermore, the expression of PLKs demonstrates a significant association with immunotyping, infiltration of immune cell, tumor mutational burden (TMB), microsatellite instability (MSI), immunological checkpoint gene activity and therapeutic effectiveness in pan-tumor tissues. Additional investigation into the correlation between the PLK family and BLCA has revealed that the expression of the PLK genes holds substantial significance in the biological processes of BLCA. Furthermore, a notable association has been observed between the copy number variation, variant status, and the degree of certain immunological cell infiltration. Of note, the expression validation and in vitro phenotypic experiments have demonstrated that PLK4 has a significant function in promoting the BLCA cell proliferation, migration, and invasion. Conclusion: Collectively, based on various databases, our results highlight the involvement of PLK gene family in the formation of different types of tumors and identify PLK-related genes that may be used for therapy.

Summary: The classic view of the lysosome as a static recycling center has been replaced with one of a dynamic and mobile hub of metabolic regulation. This revised view raises new questions about how dysfunction of this organelle causes pathology in inherited lysosomal disorders. Here we provide evidence for increased lysosomal exocytosis in the developing cartilage of three lysosomal disease zebrafish models with distinct etiologies. Dysregulated exocytosis was linked to altered cartilage development, increased activity of multiple cathepsin proteases, and cathepsin- and TGFβ-mediated pathogenesis in these models. Moreover, inhibition of cathepsin activity or direct blockade of exocytosis with small molecule modulators improved the cartilage phenotypes, reinforcing a connection between excessive extracellular protease activity and cartilage pathogenesis. This study highlights the pathogenic consequences in early cartilage development arising from uncontrolled release of lysosomal enzymes via exocytosis, and suggests that pharmacological enhancement of this process could be detrimental during tissue development.

We recently identified two virulence-associated small open reading frames (sORF) of Yersinia pestis, named yp1 and yp2, and null mutants of each individual genes were highly attenuated in virulence. Plague vaccine strain EV76 is known for strong reactogenicity, making it not suitable for use in humans. To improve the immune safety of EV76, three mutant strains of EV76, Δyp1, Δyp2, and Δyp1&yp2 were constructed and their virulence attenuation, immunogenicity, and protective efficacy in mice were evaluated. All mutant strains were attenuated by the subcutaneous (s.c.) route and exhibited more rapid clearance in tissues than the parental strain EV76. Under iron overload conditions, only the mice infected with EV76Δyp1 survived, accompanied by less draining lymph nodes damage than those infected by EV76. Analysis of cytokines secreted by splenocytes of immunized mice found that EV76Δyp2 induced higher secretion of multiple cytokines including TNF-α, IL-2, and IL-12p70 than EV76. On day 42, EV76Δyp2 or EV76Δyp1&yp2 immunized mice exhibited similar protective efficacy as EV76 when exposed to Y. pestis 201, both via s.c. or intranasal (i.n.) routes of administration. Moreover, when exposed to 200-400 LD50 Y. pestis strain 201Δcaf1 (non-encapsulated Y. pestis), EV76Δyp2 or EV76Δyp1&yp2 are able to afford about 50% protection to i.n. challenges, significantly better than the protection afforded by EV76. On 120 day, mice immunized with EV76Δyp2 or EV76Δyp1&yp2 cleared the i.n. challenge of Y. pestis 201-lux as quickly as those immunized with EV76, demonstrating 90-100% protection. Our results demonstrated that deletion of the yp2 gene is an effective strategy to attenuate virulence of Y. pestis EV76 while improving immunogenicity. Furthermore, EV76Δyp2 is a promising candidate for conferring protection against the pneumonic and bubonic forms of plague.

BackgroundHypertension significantly impacts the well-being and health of individuals globally. Hypertension management apps (HMAs) have been shown to assist patients in controlling blood pressure (BP), with their efficacy validated in clinical trials. However, the utilization of HMAs continues to be suboptimal. Presently, there is a dearth of real-world research based on big data and exploratory mining that compares Chinese and American HMAs. ObjectiveThis study aims to systematically gather HMAs and their user reviews from both China and the United States. Subsequently, using data mining techniques, the study aims to compare the user experience, satisfaction levels, influencing factors, and asymmetry between Chinese and American users of HMAs. In addition, the study seeks to assess the disparities in satisfaction and its determinants while delving into the asymmetry of these factors. MethodsThe study sourced HMAs and user reviews from 10 prominent Chinese and American app stores globally. Using the latent Dirichlet allocation (LDA) topic model, the research identified various topics within user reviews. Subsequently, the Tobit model was used to investigate the impact and distinctions of each topic on user satisfaction. The Wald test was applied to analyze differences in effects across various factors. ResultsWe examined a total of 261 HMAs along with their associated user reviews, amounting to 116,686 reviews in total. In terms of quantity and overall satisfaction levels, Chinese HMAs (n=91) and corresponding reviews (n=16,561) were notably fewer compared with their American counterparts (n=220 HMAs and n=100,125 reviews). The overall satisfaction rate among HMA users was 75.22% (87,773/116,686), with Chinese HMAs demonstrating a higher satisfaction rate (13,866/16,561, 83.73%) compared with that for American HMAs (73,907/100,125, 73.81%). Chinese users primarily focus on reliability (2165/16,561, 13.07%) and measurement accuracy (2091/16,561, 12.63%) when considering HMAs, whereas American users prioritize BP tracking (17,285/100,125, 17.26%) and data synchronization (12,837/100,125, 12.82%). Seven factors (easy to use: P

The objective of this study is to optimize the ultrasonic-assisted extraction process of Ku Shen (Sophorae Flavescentis Radix) extracts (KSE) against Vibrio parahaemolyticus and explore their anti-biofilm activity and mechanism of action. The ultrasonic-assisted extraction process of KSE optimized by single factor experiment, Box–Behnken design and response surface methodology was as follows: 93% ethanol as solvent, liquid/material ratio of 30 mL/g, ultrasonic power of 500 W, extraction temperature of 80°C and time of 30 min. Under these conditions, the diameter of inhibition circle of KSE was 15.60 ± 0.17 mm, which had no significant difference with the predicted value. The yield of dried KSE is 32.32 ± 0.57% and the content of total flavonoids in KSE was 57.02 ± 5.54%. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of KSE against V. parahaemolyticus were 0.25 and 0.5 mg/mL, respectively. Crystal violet staining, Congo red plate, spectrophotometry, CCK-8 and scanning electron microscopy were used to investigate the activity and mechanism of action of KSE against V. parahaemolyticus biofilm. The results showed that the sub-MIC of KSE could significantly inhibit biofilm formation, reduce the synthesis of polysaccharide intercellular adhesin (PIA) and the secretion of extracellular DNA. In addition, the inhibition rate of biofilm formation and clearance rate of mature biofilm of 1.0 mg/mL KSE were 85.32 and 74.04%, and the reduction rate of metabolic activity of developing and mature biofilm were 77.98 and 74.46%, respectively. These results were confirmed by visual images obtained by scanning electron microscopy. Therefore, KSE has the potential to further isolate the anti-biofilm agent and evaluate it for the preservation process of aquatic products.

Envafolimab is a Chinese domestic innovative fusion of a humanized single-domain programmed death-ligand 1 (PD-L1) antibody (dAb) and human immunoglobulin IgG1 crystalline fragment (Fc) developed for subcutaneous injections. It was granted conditional market authorization by the China National Medical Product Administration (NMPA) in December 2021. Envafolimab is used to treat adult patients with previously treated microsatellite instability—high (MSI-H) or deficient mismatch repair (dMMR) advanced solid tumors, including patients with advanced colorectal cancer disease progression who were previously administered fluorouracil, oxaliplatin, and irinotecan, as well as other patients with advanced solid tumors who experienced disease progression after receiving standard treatment and had no other alternative treatment options. However, the lack of post-marketing clinical trial data requires conducting more clinical studies on the safety and efficacy of envafolimab in order to provide scientific basis and a reference for future therapeutic applications. In this paper, we report a case of severe skin necrosis and bleeding in the area of injection after subcutaneous administration of envafolimab in a patient diagnosed with hepatocellular carcinoma. We discuss issues that must be considered before administration of a PD-L1 inhibitor subcutaneously, which could induce immune mechanisms leading to skin necrosis in the area of injection.