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Abstract Purpose County-level hospitals in China constitute a vital component of the healthcare system, delivering essential medical services, emergency care, and specialized treatments, particularly in oncology. This study aimed to comprehensively evaluate the current status of cancer diagnosis and treatment in county hospitals and assess their overall capacity. Methods A nationwide cross-sectional survey by the China Anti-cancer Association (CACA) from February to May 2023 assessed cancer diagnosis and treatment in mainland China's county hospitals. Using a multi-center approach, a fifty-five-question questionnaire was administered to oncology professionals and management staffs, focusing on hospital facilities, oncology specialists, cancer cases, treatment capabilities, and healthcare collaboration. Questionnaire reliability and validity were established in a 2022 national survey. Participants, aged 18 or older, were recruited through purposive sampling, receiving self-administered questionnaires for confidentiality. SAS 9.4 software facilitated statistical analysis. Results The study encompassed 76 county-level medical institutions, with 82.9% of them featuring established oncology departments providing comprehensive cancer care, including early screening, diagnosis, treatment, and long-term follow-up. Notably, a total of 56.6% of the institutions surveyed implemented programs for cancer screening and early diagnosis. A significant proportion of advanced cancer patients received treatment and follow-up at the county level. Persistent disparities in medical insurance policies at the county level were identified as a continuing challenge. Furthermore, 82.9% of hospitals had cultivated collaborative relationships with higher-level institutions to enhance patient care quality and treatment capacity. The study revealed a 56.6% shortage of remote collaboration platforms in these hospitals. The need for a patient-centered approach in county hospitals was underscored. Conclusion While county-level hospitals face challenges, such as a shortage of specialized oncologists and advanced resources, they exhibit progress in standardizing cancer care to enhance diagnosis and treatment in rural areas.

Abstract In this paper, we examined the elevation-dependent warming (EDW) patterns of MODIS LST across different seasons in the Qinling-Daba Mountains, further investigate the connections between the EDW patterns of Land surface temperature (LST) and land surface albedo (ALB) as well as aerosol optical depth (AOD). The key findings include: (1) Our study reveals a robust correlation between LST and air temperature in the Qinling-Daba Mountains, suggesting the feasibility of using MODIS LST to predict the temperature trends (2) During the period from 2001 to 2010, MODIS LST shows a significant EDW trend, primarily in the spring season. In contrast, a negative EDW is observed in the period during 2011–2021, which is contrary to the earlier decade, particularly during the autumn and winter seasons. (3) EDW of MODIS LST is affected by the combination of ALB and AOD. The former has a negative influence on the change of LST, particularly above 2500 m in elevation. However, the latter is negatively correlated with the trend of MODIS LST, primarily at lower and middle altitudes (0–2500 m). This study gives a comprehensive explanation for the EDW of the temporal variations of LST in the Qinling-Daba Mountains to improve our understanding of the complex interactions and potential future climate scenarios in the region.

Abstract Background Patients undergoing dialysis treatment have long been recognized as having an elevated risk of developing coronary artery disease necessitating coronary artery bypass grafting (CABG). However, the prognostic implications of CABG in dialysis-dependent patients remain underexplored. This study aimed to comprehensively assess both short- and long-term outcomes in dialysis-dependent patients undergoing CABG. Methods In this retrospective analysis, we meticulously matched 55 dialysis-dependent patients with 55 non-dialysis patients, controlling for baseline characteristics including age, sex, etiology, and date of surgery. All patients underwent CABG treatment at our institution between January 2014 and June 2022. We conducted a comparative analysis of postoperative complications and survival rates between the two groups. Results Our findings revealed that the dialysis-dependent group exhibited a significantly higher incidence of postoperative complications compared to the non-dialysis group (92.7% vs. 61.8%; p

The intestinal mucus barrier is an important line of defense against gut pathogens. Damage to this barrier brings bacteria into close contact with the epithelium, leading to intestinal inflammation. Therefore, its restoration is a promising strategy for alleviating intestinal inflammation. This study showed that Abelmoschus manihot polysaccharide (AMP) fortifies the intestinal mucus barrier by increasing mucus production, which plays a crucial role in the AMP-mediated amelioration of colitis. IL-10-deficient mouse models demonstrated that the effect of AMP on mucus production is dependent on IL-10. Moreover, bacterial depletion and replenishment confirmed that the effects of AMP on IL-10 secretion and mucus production were mediated by Akkermansia muciniphila. These findings suggest that plant polysaccharides fortify the intestinal mucus barrier by maintaining homeostasis in the gut microbiota. This demonstrates that targeting mucus barrier is a promising strategy for treating intestinal inflammation.

Abstract Yellow River Basin (YRB) is a pivotal region for energy consumption and carbon emissions (CEs) in China, with cities emerging as the main sources of regional CEs. This highlights their critical role in achieving regional sustainable development and China’s carbon neutrality. Consequently, there is a pressing need for a detailed exploration of the urban spillover effects and an in-depth analysis of the complex determinants influencing CEs within the YRB. Remote sensing data provide optimal conditions for conducting extensive studies across large geographical areas and extended time periods. This study integrates DMSP/OLS and NPP/VIIRS nighttime light datasets for a longitudinal analysis of urban CEs in the YRB. Using a harmonized dataset from DMSP/OLS and NPP/VIIRS nighttime light from 2007 to 2021, this study quantifies CEs of 58 prefecture-level cities in the YRB. By combining ESDA, STIRPAT model and spatial econometric model, this investigation further clarifies empirically the spatial spillover effects and driving factors of urban CEs. The analysis delineates a phase-wise augmentation in urban CEs, converging towards a distinct spatial distribution characterized by “lower reach > middle reach > upper reach”. The spatial autocorrelation tests unravel a complex interplay between agglomeration and differentiation patterns within urban CEs, underscored by pronounced spatial lock-in phenomena. Significantly, this study demonstrates that urbanization, economic development, energy consumption structure, green coverage rate, industrial structure, population, technological progress, and FDI each exhibit varied direct and indirect effect on urban CEs. Furthermore, it elaborates on potential policy implications and future research directions, offering crucial insights for formulating CEs mitigation strategies to advance sustainable development.

Abstract Background Numerous insect species undertake long-distance migrations on an enormous scale, with great implications for ecosystems. Given that take-off is the point where it all starts, whether and how the external light and internal circadian rhythm are involved in regulating the take-off behaviour remains largely unknown. Herein, we explore this issue in a migratory pest, Cnaphalocrocis medinalis, via behavioural observations and RNAi experiments. Results The results showed that C. medinalis moths took off under conditions where the light intensity gradually weakened to 0.1 lx during the afternoon or evening, and the take-off proportions under full spectrum or blue light were significantly higher than that under red and green light. The ultraviolet-A/blue light–sensitive type 1 cryptochrome gene (Cmedcry1) was significantly higher in take-off moths than that of non-take-off moths. In contrast, the expression of the light-insensitive CRY2 (Cmedcry2) and circadian genes (Cmedtim and Cmedper) showed no significant differences. After silencing Cmedcry1, the take-off proportion significantly decreased. Thus, Cmedcry1 is involved in the decrease in light intensity induced take-off behaviour in C. medinalis. Conclusions This study can help further explain the molecular mechanisms behind insect migration, especially light perception and signal transmission during take-off phases.

Abstract Our previous research found that fecal microbiota transplantation (FMT) and inulin synergistically affected the intestinal barrier and immune system function in chicks. However, does it promote the early immunity of the poultry gut-associated lymphoid tissue (GALT)? How does it regulate the immunity? We evaluated immune-related indicators in the serum, cecal tonsil, and intestine to determine whether FMT synergistic inulin had a stronger impact on gut health and which gene expression regulation was affected. The results showed that FMT synergistic inulin increased TGF-β secretion and intestinal goblet cell number and MUC2 expression on day 14. Expression of BAFFR, PAX5, CXCL12, and IL-2 on day 7 and expression of CXCR4 and IL-2 on day 14 in the cecal tonsils significantly increased. The transcriptome indicated that CD28 and CTLA4 were important regulatory factors in intestinal immunity. Correlation analysis showed that differential genes were related to the immunity and development of the gut and cecal tonsil. FMT synergistic inulin promoted the development of GALT, which improved the early-stage immunity of the intestine by regulating CD28 and CTLA4. This provided new measures for replacing antibiotic use and reducing the use of therapeutic drugs while laying a technical foundation for achieving anti-antibiotic production of poultry products.

Abstract Background As a recognized win–win-win approach to international debt relief, Debt-to-Health(D2H)has successfully translated debt repayments into investments in health-related projects. Although D2H has experienced modifications and periodic suspension, it has been playing an increasingly important role in resource mobilization in public health, particularly for low-and middle-income countries deep in debt. Main text D2H, as a practical health financing instrument, is not fully evidenced and gauged by academic literature though. We employed a five-step scoping review methodology. After posing questions, we conducted comprehensive literature searches across three databases and one official website to identify relevant studies.We also supplemented our research with expert interviews. Through this review and interviews, we were able to define the concept and structure of D2H, identify stakeholders, and assess its current shortcomings. Finally, we proposed relevant countermeasures and suggestions. Conclusion This paper examines the D2H project's implementation structure and influencing variables, as well as the current research plan's limitations, with a focus on the role health funding institutions have played during the project's whole life. Simultaneously, it examines the interdependencies between debtor nations, creditor nations, and health financing establishments, establishing the groundwork for augmenting and revamping D2H within the ever-changing worldwide context of health development assistance.

It is well known that common orthopedic implant titanium materials have a higher Young's modulus (100+GPa) than bone. Stress shielding leaves the neighboring bone unstressed for long periods of time and bone resorption occurs around the implant, which triggers implant failure. Here, we developed a novel Ti–Mo–Zr alloy with a customizable Young's modulus by using in situ alloying and laser additive manufacturing (AM) methods. Electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) were used to elucidate the distribution of submicron Mo particles in the materials, and selected laser melting (SLM) was used to customize the spatial concentration of Mo elements in novel alloys in a predictable way. By regulating the concentration and distribution of unmelted Mo particles, it is possible to tailor the grain growth angle and phases of the alloy. This results in excellent comprehensive mechanical properties for the alloys with a customizable Young's modulus ranging from 59.3 to 83.6 GPa, tensile strength from 564 to 1045 MPa, and a fracture strain of up to 13.1%. Orthopedic implants with a customizable Young's modulus can be adapted to bone tissues in different body parts, providing endless possibilities for personalized surgical solutions for patients. The economic potential for such materials in smart medical is enormous.

Abstract Background Fatty liver disease causes huge economic losses in the poultry industry due to its high occurrence and lethality rate. Three-dimensional (3D) chromatin architecture takes part in disease processing by regulating transcriptional reprogramming. The study is carried out to investigate the alterations of hepatic 3D genome and H3K27ac profiling in early fatty liver (FLS) and reveal their effect on hepatic transcriptional reprogramming in laying hens. Results Results show that FLS model is constructed with obvious phenotypes including hepatic visible lipid deposition as well as higher total triglyceride and cholesterol in serum. A/B compartment switching, topologically associating domain (TAD) and chromatin loop changes are identified by high-throughput/resolution chromosome conformation capture (HiC) technology. Targeted genes of these alternations in hepatic 3D genome organization significantly enrich pathways related to lipid metabolism and hepatic damage. H3K27ac differential peaks and differential expression genes (DEGs) identified through RNA-seq analysis are also enriched in these pathways. Notably, certain DEGs are found to correspond with changes in 3D chromatin structure and H3K27ac binding in their promoters. DNA motif analysis reveals that candidate transcription factors are implicated in regulating transcriptional reprogramming. Furthermore, disturbed folate metabolism is observed, as evidenced by lower folate levels and altered enzyme expression. Conclusion Our findings establish a link between transcriptional reprogramming changes and 3D chromatin structure variations during early FLS formation, which provides candidate transcription factors and folate as targets for FLS prevention or treatment.

AbstractIt has been reported that CDK8 plays a key role in acute myeloid leukaemia. Here, a total of 40 compounds were rational designed and synthesised based on the previous SAR. Among them, compound 12 (3-(3-(furan-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide) showed the most potent inhibiting activity against CDK8 with an IC50 value of 39.2 ± 6.3 nM and anti AML cell proliferation activity (molm-13 GC50 = 0.02 ± 0.01 μM, MV4-11 GC50 = 0.03 ± 0.01 μM). Mechanistic studies revealed that this compound 12 could inhibit the phosphorylation of STAT-1 and STAT-5. Importantly, compound 12 showed relative good bioavailability (F = 38.80%) and low toxicity in vivo. This study has great significance for the discovery of more efficient CDK8 inhibitors and the development of drugs for treating AML in the future.

Background The occurrence of chronic inflammation resulting from infection with human papillomaviruses is an important factor in the development of cervical cancer (CC); thus, deciphering the crosstalk between the tumor microenvironment and innate immune cells during the establishment of immune tolerance is vital for identifying potential treatment strategies.Methods Single-cell RNA sequencing data and primary tumor samples from patients with CC were used to evaluate the functional role of Siglec-10 on dendritic cells (DCs). Patient-derived tumor fragment platforms were used to examine the ability of Siglec-10 blockade to reinvigorate DC-mediate T-cell activation and tumor clearance.Results Here, we demonstrated that Siglec-10 is a prominent inhibitory checkpoint for DCs infiltrated in CC. CC epithelial cells use their aberrant surface sialylated structures to induce the transformation of conventional DCs into phenotypes characterized by low immunogenicity and high immunotolerance. Additionally, Siglec-10+ DCs suppress the function of adaptive T cells via galectin-9 signaling to strengthen the immunosuppressive CC microenvironment. Disturbance of Siglec-10 signaling restored the DC-mediated tumoricidal response and increased adaptive T cells sensitivity to programmed cell death protein 1 inhibition.Conclusion Our study confirms the checkpoint role of Siglec-10 on DCs and proposes that targeting Siglec-10 may be a promising avenue for immunotherapy against CC.

Ischemic heart disease (IHD) can trigger responses from the innate immune system, provoke aseptic inflammatory processes, and result in the recruitment and accumulation of neutrophils. Excessive recruitment of neutrophils is a potential driver of persistent cardiac inflammation. Once recruited, neutrophils are capable of secreting a plethora of inflammatory and chemotactic agents that intensify the inflammatory cascade. Additionally, neutrophils may obstruct microvasculature within the inflamed region, further augmenting myocardial injury in the context of IHD. Immune-related molecules mediate the recruitment process of neutrophils, such as immune receptors and ligands, immune active molecules, and immunocytes. Non-immune-related molecular pathways represented by pro-resolving lipid mediators are also involved in the regulation of NR. Finally, we discuss novel regulating strategies, including targeted intervention, agents, and phytochemical strategies. This review describes in as much detail as possible the upstream molecular mechanism and external intervention strategies for regulating NR, which represents a promising therapeutic avenue for IHD.

Abstract Injectable biomaterials have garnered increasing attention for their potential and beneficial applications in minimally invasive surgical procedures and tissue regeneration. Extracellular matrix (ECM) hydrogels and porous synthetic polymer microspheres can be prepared for injectable administration to achieve in situ tissue regeneration. However, the rapid degradation of ECM hydrogels and the poor injectability and biological inertness of most polymeric microspheres limit their pro-regenerative capabilities. Here, we develop a biomaterial system consisting of elastic porous poly(l-lactide-co-ε-caprolactone) (PLCL) microspheres mixed with ECM hydrogels as injectable composites with interleukin-4 (IL-4) and insulin-like growth factor-1 (IGF-1) dual-release functionality. The developed multifunctional composites have favorable injectability and biocompatibility, and regulate the behavior of macrophages and myogenic cells following injection into muscle tissue. The elicited promotive effects on tissue regeneration are evidenced by enhanced neomusle formation, vascularization, and neuralization at 2-months post-implantation in a male rat model of volumetric muscle loss. Our developed system provides a promising strategy for engineering bioactive injectable composites that demonstrates desirable properties for clinical use and holds translational potential for application as a minimally invasive and pro-regenerative implant material in multiple types of surgical procedures.

As one of the important energy industries, the safe production of coal mines not only concerns the safety of employees, but also affects the sustainable development of society. Recent rescue cases have shown that the layout of material bases and the allocation of emergency materials need to be further optimized. For this problem, this paper adopts the material hierarchical reserve mode for the first time, combining the material hierarchical reserve mode, multi-level material bases selection model, and the Fuzzy Analytic Hierarchy Process (FAHP) method to determine the optimal location of the coal mine material bases in Liaoning Province. Determine the reserve level of emergency materials through evaluation and clustering analysis of various emergency materials. Improve the traditional gravity model and construct a multi-objective planning model for multi-level material bases site selection. Apply the reserve level of emergency materials and real regional data to the site selection model, and use the Non-dominated Sorting Genetic Algorithm III (NSGA-III) to solve the model. Then, the optimal site selection scheme was selected using FAHP, and sensitivity analysis was conducted. The research results indicate that: 1) 9 county-level, 6 city-level and 2 provincial-level material bases will be constructed; 2) location selection of material bases is not only affected by costs, but also by the density of road networks; 3) use of hierarchical material reserve mode can significantly reduce the construction cost of material bases. Compared to the traditional material reserve mode, it can reduce costs by 86.6%. Compared to a single-level material bases, it can still reduce costs by 74.7%. The research results of this paper can be used for the selection of emergency material bases and the allocation of emergency material reserves, which can reduce costs and promote the improvement of regional emergency rescue capabilities.

Chronic obstructive pulmonary disease (COPD) kills more than 3 million people worldwide every year. Despite progress in the treatment of symptoms and prevention of acute exacerbations, few advances have been made to ameliorate disease progression or affect mortality. Exercise plays a positive role in the prevention and treatment of diaphragm dysfunction in COPD, and the changes in diaphragm structure and function induced by exercise are closely related to the regulation of oxidative stress. But the mechanism remains unclear. So the aim of this study was to reveal the therapeutic mechanism of exercise to COPD using both in vivo and in vitro experiments. In this study, cigarette smoke (CS) induced COPD mice model, treadmill aerobic training for COPD mice were constructed and cigarette smoke extract (CSE) induced bronchial epithelial cells (BECs) model were used for COPD study. Bioinformatics analysis, luciferase reporting analysis, and RT-qPCR detection were used to clarify the interacted relationship among lncRNA, miRNA, and mRNA. ROS, inflammatory cytokines expression, and EMT relative protein α-SMA were detected using immunofluorescence and ELISA detection. The result shows that exercise ameliorates COPD induced lung injury by inhibit ROS, inflammation, and epithelial-mesenchymal transition (EMT) relative protein α-SMA expression. RT-qPCR detection shows that lnc-H19 expression was increased in lung tissues of COPD mice. Exercise decreased COPD induced lnc-H19 expression. Downregulation lnc-H19 inhibits COPD mediated lung injury. Bioinformatics analysis and luciferase reporting analysis confirmed that miR-181 and PDCD4 were downstream targets of lnc-H19. Upregulation of PDCD4 or downregulation of miR-181 reversed the protective effect of si-lnc-H19 to BECs after exposure to CSE. In conclusion, lncRNA H19 contributes to smoke-related chronic obstructive pulmonary disease by targeting miR-181/PDCD4 Axis.

AbstractContext Ginsenoside metabolite compound K (CK) is an active metabolite produced by ginsenosides in vivo that has an anti-arthritic effect related to the glucocorticoid receptor (GR). However, the potential mechanisms of CK remain unclear.Objective This study explores the role and potential mechanisms of CK in vivo and in vitro.Materials and methods Adjuvant arthritis (AA) model was induced in Sprague-Dawley (SD) rats; the rats were randomly divided into four groups (n = 10): normal, AA, CK (80 mg/kg), and dexamethasone (Dex) group (1 mg/kg). From day 15, rats were treated with CK (once a day, i.g.) and Dex (once every 3 days, i.p.) for 18 days. To further verify the mechanism of CK, fibroblast-like synoviocytes (FLS) were stimulated by tumour necrosis factor α (TNF-α) to establish an inflammatory model in vitro.Results CK (80 mg/kg) reduced paw swelling (52%) and arthritis global assessment (31%) compared to that in AA rats. In addition, CK (80 mg/kg) suppressed GLUT1 (38%), HK2 (50%), and PKM2 (56%) levels compared with those in AA FLS. However, the effects of CK (30 μM) on these events were weakened or enhanced after GR knockdown or overexpression in FLS stimulated by TNF-α (30 ng/mL). CK (80 mg/kg) also downregulated the expression of P65 (61%), p-IκB (92%), and HIF-1α (59%).Discussion and conclusions The inhibition of CK on glycolysis and the NF-κB/HIF-1α pathway is potentially mediated through activating GR. These findings provide experimental evidence for elucidating the molecular mechanism of CK in treating rheumatoid arthritis (RA).

Diacetyl is a flavor compound in wine with a low threshold (1–2 mg/L). It is produced during alcoholic fermentation (AF) Saccharomyces and malolactic fermentation (MLF) initiated by lactic acid bacteria (LAB). Whereas, the environment after AF suppresses the normal metabolism of LAB after AF. Researchs have shown the influence on diacetyl mechanisms of the genes ILV2, ILV6, ILV3, ILV5, BDH1, BDH2, and gene aldB from Lactobacillus plantarum in Saccharomyce uvarum WY1. While we found that the diacetyl contents produced by mutants after MLF (Co-fermentation and Seq-fermentation) were significantly improved compared to AF alone. Moreover, the genes mae1 and mae2 from S. pombe, and gene mleS from L. lactis exhibited significant effect on deacidification in our previous study, but the diacetyl of the mutants showed obvious improvement in this study. Thus the effects of association mutation of genes (ILV2, ILV6, ILV3, ILV5, BDH1, BDH2, aldB, mae1, and mleS) on deacidification, diacetyl and other flavors (organic acids, higher alcohols and esters) metabolism in S. uvarum after AF were detected in the study. Among all the mutants, strains V6AmS, V635mS, and V6B12mS showed the most favorable results. Specifically, the L-malic acid contents decreased to 1.26 g/L, 1.18 g/L, and 1.19 g/L, respectively. Concurrently, diacetyl levels were reduced by 52.56%, 61.84%, and 65.31%. The production of n-propanol increased by 18.84%, 20.89%, and 28.12%, whereas isobutanol levels decreased by 37.01%, 42.36%, and 44.04%, and isoamyl alcohol levels decreased by 19.28%, 19.79%, and 16.74%, compared to the parental strain WY1. Additionally, the concentration of lactate ester in the wine increased to 13.162 mg/L, 14.729 mg/L, and 14.236 mg/L, respectively.

Current shale gas well production capacity predictions primarily rely on analytical and numerical simulation methods, which necessitate extensive calculations and manual parameter tuning and produce lowly accurate predictions. Although employing neural networks yields highly accurate predictions, they can easily fall into local optima. This paper suggests a new way to use Cuckoo Search (CS)-optimized neural networks to make shale gas well production capacity predictions more accurate and to solve the problem of local optima. It aims to assist engineers in devising more effective development plans and production strategies, optimizing resource allocation, and reducing risk. The method first analyzes the factors influencing the production capacity of shale gas wells in a block located in western China through correlation coefficients. It identifies the main factors affecting the gas test absolute open flow as organic carbon content, small-layer passage rate, fracture pressure, acid volume, pump-in fluid volume, brittle mineral content in the rock, and rock density. Subsequently, we used the CS algorithm to conduct the global training of the neural network, avoiding the problem of local optima, and established a neural network model for predicting shale gas well production capacity optimized by the CS algorithm. A comparative analysis with other relevant methods demonstrates that the CS-optimized neural network model can accurately predict production capacity, enabling a more rational and effective exploitation of shale gas resources, which lower development costs and increase the economic returns of oil and gas fields. Compared to numerical simulation, SVM, and BP neural network algorithms, the CS-optimized BP neural network (CS-BP) exhibits significantly lower prediction error. Its correlation coefficient between predicted and actual values reaches as high as 0.9924. Verification experiments conducted on another shale gas well also demonstrate that, in comparison to the BP neural network algorithm, CS-BP offers superior prediction performance, with model validation showing a prediction error of only 0.05. This study can facilitate more rational and efficient exploitation of shale gas resources, reduce development costs, and enhance the economic benefits of oil and gas fields.

Background and objective: Spatial interaction between tumor-infiltrating lymphocytes (TILs) and tumor cells is valuable in predicting the effectiveness of immune response and prognosis amongst patients with lung adenocarcinoma (LUAD). Recent evidence suggests that the spatial distance between tumor cells and lymphocytes also influences the immune responses, but the distance analysis based on Hematoxylin and Eosin (H&E) -stained whole-slide images (WSIs) remains insufficient. To address this issue, we aim to explore the relationship between distance and prognosis prediction of patients with LUAD in this study. Methods: We recruited patients with resectable LUAD from three independent cohorts in this multi-center study. We proposed a simple but effective deep learning-driven workflow to automatically segment different cell types in the tumor region using the HoVer-Net model, and quantified the spatial distance (DIST) between tumor cells and lymphocytes based on H&E-stained WSIs. The association of DIST with disease-free survival (DFS) was explored in the discovery set (D1, n = 276) and the two validation sets (V1, n = 139; V2, n = 115). Results: In multivariable analysis, the low DIST group was associated with significantly better DFS in the discovery set (D1, HR, 0.61; 95 % CI, 0.40–0.94; p = 0.027) and the two validation sets (V1, HR, 0.54; 95 % CI, 0.32–0.91; p = 0.022; V2, HR, 0.44; 95 % CI, 0.24–0.81; p = 0.009). By integrating the DIST with clinicopathological factors, the integrated model (full model) had better discrimination for DFS in the discovery set (C-index, D1, 0.745 vs. 0.723) and the two validation sets (V1, 0.621 vs. 0.596; V2, 0.671 vs. 0.650). Furthermore, the computerized DIST was associated with immune phenotypes such as immune-desert and inflamed phenotypes. Conclusions: The integration of DIST with clinicopathological factors could improve the stratification performance of patients with resectable LUAD, was beneficial for the prognosis prediction of LUAD patients, and was also expected to assist physicians in individualized treatment.

ABSTRACT: Excess abdominal fat reduces carcass yield and feed conversion ratio, thereby resulting in significant economic losses in the poultry industry. Our previous study demonstrated that dietary addition of folic acid reduced fat deposition and changed gut microbiota and short-chain fatty acid. However, whether folic acid regulating abdominal fat deposition was mediated by gut microbiota was unclear. A total of 210 one-day-old broiler chickens were divided into 3 groups including the control (CON), folic acid (FA), and fecal microbiota transplantation (FMT) groups. From 14th day, broiler chickens in CON and FA groups were given perfusion administration with 1 mL diluent daily, while 1 mL fecal microbiota transplantation suspension from FA group prepared before was perfusion in FMT group receiving control diets. The result showed that abdominal fat percentage was significantly lower in FA and FMT groups when compared with CON group (P < 0.05). Morphology analysis revealed that the villus height of jejunum and ileum were significantly higher in FMT group (P < 0.05), and the villus height of jejunum was also significantly higher in FA group (P < 0.05), while the diameter and cross-sectional area (CSA) of adipocytes were significantly decreased in FA and FMT groups when compared with CON group (P < 0.05). Western blot results indicated that the expression levels of FOXO1 and PLIN1 in FMT group were significantly increased (P < 0.05), whereas the expression levels of PPARγ, C/EBPα, and FABP4 were significantly decreased (P < 0.05). Additionally, the Chao1, Observed-species, Shannon and Simpson indexes in FA and FMT groups were significantly higher (P < 0.05), but the microbiota were similar between FMT and FA groups (P < 0.05). LEfSe analysis determined that Lactobacillus, Clostridium and Dehalobacterium were found to be predominant in FA group, while Oscillospira, Shigella, and Streptococcus were the dominant microflora in FMT group. Furthermore, these cecal microbiota were mostly involved in infectious disease, cellular community prokaryotes, cell motility and signal transduction in FA group (P < 0.05), whereas functional capacities involved in signal transduction, cell motility, infectious disease and environment adaptation were enriched significantly of cecal microbiota in FMT group (P < 0.05). In summary, both fecal microbiota transplantation from the broiler chickens of dietary added folic acid and dietary folic acid addition effectively reduced abdominal fat deposition, indicating that the regulatory effect of folic acid on abdominal fat deposition was mediated partly by gut microbiota in broiler chickens.

Abstract Background Adolescent depression has grown to be a major social concern in China. During the coronavirus pandemic, the incidence of depression among Chinese adolescents increased substantially. More research is required to inform the prevention and intervention of adolescent depression in China. Depression is associated with Early Maladaptive Schemas (EMSs). Childhood abuse and neglect are distal antecedents of adolescent depression. It is not known how depression and EMSs interact in adolescence and how childhood abuse and neglect contribute to this relationship. This study aimed to examine the reciprocal relationships between depression and EMSs, as well as the long-term effects of childhood abuse and neglect on depression and EMSs during adolescence. The work also investigates gender differences in these mechanisms. Methods Using a two-wave longitudinal design, we recruited 3,485 Chinese adolescents (M age = 13.2; 43.2% females) from three Shanxi Province, China middle schools. All participants completed self-report questionnaires addressing childhood abuse and neglect, depression, and EMSs. Structural equation models examined reciprocal relationships between depression and EMS, as well as the effect of childhood abuse and neglect on depression and EMSs. Multi-group analysis addressed gender differences. Results Results indicated that greater depression predicted more EMSs measured later, but EMSs did not predict subsequent depression. Childhood abuse and neglect had different effects on depression and EMSs during adolescence. Specifically, exposure to childhood abuse related to more severe depression and EMSs in adolescence and contributed to the perpetuation of EMSs by increasing depression. Exposure to childhood neglect showed a direct effect on depression and indirectly reinforced subsequent EMSs through depression. There were no gender differences. Conclusion These findings contribute to a better understanding of the emergence and course of depression in early adolescence, suggesting that childhood abuse and neglect are critical early risk factors. Additionally, depression plays a key role in promoting schema perpetuation among adolescents exposed to childhood maltreatment, providing important implications for relevant prevention and intervention in early adolescence.

Laminated metal composites (LMCs) of titanium and aluminum (Ti/Al), combining the high strength and thermal stability of titanium with the low density and corrosion resistance of aluminum, hold substantial promise for industrial applications. Utilizing diffusion bonding under optimal processing conditions—specifically a bonding temperature of 550 °C and a holding time of 120 min—an average interfacial shear strength of 68.7 MPa was achieved. Transmission electron microscopy (TEM) revealed a metallurgically bonded interface facilitated by the mutual atomic diffusion of titanium and aluminum; this diffusion layer predominantly comprises the TiAl3 phase. Detailed insights into the microstructural evolution at the interface, including dislocation configurations, were also obtained in this study. The Burgers vectors of these dislocations were determined using the two-beam electron diffraction contrast imaging method. Based on these results, it can be elucidated that the deformation mechanism of Ti layer was dominated by the dislocation slip (mainly prismatic and the basal slip), while the coordinated deformation of TiAl3/Al interface benefitted by the dislocations gliding across the interface.

Abstract Background Cervical cancer (CC) is the fourth most common cancer in women worldwide. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation of the mechanism of CC immune remodeling and exploration of novel treatment targets. This study aimed to investigate the mechanism of CC immune remodeling and explore potential therapeutic targets. Methods We conducted single‐cell RNA sequencing on a total of 17 clinical specimens, including normal cervical tissues, high‐grade squamous intraepithelial lesions, and CC tissues. To validate our findings, we conducted multicolor immunohistochemical staining of CC tissues and constructed a subcutaneous tumorigenesis model in C57BL/6 mice using murine CC cell lines (TC1) to evaluate the effectiveness of combination therapy involving indoleamine 2,3‐dioxygenase 1 (IDO1) inhibition and immune checkpoint blockade (ICB). We used the unpaired two‐tailed Student's t‐test, Mann‐Whitney test, or Kruskal‐Wallis test to compare continuous data between two groups and one‐way ANOVA with Tukey's post hoc test to compare data between multiple groups. Results Malignant cervical epithelial cells did not manifest noticeable signs of tumor escape, whereas lysosomal‐associated membrane protein 3‐positive (LAMP3+) dendritic cells (DCs) in a mature state with immunoregulatory roles were found to express IDO1 and affect tryptophan metabolism. These cells interacted with both tumor‐reactive exhausted CD8+ T cells and CD4+ regulatory T cells, synergistically forming a vicious immunosuppressive cycle and mediating CC immune escape. Further validation through multicolor immunohistochemical staining showed co‐localization of neoantigen‐reactive T cells (CD3+, CD4+/CD8+, and PD‐1+) and LAMP3+ DCs (CD80+ and PD‐L1+). Additionally, a combination of the IDO1 inhibitor with an ICB agent significantly reduced tumor volume in the mouse model of CC compared with an ICB agent alone. Conclusions Our study suggested that a combination treatment consisting of targeting IDO1 and ICB agent could improve the therapeutic efficacy of current CC immunotherapies. Additionally, our results provided crucial insights for designing drugs and conducting future clinical trials for CC.

During malolactic fermentation (MLF) of vinification, the harsh L–malic acid undergoes transformation into the milder L–lactic acid, and via decarboxylation reactions it is catalyzed by malolactic enzymes in LAB. The use of bacterial malolactic starter cultures, which usually present challenges in the industry as the suboptimal conditions after alcoholic fermentation (AF), including nutrient limitations, low temperatures, acidic pH levels, elevated alcohol, and sulfur dioxide concentrations after AF, lead to “stuck” or “sluggish” MLF and spoilage of wines. Saccharomyces uvarum has interesting oenological properties and provides a stronger aromatic intensity than Saccharomyces cerevisiae in AF. In the study, the biological pathways of deacidification were constructed in S. uvarum, which made the S. uvarum carry out the AF and MLF simultaneously, as different genes encoding malolactic enzyme (mleS or mleA), malic enzyme (MAE2), and malate permease (melP or MAE1) from Schizosaccharomyces pombe, Lactococcus lactis, Oenococcus oeni, and Lactobacillus plantarum were heterologously expressed. For further inquiry, the effect of L–malic acid metabolism on the flavor balance in wine, the related flavor substances, higher alcohols, and esters production, were detected. Of all the recombinants, the strains WYm1SN with coexpression of malate permease gene MAE1 from S. pombe and malolactic enzyme gene mleS from L. lactis and WYm1m2 with coexpression of gene MAE1 and malate permease gene MAE2 from S. pombe could reduce the L–malic acid contents to about 1 g/L, and in which the mutant WYm1SN exhibited the best effect on the flavor quality improvement.

To make comprehensive use of maize stover, cellulase degradation of maize stover was accelerated. In this paper, maize straw was used as raw material, and reducing sugar yield was the main indicator. The reducing sugar yield was determined by the DNS method after enzymatic digestion of maize straw by ammonification pretreatment, and the effects of ammonification agent type, concentration, solid content and ammonification time on the enzymatic sugar production from maize straw were investigated. The results showed that the highest reducing sugar yield of 314.18 mg/mL was achieved under this condition with ammonium carbonate as the ammoniating agent, ammoniating agent concentration of 20%, solid content of 50% and ammoniating time of 11 d, which was 51.80% higher compared to direct enzymatic digestion of the straw. In addition, it was found by SEM that the structure of lignin and cellulose changed after the ammoniated pretreatment of rice straw with ammonium carbonate, with the surface structure becoming rough and loose and the cellulose exposed, which was more favorable to the action of cellulase. In addition, FTIR revealed that the absorption peaks of maize straw at 2920 and 1650 cm−1 were weakened after ammoniation treatment, and the reduction of their peaks represented to some extent the destruction of the lignin structure. Overall, the enzymatic digestion of maize stover was more favorable after the ammoniated pretreatment of maize stover with ammonium carbonate.

Noni fruits have gained considerable popularity as dietary supplements. However, the major constituents, the laxative activity, and the toxicity of Noni fruit remains still unknown. The purpose of the present study was, therefore, to analyze the constituents of methanol extract of Noni fruit by UPLC-MS, and further evaluate laxative activity and safety aspects of this Noni fruit-derived products in mice. UPLC-MS analysis identified eleven major constituents from this Noni fruit extract. Administration of this extract obviously shortened the time of first fecal excrement, significantly increased the total number and the weight of stools, and remarkably restored the intestinal transit to normal level in the constipated mice, with low toxicity to liver and kidney, and meanwhile, the abundance, composition, and function of gut microbiota remained homeostasis. These results revealed the laxative activity of the methanol extract of Noni fruit with low toxicity and no influence on gut microbiota.

Highlights AhR regulates remyelination following cuprizone-induced demyelination. Deletion of AhR in adult microglia restrains efficient remyelination. Microglial AhR deficiency causes myelin debris accumulation and impairs phagocytic function. Microglial AhR mediates phagocytosis of microglia via SYK.

The inertness of synthetic polymer materials and the insufficient mechanical strength of reprocessed decellularized extracellular matrix (dECM) limited their promotive efforts on tissue regeneration. Here, we prepared a hybrid scaffold composed of PCL microfibers and human placental extracellular matrix (pECM) nanofibers by co-electrospinning, which was grafted with heparin and further absorbed with IL-4. The hybrid scaffold with improved hemocompatibility firstly switched macrophages to anti-inflammatory phenotype (increased by 18.1%) and then promoted migration, NO production, tube formation of endothelial cells (ECs), and migration and maturation of vascular smooth muscle cells (VSMCs), and ECM deposition in vitro and in vivo. ECs coverage rate increased by 8.6% and the thickness of the smooth muscle layer was 1.8 times more than PCL grafts at 12 wks. Our study realized the complementary advantages of synthetic polymer materials and dECM materials, and opened intriguing perspectives for the design and construction of small-diameter vascular grafts (SDVGs) and immune-regulated materials for other tissue regeneration.

Plague is an endemic infectious disease caused by Yersinia pestis. In this study, we isolated fourteen phages with similar sequence arrangements to phage 186; these phages exhibited different lytic abilities in Enterobacteriaceae strains. To illustrate the phylogenetic relationships and evolutionary relationships between previously designated 186-type phages, we analysed the complete sequences and important genes of the phages, including whole-genome average nucleotide identity (ANI) and collinearity comparison, evolutionary analysis of four conserved structural genes (V, T, R, and Q genes), and analysis of the regulatory genes (cI, apl, and cII) and integrase gene (int). Phylogenetic analysis revealed that thirteen of the newly isolated phages belong to the genus Eganvirus and one belongs to the genus Felsduovirus in the family Peduoviridae, and these Eganvirus phages can be roughly clustered into three subgroups. The topological relationships exhibited by the whole-genome and structural genes seemed similar and stable, while the regulatory genes presented different topological relationships with the structural genes, and these results indicated that there was some homologous recombination in the regulatory genes. These newly isolated 186-type phages were mostly isolated from dogs, suggesting that the resistance of Canidae to Y. pestis infection may be related to the wide distribution of phages with lytic capability.

Obesity stands as a significant risk factor for type 2 diabetes, hyperlipidemia, and cardiovascular diseases, intertwining increased inflammation and decreased adipogenesis with metabolic disorders. Studies have highlighted the correlation between Caspase-1 and inflammation in obesity, elucidating its essential role in the biological functions of adipose tissue. However, the impact of Caspase-1 on adipogenesis and the underlying mechanisms remain largely elusive. In our study, we observed a positive correlation between Caspase-1 expression and obesity and its association with adipogenesis. In vivo experiments revealed that, under normal diet conditions, Caspase-1 deficiency improved glucose homeostasis, stimulated subcutaneous adipose tissue expansion, and enhanced adipogenesis. Furthermore, our findings indicate that Caspase-1 deficiency promotes the expression of autophagy-related proteins and inhibits autophagy with 3-MA or CQ blocked Caspase-1 deficiency-induced adipogenesis in vitro. Notably, Caspase-1 deficiency promotes adipogenesis via Atg7-mediated autophagy activation. In addition, Caspase-1 deficiency resisted against high-fat diet-induced obesity and glucose intolerance. Our study proposes the downregulation of Caspase-1 as a promising strategy for mitigating obesity and its associated metabolic disorders.

For the development of an idyllic rural landscape, an accurate survey of rural buildings is essential. The extraction of rural structures from unmanned aerial vehicle (UAV) remote sensing imagery is prone to errors such as misclassifications, omissions, and subpar edge detailing. This study introduces a multi-scale fusion and detail enhancement network for rural building extraction, termed the Multi-Attention-Detail U-shaped Network (MAD-UNet). Initially, an atrous convolutional pyramid pooling module is integrated between the encoder and decoder to enhance the main network’s ability to identify buildings of varying sizes, thereby reducing omissions. Additionally, a Multi-scale Feature Fusion Module (MFFM) is constructed within the decoder, utilizing superficial detail features to refine the layered detail information, which improves the extraction of small-sized structures and their edges. A coordination attention mechanism and deep supervision modules are simultaneously incorporated to minimize misclassifications. MAD-UNet has been tested on a private UAV building dataset and the publicly available Wuhan University (WHU) Building Dataset and benchmarked against models such as U-Net, PSPNet, DeepLabV3+, HRNet, ISANet, and AGSCNet, achieving Intersection over Union (IoU) scores of 77.43% and 91.02%, respectively. The results demonstrate its effectiveness in extracting rural buildings from UAV remote sensing images across different regions.

Forecasting air quality plays a crucial role in preventing and controlling air pollution. It is particularly significant for improving preparedness for heavily polluted weather conditions and ensuring the health and safety of the population. In this study, a novel deep learning model for predicting air quality spatio-temporal variations is introduced. The model, named graph long short-term memory with multi-head attention (GLSTMMA), is designed to capture the temporal patterns and spatial relationships within multivariate time series data related to air quality. The GLSTMMA model utilizes a hybrid neural network architecture to effectively learn the complex dependencies and correlations present in the data. The extraction of spatial features related to air quality involves the utilization of a graph convolutional network (GCN) to collect air quality data based on the geographical distribution of monitoring sites. The resulting graph structure is imported into a long short-term memory (LSTM) network to establish a Graph LSTM unit, facilitating the extraction of temporal dependencies in air quality. Leveraging a Graph LSTM unit, an encoder-multiple-attention decoder framework is formulated to enable a more profound and efficient exploration of spatio-temporal correlation features within air quality time series data. The research utilizes the 2019–2021 multi-source air quality dataset of Qinghai Province for experimental assessment. The results indicate that the model effectively leverages the impact of multi-source data, resulting in optimal accuracy in predicting six air pollutants.

Abstract Background Cockayne syndrome (CS, OMIM #133540, #216400) is a rare autosomal recessive disease involving multiple systems, typically characterized by microcephaly, premature aging, growth retardation, neurosensory abnormalities, and photosensitivity. The age of onset is related to the severity of the clinical phenotype, which may lead to fatal outcomes. Methods We report a 3‐year‐old girl who presented with photosensitivity, gait abnormalities, stunting, and microcephaly and showed atypical clinical classification due to mild clinical manifestations at an early onset age. Results Next‐generation sequencing reveals the frameshift mutation (c.394_398del, p.Leu132Asnfs*6) and a novel microdeletion of ERCC8 (exon4del, p.Arg92fs). Conclusion Therefore, it is still necessary to carry out next‐generation sequencing for CS patients with atypical clinical manifestations, which is essential for diagnosis and accurate genetic counseling.

Summary: Background: Glypican-3 (GPC3) is a well-characterized hepatocellular carcinoma (HCC)-associated antigen and a promising target for HCC treatment. CT017 CAR T cells were engineered to co-express CAR-GPC3 and runt-related transcription factor 3 (RUNX3), which triggers CD8+ T-cell infiltration into the cancer microenvironment. Methods: This single-center, single-arm, open-label, phase I clinical study enrolled heavily pretreated patients with GPC3-positive HCC between August 2019 and December 2020 (NCT03980288). Patients were treated with CT017 CAR T cells at a dose of 250 × 106 cells. The primary objective was to assess the safety and tolerability of this first-in-human product. Findings: Six patients received 7 infusions (one patient received 2 infusions) at the 250 × 106 cells dose. Three patients received CT017 monotherapy, and three patients received CT017-tyrosine kinase inhibitor (TKI) combination therapy at the first infusion. One patient received CT017-TKI combination therapy at the second infusion after CT017 monotherapy. All patients experienced cytokine release syndrome (CRS), with 50% (3/6) at Grade 2, 50% (3/6) at Grade 3, and all events resolved after treatment. No immune effector cell-associated neurotoxicity syndrome was observed. Dose escalation was not performed due to the investigator’s decision regarding safety. Of six evaluable patients, one achieved partial response and two had stable disease for a 16.7% objective response rate, 50% disease control rate, 3.5-month median progression-free survival, 3.2-month median duration of disease control, and 7.9-month median overall survival (OS) with 7.87-month median follow-up. The longest OS was 18.2 months after CT017 infusion. Interpretation: Current preliminary phase I data showed a manageable safety profile and promising antitumor activities of CT017 for patients with advanced HCC. These results need to be confirmed in a robust clinical trial. Funding: This study was funded by CARsgen Therapeutics Co., Ltd.

Summary: The increased amount of tertiary lymphoid structures (TLSs) is associated with a favorable prognosis in patients with lung adenocarcinoma (LUAD). However, evaluating TLSs manually is an experience-dependent and time-consuming process, which limits its clinical application. In this multi-center study, we developed an automated computational workflow for quantifying the TLS density in the tumor region of routine hematoxylin and eosin (H&E)-stained whole-slide images (WSIs). The association between the computerized TLS density and disease-free survival (DFS) was further explored in 802 patients with resectable LUAD of three cohorts. Additionally, a Cox proportional hazard regression model, incorporating clinicopathological variables and the TLS density, was established to assess its prognostic ability. The computerized TLS density was an independent prognostic biomarker in patients with resectable LUAD. The integration of the TLS density with clinicopathological variables could support individualized clinical decision-making by improving prognostic stratification.

ABSTRACT: Excess abdominal fat is a common phenomenon in broiler chickens. Gut microbiota could regulate lipid metabolism through their effects on short-chain fatty acids (SCFAs) production. This study was conducted to investigate the potential relationship between abdominal fat development and cecal microorganism populations. Abdominal fat and cecum contents were collected at 3, 7, 14, 21, 28, 35, and 42 d of age. The results showed that abdominal fat weight increased with age. The abdominal fat percentage was higher between 7 and 21 d of age than at 3 d (P < 0.05), and it increased again at 28 to 42 d (P < 0.05). Morphological analysis showed that adipocyte diameter and cross-sectional area (CSA) increased significantly after 14 d of age (P < 0.05). Moreover, gut microbiota analysis indicated that the Chao1 and Shannon indices were higher between 14 and 28 d than at 3 d of age (P < 0.05). Furthermore, LEfse analysis revealed that Faecalibacterium, Anaerotruncus, Anaeroplasma, Subdoligranulum, and Clostridium emerged to become dominant at 14 d. A greater abundance of Bacteroides, Ruminococcus, Dehalobacterium, and Lactobacillus were determined at 28 d when compared with 14 d of age. Parabacteroides, Ochrobactrum, Lactobacillus, Blautia, Alistipes, Dehalobacterium, Odoribacter, and Suuterella were found to be predominant at 42 d. PICRUSt analysis revealed that amino acid metabolism, lipid metabolism, and terpenoids and polyketides metabolism were elevated at 14 d; the immune and digestive systems were significantly developed at 28 d. In addition, cecum propionic acid and butyric acid contents gradually increased (P < 0.05), while the isobutyric acid contents gradually decreased with advancing age (P < 0.05). Correlation analysis among SCFAs, differential genera and abdominal fat suggested that Coprobacillus, Shigella, and Butyricicoccus had negative correlations with propionic acid, butyric acid, and abdominal fat weight, but positive correlations with isobutyric acid. Isobutyric acid was identified as being negatively associated with abdominal fat weight, while the reverse was found for propionic acid and butyric acid. In conclusion, abdominal fat development is correlated with the emergence of specific microbes and d 14 may be a pivotal age for establishing this relationship.

Abstract Palmitoylation of proteins plays important roles in various physiological processes, such as cell proliferation, inflammation, cell differentiation etc. However, inhibition of protein palmitoylation has led to few new drugs to date. ZDHHC5 serves as a key enzyme to catalyze palmitoylation on SSTR5 (a proven anti-proliferation receptor in pancreatic cells). Herein, we compare single-cell transcriptome data between pancreatic cancer tissues and normal pancreas tissues and identify that ZDHHC5 is a potential target to inhibit proliferation of pancreatic cancer cells. In addition, we report the repositioning of an orphan drug (Lomitapide) as an inhibitor of ZDHHC5, and we speculate that this inhibitor may be able to block palmitylation on SSTR5. Pharmacological blockade of ZDHHC5 with Lomitapide results in attenuated cancer cell growth and proliferation which collectively contributes to antitumor responses in vitro and in vivo. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of ZDHHC5 in pancreatic cancer, representing a new class of palmitoylation targeted therapy and laying a framework for paradigm-shifting therapies targeting cancer cell palmitoylation.

Abstract Spray-induced gene silencing (SIGS) can inhibit plant diseases by topical application of double- (dsRNA) or single-stranded (sRNA) RNA molecules onto plants to silence virulence-related pathogen genes. However, the on-field application of SIGS is limited by the instability of naked RNA and low RNA uptake by pathogens. Nanoparticles have been used as RNA carriers to enhance RNA silencing. Rice sheath blight caused by Rhizoctonia solani (R. solani) is one of the most devastating fungal diseases in rice (Oryza sativa L.). In this study, we aimed to explore the protective effects of nanoparticle-delivered dsRNA against rice sheath blight. The key pathogenic genes, RsAGO1 and RsAGO2, of R. solani were screened as targets for dsRNA. Chitosan (CS), polyethyleneimine (PEI), protamine, carbon quantum dot (CQD), polyamidoamine (PAMAM), and chitosan/SPc complex (CSC) were selected as dsRNA carriers. All the evaluated nanoparticles could assemble with dsRNA to form nanoparticle-dsRNA complexes, and CQD and CSC showed improved dsRNA load capacity. Particularly, CSC could enhance the stability of dsRNA and cause a 7% reduction in fluorescence intensity after nuclease treatment. CSC and CS effectively enhanced the efficiency of dsRNA uptake by pathogens. Furthermore, CSC could reduce pathogen infection and prolong the protection time of dsRNA by up to 20 days. Overall, this study provides a novel and efficacious SIGS-based strategy for producing RNA-based fungicides.

Abstract Background Tumor histomorphology analysis plays a crucial role in predicting the prognosis of resectable lung adenocarcinoma (LUAD). Computer-extracted image texture features have been previously shown to be correlated with outcome. However, a comprehensive, quantitative, and interpretable predictor remains to be developed. Methods In this multi-center study, we included patients with resectable LUAD from four independent cohorts. An automated pipeline was designed for extracting texture features from the tumor region in hematoxylin and eosin (H&E)-stained whole slide images (WSIs) at multiple magnifications. A multi-scale pathology image texture signature (MPIS) was constructed with the discriminative texture features in terms of overall survival (OS) selected by the LASSO method. The prognostic value of MPIS for OS was evaluated through univariable and multivariable analysis in the discovery set (n = 111) and the three external validation sets (V1, n = 115; V2, n = 116; and V3, n = 246). We constructed a Cox proportional hazards model incorporating clinicopathological variables and MPIS to assess whether MPIS could improve prognostic stratification. We also performed histo-genomics analysis to explore the associations between texture features and biological pathways. Results A set of eight texture features was selected to construct MPIS. In multivariable analysis, a higher MPIS was associated with significantly worse OS in the discovery set (HR 5.32, 95%CI 1.72–16.44; P = 0.0037) and the three external validation sets (V1: HR 2.63, 95%CI 1.10–6.29, P = 0.0292; V2: HR 2.99, 95%CI 1.34–6.66, P = 0.0075; V3: HR 1.93, 95%CI 1.15–3.23, P = 0.0125). The model that integrated clinicopathological variables and MPIS had better discrimination for OS compared to the clinicopathological variables-based model in the discovery set (C-index, 0.837 vs. 0.798) and the three external validation sets (V1: 0.704 vs. 0.679; V2: 0.728 vs. 0.666; V3: 0.696 vs. 0.669). Furthermore, the identified texture features were associated with biological pathways, such as cytokine activity, structural constituent of cytoskeleton, and extracellular matrix structural constituent. Conclusions MPIS was an independent prognostic biomarker that was robust and interpretable. Integration of MPIS with clinicopathological variables improved prognostic stratification in resectable LUAD and might help enhance the quality of individualized postoperative care.

Abstract Understanding how Baijiu facilitates blood circulation and prevents blood stasis is crucial for revealing the mechanism of Baijiu for cardiovascular disease (CVD) risk reduction. Here we established a zebrafish thrombosis model induced using arachidonic acid (AA) to quantitatively evaluate the antithrombotic effect of Wuliangye Baijiu. The prevention and reduction effects of aspirin, Wuliangye, and ethanol on thrombosis were compared using imaging and molecular characterization. Wuliangye Baijiu reduces thrombotic risks and oxidative stress in the AA-treated zebrafish, while ethanol with the same concentration has no similar effect. The prevention and reduction effects of Wuliangye on thrombosis are attributed to the change in the metabolic and signaling pathways related to platelet aggregation and adhesion, oxidative stress and inflammatory response.

Abstract Object Scarlet fever is an acute respiratory infectious disease that endangers public health and imposes a huge economic burden. In this paper, we systematically studied its spatial and temporal evolution and explore its potential ecological drivers. The goal of this research is to provide a reference for analysis based on surveillance data of scarlet fever and other acute respiratory infectious illnesses, and offer suggestions for prevention and control. Method This research is based on a spatiotemporal multivariate model (Endemic-Epidemic model). Firstly, we described the epidemiology status of the scarlet fever epidemic in Sichuan Province from 2016 to 2019. Secondly, we used spatial autocorrelation analysis to understand the spatial pattern. Thirdly, we applied the endemic-epidemic model to analyze the spatiotemporal dynamics by quantitatively decomposing cases into endemic, autoregressive, and spatiotemporal components. Finally, we explored potential ecological drivers that could influence the spread of scarlet fever. Results From 2016 to 2019, the incidence of scarlet fever in Sichuan Province varied much among cities. In terms of temporal distribution, there were 1–2 epidemic peaks per year, and they were mainly concentrated from April to June and October to December. In terms of transmission, the endemic and temporal spread were predominant. Our findings imply that the school holiday could help to reduce the spread of scarlet fever, and a standard increase in Gross Domestic Product (GDP) was associated with 2.6 folds contributions to the epidemic among cities. Conclusion Scarlet fever outbreaks are more susceptible to previous cases, as temporal spread accounted for major transmission in many areas in Sichuan Province. The school holidays and GDP can influence the spread of infectious diseases. Given that covariates could not fully explain heterogeneity, adding random effects was essential to improve accuracy. Paying attention to critical populations and hotspots, as well as understanding potential drivers, is recommended for acute respiratory infections such as scarlet fever. For example, our study reveals GDP is positively associated with spatial spread, indicating we should consider GDP as an important factor when analyzing the potential drivers of acute infectious disease.

Presenilin isoforms (PS1 and PS2) containing γ-secretase show contrasting sensitivity to MRK-560. Here, the authors determined cryo-EM structures of PS1/PS2-complexes treated with MRK-560 and identified key residues responsible for the isoform-dependent selectivity.

Rural business environments and informational sources play a pivotal role in shaping the dynamics of pesticide utilization in the agricultural sector. This study investigates the intricate mechanisms through which these environments impact farmers’ pesticide utilization practices and elucidates the key factors within rural business environments and information channels that influence such behaviors. By identifying effective strategies to promote judicious pesticide use among agricultural practitioners, this research aims to enhance the government’s ability to provide precise guidance to farmers, ultimately contributing to the preservation of ecological integrity. Employing grounded theory in conjunction with a series of comprehensive interviews with 32 cowpea farmers to gain firsthand insights, our investigation yielded the following key findings: (1) the enhancement of rural business environments has mitigated the impact of neighborhood influences on farmers’ pesticide use behavior; (2) farmers predominantly base their pesticide choices on verifiable information; (3) the influence of pesticide retailers on farmers’ pesticide use has significantly increased. Based on these findings, a dual-pronged approach is proposed. First, there should be sustained commitment to bolstering rural infrastructure, enhancing the entrepreneurial climate in rural regions, and fostering market liberalization. Second, it is imperative to disseminate advanced pesticide knowledge, demarcate effective information, and intensify dissemination efforts.

In the Qinghai-Tibet Plateau region, operational deficiencies and limited maintenance capacities often impair automatic air quality monitoring stations. This results in frequent data omissions, compromising the reliability of environmental assessment data. Therefore, an effective data imputation method is required to address the gaps in observational records. Utilizing a Sequence-to-Sequence framework, we introduce a model termed Bidirectional Recurrent Imputation for Time Series-Attention-based Long Short-Term Memory (BRITS-ALSTM). The encoder of BRITS-ALSTM applies BRITS to integrate single-station historical characteristics with multi-station correlation features. Concurrently, the decoder employs LSTM within an attention mechanism to capitalize on previously observed data, thereby generating hourly imputations for missing air quality data values. The model was trained using six types of air quality data from 16 stations across Qinghai Province. Through localized testing and parameter optimization, BRITS-ALSTM achieved a reduction in mean relative error (MRE) by 74.88% compared to the baseline mean-filling approach. Additionally, ablation studies demonstrated an improvement in the coefficient of determination R-squared (R2) from 0.67 to 0.76, outperforming the standalone BRITS. Consequently, BRITS-ALSTM enhances the accuracy of air quality data evaluations in the Tibetan Plateau and offers an efficacious strategy for data imputation in elevated terrains.

Abstract Background Most ovarian cancers are diagnosed at advanced stages characterized by abdominal dissemination and frequently exhibit chemoresistance. Pyruvate dehydrogenase kinase 2 (PDK2) regulates the switch between glycolysis and oxidative phosphorylation and contributes to tumor progression and chemoresistance. Here, we investigated the effects of PDK2 blockade on metabolic reprogramming and cisplatin sensitivity and evaluated the in vivo antitumor effects of PDK2 shRNA in chemoresistant ovarian cancer using retro-inverso follicle-stimulating hormone peptide-modified nanoparticle as carriers. Methods The expression of PDK2 was detected by immunohistochemistry, Western blot and real-time PCR. Cell proliferation and apoptosis were detected using CCK-8 and flow cytometry. Cell migration was detected by Transwell assay. Seahorse Analyzer was used to evaluate metabolic changes. The cisplatin-resistant ovarian cancer cells A2780cp were used to establish the mouse model of peritoneal metastatic ovarian cancer. Results A higher expression level of PDK2 was observed in chemoresistant ovarian cancer tissues and cell lines and was associated with shorter progression-free survival. PDK2 knockdown inhibited proliferation and migration and promoted apoptosis of both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Cisplatin sensitivity was increased even in cisplatin-resistant ovarian cancer cells. Mechanistically, PDK2 knockdown resulted in an increased oxygen consumption rate and decreased extracellular acidification rate, along with reduced lactate production, increased PDHC activity and increased levels of electron transport chain complexes III and V. The metabolism switched from glycolysis to oxidative phosphorylation. Finally, to specifically and effectively deliver PDK2 shRNA in vivo, we formulated a targeted delivery system containing retro-inverso follicle-stimulating hormone peptide as a targeting moiety and polyethylene glycol–polyethylenimine copolymers as carriers. The nanoparticle complex significantly suppressed tumor growth and peritoneal metastasis of cisplatin-resistant ovarian cancer without obvious toxicities. Conclusions Our findings showed the link between metabolic reprogramming and chemoresistance in ovarian cancer and provided an effective targeting strategy for switching metabolic pathways in cancer therapy.

Abstract Background High immune infiltration is associated with favourable prognosis in patients with non-small-cell lung cancer (NSCLC), but an automated workflow for characterizing immune infiltration, with high validity and reliability, remains to be developed. Methods We performed a multicentre retrospective study of patients with completely resected NSCLC. We developed an image analysis workflow for automatically evaluating the density of CD3+ and CD8+ T-cells in the tumour regions on immunohistochemistry (IHC)-stained whole-slide images (WSIs), and proposed an immune scoring system “I-score” based on the automated assessed cell density. Results A discovery cohort (n = 145) and a validation cohort (n = 180) were used to assess the prognostic value of the I-score for disease-free survival (DFS). The I-score (two-category) was an independent prognostic factor after adjusting for other clinicopathologic factors. Compared with a low I-score (two-category), a high I-score was associated with significantly superior DFS in the discovery cohort (adjusted hazard ratio [HR], 0.54; 95% confidence interval [CI] 0.33–0.86; P = 0.010) and validation cohort (adjusted HR, 0.57; 95% CI 0.36–0.92; P = 0.022). The I-score improved the prognostic stratification when integrating it into the Cox proportional hazard regression models with other risk factors (discovery cohort, C-index 0.742 vs. 0.728; validation cohort, C-index 0.695 vs. 0.685). Conclusion This automated workflow and immune scoring system would advance the clinical application of immune microenvironment evaluation and support the clinical decision making for patients with resected NSCLC.