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Abstract Colorectal cancer (CRC) is a prevalent malignant tumor of the gastrointestinal system, with the third and second highest incidence and mortality rates globally in 2020, respectively. Immunotherapy has developed rapidly in recent years. Natural killer (NK) cells have received increasing attention in the field of tumor immunotherapy due to their recognition and killing tumor cells without the limitations of major histocompatibility complexes. However, constraints within the tumor microenvironment that impede the infiltration and proliferation of NK cells result in poor efficacy of NK cell therapy for solid tumors. Oncolytic viral therapy is an immunogenic treatment with the potential to enhance anti-tumour immune responses and promote immune cell infiltration. In this study, we synergistically combine NK cells with an oncolytic adenovirus carrying Decorin (rAd.DCN) for the treatment of colorectal cancer (CRC) in a xenograft mouse model. By using Flow cytometry, real-time quantitative PCR and Calcein-AM release assay, we found that rAd.DCN could effectively promote proliferation, activation and degranulation of NK cells, up-regulate expression and secretion of NK cell killing activity-related factors, and enhance their killing activity. The efficacy is better than that of the blank control oncolytic virus rAd.Null. Combined treatment significantly inhibited tumor growth, increased the number of NK cells in peripheral blood, promoted the killing function of NK cells, and increased the expression levels of perforin and IFN-γ. At the same time, more NK cells were recruited to infiltrate tumor tissue. Our study established the feasibility of combination NK cells and oncolytic adenovirus application, thus expanding the scope of potentially curative treatments for NK cells in CRC.

Lanthanum lithium titanate is one of the promising electrolytes for solid-state lithium-ion batteries due to its high bulk ionic conductivity up to ∼10−3 S/cm. However, the practical application of this material has been bottlenecked by high grain boundary (GB) resistance, while the underlying mechanism is still under debate. Here we report a comprehensive study with direct evidence to reveal the origin of high GB resistance in La2/3–xLi3xTiO3 (LLTO). Atomic-scale observations via advanced scanning transmission electron microscopy show that the GBs are uniformly subject to subsurface segregation of La atoms to compensate for the excess surface charges. The La segregation leads to an abrupt decrease of charge carrier concentration neighboring GBs and hence is supposed to have deleterious effect on GB conductivity. The findings suggest a novel mechanism of space-charge-induced cation segregation, which shed lights on the intrinsic origin of low GB ionic conductivity in LLTO.

Abstract Background In clinical oncology practice, patient-reported outcomes (PROs) are essential for assessing the symptom burden, quality of life, and psychological status of patients. However, there remains a gap between the use of PROs in an oncologic setting and its implementation. Furthermore, numerous reviews in PRO implementation are often based on one particular technology, setting, or health condition, making it difficult to obtain a comprehensive and coherent summary of available evidence to help plan and undertake implementation. This systematic review aims to identify and integrate enablers and barriers to PRO implementation through the comprehensive framework for implementation research (CFIR) to provide a reference for implementing patient-reported outcomes management in oncology settings. Methods This review strictly observed the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. PubMed, Web of Science, CINAHL, Embase, and PsycINFO databases were systematically searched using a three-step search strategy. The search was limited from the inception of each database to April 2024. Articles describing facilitators and barriers to implementing PROs in clinical oncology practice were included. Two researchers screened the literature independently, and the quality assessment of cross-sectional, qualitative, and mixed studies was completed using the critical appraisal tools recommended by Joanna Briggs Institute (JBI) and the mixed methods assessment tool, respectively. Basic information about the included studies and determinants affecting PRO implementation was extracted, and coding categorization of facilitators and barriers was completed based on the 48 constructs provided by the CFIR framework. Results We included 30 studies from 5,649 search results, including 25 original and 5 review studies. The quality of the literature for qualitative studies was generally good, and the quality for quantitative and mixed studies was assessed as fair. We identified 52 facilitators and 50 barriers in the included literature, covering the domains used in the CFIR framework and 39 constructs, mainly including "Innovation Evidence-Base", "Innovation Complexity", "Innovation Design", "Structural Characteristics", "Compatibility", "Incentive Systems", "Access to Knowledge & Information", "Innovation Deliverers", "Innovation Recipients", and "Planning". Conclusions This systematic review integrated facilitators and barriers affecting PRO implementation in routine oncology clinical practice settings and categorized them through the CFIR framework. These influencing factors should be fully considered in future clinical practice to ensure the successful implementation of PROs. Trial registration It has been registered prospectively in PROSPERO under the registration number 42024532983.

Abstract Background To investigate the association between low transthyretin (prealbumin) concentration and mortality or readmission for all causes in elderly inpatients. Methods This analysis is based on a prospective cohort study conducted from September 2018 to April 2019 in ten wards of three tertiary referral hospitals in Beijing. Patients aged 65 years or older were enrolled, and their clinical data, laboratory test results, and auxiliary test results for patients were collected. A three-year follow-up was conducted with patients. Based on the 5th and 95th percentiles of transthyretin concentration, patients were split into three groups. The correlation between transthyretin concentration and the outcome of elderly hospitalized patients was investigated. The primary outcome of the research was death or readmission from all causes within three years. Results Among the 636 individuals in the study, 335 (52.7%) were males, with a median age of 74.7 years (interquartile range [IQR]: 69.3–80.1). During a median follow-up period of 1,099.0 days (IQR: 1,016.3-1,135.0), 363 individuals (57.0%) experienced all-cause mortality or readmission events. Patients with transthyretin concentrations at or below the 5th percentile had a significantly increased risk of all-cause mortality or readmission compared to those with concentrations between the 5th and 95th percentiles (hazard ratio [HR]: 2.25; 95% confidence interval [CI]: 1.55–3.26). Even after adjusting for potential confounders, low transthyretin concentration remained an independent risk factor for poor prognosis in elderly inpatients (HR: 1.84; 95% CI: 1.03–3.28). Since women have consistently lower baseline transthyretin levels than men, we performed gender-specific analysis. We found that low transthyretin concentration is an independent risk factor for adverse prognosis in elderly male inpatients (HR: 2.99; 95% CI: 1.35–6.62) but not in females. Conclusions Low transthyretin concentrations are associated with increased all-cause mortality or readmission in elderly inpatients, particularly among male patients. Graphical Abstract

Abstract Tuberculosis has been one of the most common communicable diseases raising global concerns. Accurately predicting the incidence of Tuberculosis remains challenging. Here we constructed a time-series analysis and fusion tool using multi-source data, and aimed to more accurately predict the incidence trend of tuberculosis of Anhui Province from 2013 to 2023. Random forest algorithm (RF), Feature Recursive Elimination (RFE) and Least absolute shrinkage and selection operator (LASSO) were implemented to improve the derivation of features related to infectious diseases and feature work. Based on the characteristics of infectious disease data, a model of RF-RFE-LASSO integrated particle swarm optimization multiple inputs long short term memory recurrent neural network (RRL-PSO-MiLSTM) was created to perform more accurate prediction. Results showed that the PSO-MiLSTM achieved excellent prediction results compared with common single-input and multi-input time-series models (test set MSE:42.3555, MAE: 59.3333, RMSE: 146.7237, MAPE: 2.1133, R 2 : 0.8634). PSO-MiLSTM enriches and complements the methodological research content of calibrating the time-series predictive analysis of infectious diseases using multi-source data, and can be used as a brand-new benchmark for the analysis of influencing factors and trend prediction of infectious diseases at the public health level in the future, as well as providing a reference for incidence rate prediction of infectious diseases.

The autophagy–lysosome axis is an evolutionarily conserved intracellular degradation pathway which constitutes an important component of host innate immunity against microbial infections. Here, we show that African swine fever virus (ASFV), one of most devastating pathogens to the worldwide swine industry, can reshape the autophagy–lysosome axis by recruiting the critical lysosome membrane proteins (LAMP1 and LAMP2) to viral factories while inhibiting autophagic induction in macrophages. The screening of viral membrane proteins led to the identification of several ASFV membrane proteins, exemplified by viral protein pEP153R, that could significantly alter the subcellular localization of LAMP1/2 when expressed alone in transfected cells. Further analysis showed that pEP153R was also a component of viral factories and could induce endoplasmic reticulum (ER) retention of LAMP1/2, leading to the inhibition of the fusion of autophagosomes with lysosomes. Interestingly, the ASFV mutant lacking EP153R could still actively recruit LAMP into viral factories (VFs) and inhibit autophagic flux, indicating the existence of a functional redundancy of other viral proteins in the absence of pEP153R and highlighting the complexity of ASFV replication biology. Taken together, our results reveal novel information about the interplay of ASFV with the autophagy–lysosome axis and a previously unrecognized function of ASFV protein pEP153R in regulating the cellular autophagic process.

Abstract Shiga toxin-producing Escherichia coli (STEC) can cause mild diarrhea even severe hemolytic uremic syndrome (HUS). Shiga toxin (Stx) is the primary virulence factor. Two Stx types and several subtypes have been identified. STEC strains encoding stx2f (Stx2f-STECs) are frequently identified from pigeons. Stx2f was initially considered to be associated with mild symptoms, more recently Stx2f-STECs have been isolated from HUS cases, indicating their pathogenic potential. Here, we investigated the prevalence of Stx2f-STECs among domestic pigeons in two regions in China, characterized the strains using whole-genome sequencing (WGS), and assessed the Stx2f transcriptions. Thirty-two Stx2f-STECs (4.36%) were culture-positive out of 734 fecal samples (one strain per sample). No other stx subtype-containing strain was isolated. Four serotypes and two sequence types were determined, and a novel sequence type ST15057 was identified. All strains harbored the E. coli attaching and effacing gene eae. Two types of Stx2f prophages were assigned. Stx2f-STECs showed variable Stx transcription levels induced by mitomycin C. Whole genome single-nucleotide polymorphism (wgSNP) analysis revealed different genetic backgrounds between pigeon-derived strains and those from diarrheal or HUS patients. In contrast, pigeon-derived Stx2f-STECs from diverse regions exhibited genetic similarity. Our study reports the prevalence and characteristics of Stx2f-STECs from pigeons in China. The pigeon-derived strains might pose low public health risk.

Abstract. Background:. Very low birth weight (VLBW) infants are the key populations in neonatology, wherein morbidity and mortality remain major challenges. The study aimed to analyze the clinical characteristics of VLBW infants. Methods:. A retrospective cohort study was conducted in West China Second Hospital between January 2016 and December 2021. Neonates with a birth weight of

This paper aimed to investigate the antioxidant activity of buckwheat bee pollen polysaccharides (BWPP) during the in vitro gastrointestinal digestion. The crude polysaccharides were purified using DEAE-52 cellulose column and their antioxidant activity during in vitro simulated gastric and intestinal digestion was studied. The results showed that after purification by DEAE-52 cellulose column chromatography, the highest total sugar content component BWPP-1 was obtained, which was mainly composed of Glc, Xyl, Ara, etc. The infrared spectrum showed that BWPP-1 had obvious polysaccharide characteristic absorption peaks. During the simulated in vitro gastrointestinal digestion, the ABTS+· scavenging rates of BWPP and BWPP-1 reached their maximum values at 60 minutes of simulated gastric juice digestion, which were 86.39%±1.28% and 90.38%±2.78%, respectively. There was a significant difference compared to other digestion times (P0.05). When simulating intestinal digestion, the maximum clearance rates of ABTS+· by BWPP and BWPP-1 reached 88.67%±0.40% and 91.82%±2.77% at 60 minutes, and the difference between the two was not significant (P>0.05). The DPPH· scavenging rates reached their peak values at 240 minutes of 57.11%±0.06% and 65.67%±3.67%, with significant difference (P

Percutaneous coronary intervention (PCI) is an important treatment strategy for patients with coronary artery disease. However, bleeding after PCI significantly increases the mortality risk. The search for prognostic predictors and optimal antiplatelet therapy for patients with high bleeding risk (HBR) after PCI has been a much researched upon topic in current cardiovascular research. However, there is no widely accepted prognostic model or recommended antiplatelet therapy for patients with PCI-HBR. In this trial, based on prospective multi-center database building, we will analyze the adverse prognostic predictors for patients with PCI-HBR, observe the types of antiplatelet drugs and duration of dual antiplatelet therapy in PCI-HBR patients, and compare the safety and feasibility of different antiplatelet regimens and treatment courses. The prognostic analysis and an appropriate antiplatelet strategy for patients with PCI and high bleeding risk (PPP-PCI) trial will help analyze bleeding risk factors in PCI-HBR patients and explore the appropriate antiplatelet treatment options. This study is registered with ClinicalTrials.gov (NCT05369442). The Research Ethics Committee of West China Hospital authorized this study (2022 Review #269). The trial results will be published in peer-reviewed journals and at conferences.

Abstract Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.

Abstract Background Global warming has greatly increased the impact of high temperatures on crops, resulting in reduced yields and increased mortality. This phenomenon is of significant importance to the rose flower industry because high-temperature stress leads to bud dormancy or even death, reducing ornamental value and incurring economic losses. Understanding the molecular mechanisms underlying the response and resistance of roses to high-temperature stress can serve as an important reference for cultivating high-temperature-stress-resistant roses. Results To evaluate the impact of high temperatures on rose plants, we measured physiological indices in rose leaves following heat stress. Protein and chlorophyll contents were significantly decreased, whereas proline and malondialdehyde (MDA) contents, and peroxidase (POD) activity were increased. Subsequently, transcriptomics and metabolomics analyses identified 4,652 common differentially expressed genes (DEGs) and 57 common differentially abundant metabolites (DAMs) in rose plants from four groups. Enrichment analysis showed that DEGs and DAMs were primarily involved in the mitogen-activated protein kinases (MAPK) signaling pathway, plant hormone signal transduction, alpha-linolenic acid metabolism, phenylpropanoid biosynthesis, and flavonoid biosynthesis. The combined analysis of the DEGs and DAMs revealed that flavonoid biosynthesis pathway-related genes, such as chalcone isomerase (CHI), shikimate O-hydroxycinnamoyl transferase (HCT), flavonol synthase (FLS), and bifunctional dihydroflavonol 4-reductase/flavanone 4-reductase (DFR), were downregulated after heat stress. Moreover, in the MAPK signaling pathway, the expression of genes related to jasmonic acid exhibited a decrease, but ethylene receptor (ETR/ERS), P-type Cu + transporter (RAN1), ethylene-insensitive protein 2/3 (EIN2), ethylene-responsive transcription factor 1 (ERF1), and basic endochitinase B (ChiB), which are associated with the ethylene pathway, were mostly upregulated. Furthermore, heterologous overexpression of the heat stress-responsive gene RcHSP70 increased resistance to heat stress in Arabidopsis thaliana. Conclusion The results of this study indicated that the flavonoid biosynthesis pathway, MAPK signaling pathway, and plant hormones may be involved in high-temperature resistance in roses. Constitutive expression of RcHSP70 may contribute to increasing high-temperature tolerance. This study provides new insights into the genes and metabolites induced in roses in response to high temperature, and the results provide a reference for analyzing the molecular mechanisms underlying resistance to heat stress in roses.

Abstract Background We concurrently developed a prospective study to assess clinical outcomes among patients receiving 9-month bedaquiline (BDQ)-containing regimens, aiming to provide valuable data on the use of this short-course regimen in China. Methods This open-label, randomized, controlled, multicenter, non-inferiority trial was conducted at sixteen hospitals, and enrolled participants aged 18 years and older with pulmonary rifampicin/multidrug tuberculosis. Participants were randomly assigned, in a 1:1 ratio. Individuals within the standard-regimen group received 6 months of BDQ, linezolid, levofloxacin, clofazimine, and cycloserine plus 12 months of levofloxacin, and any three potentially effective drugs from clofazimine, cycloserine pyrazinamide, ethambutol and protionamide, whereas individuals within shorter-regimen group received 9 months of BDQ, linezolid, levofloxacin, clofazimine and cycloserine. The primary outcome was the percentage of participants with a composite unfavorable outcome (treatment failure, death, treatment discontinuation, or loss to follow-up) by the end of the treatment course after randomization in the modified intention-to-treat population. The noninferiority margin was 10%. This trial was registered with www.chictr.org.cn , ChiCTR2000029012. Results Between Jan 1, 2020, and Dec 31, 2023, 264 were screened and randomly assigned, 132 of 264 participants were assigned to the standard-regimen group and 132 were assigned to the shorter-regimen. Thirty-three (12.55%) of 264 participants were excluded from the modified intention-to-treat analysis. As a result, 231 participants were included in the modified intention-to-treat analysis (116 in the standard-regimen group and 115 in the shorter-regimen group).In the modified intention-to-treat population, unfavorable outcomes were reported in 19 (16.5%) of 115 participants for whom the outcome was assessable in the shorter-regimen group and 26 (22.4%) of 116 participants in the standard care group (risk difference 5.9 percentage points (97.5% CI − 5.8 to 17.5)). One death was reported in the standard-regimen group. The incidence of QTcF prolongation in the shorter-regimen group (22.6%, 26/115) was similar to the standard-regimen group (24.1%, 28/116). Conclusions The 9-month, all-oral regimen is safe and efficacious for the treatment of pulmonary rifampicin/multidrug-resistant tuberculosis. The high incidence of QTc prolongation associated with the use of BDQ highlights the urgent need of routine electrocardiogram monitoring under treatment with BDQ-containing regimens in the Chinese population.

Abstract The increasing amount of coal gasification fine slag (CGFS) necessitates its resource utilization. CGFS, mainly composed of porous carbonaceous particles and partially fused spherical or agglomerated ash particles, is an inexpensive and high-quality raw material for preparing adsorbent materials. However, the challenge remains in developing a simple, low-cost, and environmentally friendly method to produce high-performance porous materials from CGFS. In this study, a one-step treatment method using 2 mol/L nitric acid under hydrothermal conditions was proposed for CGFS. The adsorbent material (CGFS-2 M) prepared under a solid–liquid ratio of 2:5 and an initial concentration of 200 mg/L methylene blue (MB) exhibited an equilibrium adsorption capacity as high as 210.20 mg/g. The excellent adsorption performance of CGFS-2 M can be attributed to several factors: acid leaching for mineral removal and pore formation, resulting in a specific surface area and total pore volume 2.2 and 1.6 times that of untreated CGFS, respectively, and an optimized mesoporous pore size distribution favorable for MB adsorption; optimal mineral removal and a well-defined carbon microcrystal structure providing more space for MB adsorption; nitric acid treatment increasing the surface oxygen content and hydrophilicity, enhancing its ability to remove MB. The synergistic effect of pore structure improvement and surface modification indicates a feasible research direction for enhancing the performance of CGFS-based adsorbent materials. These results provide theoretical support for the development of efficient CGFS-based adsorbents.

Abstract Bortezomib, lenalidomide, and dexamethasone (VRD), and bortezomib, doxorubicin, and dexamethasone (PAD), are commonly used in induction regimens for patients with newly diagnosed multiple myeloma (NDMM) in China. This real-world study enrolled 390 patients, 195 receiving VRD and 195 receiving PAD induction. The primary endpoint was progression-free survival (PFS) and stringent complete remission/complete remission. Across the entire cohort, VRD demonstrated significantly improved five-year overall survival (OS) (74% vs. 59%, p = 0.0024) and five-year PFS (67% vs. 37%, p = 0.0018) compared to PAD. Notably, the median OS and PFS were not reached for VRD-treated patients, while they were 77 months (60-not reached [NR]) and 46 months (36-NR), respectively, for PAD. In patients with standard-risk cytogenetics, VRD showed superior five-year OS (83% vs. 58%, p = 0.0038) and PFS (78% vs. 48%, p = 0.0091) compared to PAD. However, these differences were not statistically significant in high-risk patients. For transplanted patients, VRD was associated with superior five-year OS (91% vs. 67%, p = 0.014) and PFS (79% vs. 47%, p = 0.015) compared to PAD. In non-transplanted patients, VRD showed a trend towards improved five-year OS (p = 0.085) and PFS (p = 0.073) compared to the PAD group. In conclusion, VRD displayed superior OS and PFS outcomes in standard-risk patients and those who underwent transplantation. These findings suggest potential advantages of VRD over PAD in real-world clinical settings for NDMM treatment. However, due to the imbalance in transplantation rates between the VRD and PAD groups, limitations in testing for high-risk cytogenetic abnormalities (HRA), and the difference between the received cycles and salvage therapies, the conclusions of this study should be interpreted with caution.

ObjectiveTo evaluate the current status of hypertension prevention and control management operation mechanisms in Chinese mainland, explore the impact of their improvement on hypertension prevention and control effects, and provide a reference for enhancing hypertension prevention and control management. MethodsPolicy documents related to hypertension prevention and control from January 1 2000 to December 31, 2018 in 31 provinces (municipalities and autonomous regions) in Chinese mainland were collected. The current status of hypertension prevention and control management operation mechanisms in Chinese mainland was systematically evaluated according to the appropriate public health system evaluation model and standard. A logistic regression model was used to analyze the impact of the improvement of management operation mechanisms on hypertension prevention and control effects. ResultsIn 2018, the appropriateness of hypertension prevention and control management operation mechanisms in Chinese mainland was 43.68%, with an increase of 21.64% compared to 2000, but there was still a gap of 48.61% from the appropriate standard. Among them, the appropriateness of coordination and incentive mechanisms was the lowest (14.03%), and the appropriateness of planning and evaluation mechanisms was the highest (63.04%). In terms of specific positioning, the coverage of medium and long-term plans (100.00%) and the completeness of content and form (94.45%) were relatively high, while the feasibility of management mechanisms was only 9.76%. The results of logistic regression analysis showed that the improvement of management operation mechanisms helped control blood pressure in hypertensive patients (OR = 1.012, P = 0.007) and maintain the stability of patients’ blood pressure (OR = 1.010, P = 0.029). Conclusion From 2000 to 2018, the construction of hypertension prevention and control management mechanisms in Chinese mainland tended to be improved, effectively promoting the improvement of hypertension prevention and control management levels. However, it is still necessary to further establish and improve coordination and incentive mechanisms and clarify the division of departmental responsibilities.

Deep coalbed methane (CBM) has become one of the most significant potential sources of natural gas in China. However, the exploration and development of deep CBM in China is still in an initial stage, and its accumulation-forming characteristics require further study. Therefore, taking the No. 8 deep coal seam in the central-eastern region of Ordos Basin as an example, this study investigated the geologic characteristics of CBM accumulations to establish a numerical model. The evolution of the burial and accumulation of CBM in the area was reconstructed. The modeling results suggest that the No. 8 coal seam experienced continuous subsidence from the Late Cretaceous to the Triassic, alternating subsidence and uplift during the Jurassic, rapid burial throughout the Early Cretaceous, and continuous uplift since the Late Cretaceous. The coal reached its maximum maturity at the end of the Early Cretaceous. Furthermore, CBM generation in the region was divided into four stages of thermal events—biogenic and early thermogenic gas, cracking of light oil into gas, cracking of the remaining kerogen into gas, and hydrocarbon generation ceasing—which accelerated coal maturity and generation. The adsorption capacity presented an overall declining trend prior to the end of the Cretaceous, followed by a rapid increase since the Late Cretaceous. As for adsorption mass evolution, the CBM successively underwent unsaturated minor adsorption, unsaturated rapid-rising adsorption, saturated decreasing adsorption, and saturated rising adsorption. The in-situ gas mass was found to be controlled by a combination of generation, adsorption, and expulsion of hydrocarbons, with its present-day value being 9–29 × 104 t/km2 and the corresponding gas volume per ton of coal being 12–28 m3/t. Moreover, free gas evolution initially showed an increasing trend, followed by a decline, ultimately accounting for 11%–28% of the total gas content.

Abstract Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Abstract Ground subsidence caused by extraction of longwall panels has always been a great concern all over the world. Conventional longwall mining system (CLMS) gives rise to wavy subsidence causing great damage to surface structures. A coal mine in Shanxi, China, utilizes a split-level longwall layout (SLL) for a sub-horizontal No. 8 coal seam to improve the cavability of mudstone interlayer and top coal. This layout, however, also produced unexpectedly favorable surface subsidence. Subsidence of No. 6 and No. 8 longwall panels was monitored while mining was conducted. Field instrumentation and numerical simulation were carried out. It is demonstrated that an asymmetric subsidence profile with stepped subsidence and cracks occurred on the tailgate side but relatively mild and smooth deformation on the other. Due to elimination of conventional parallelepiped gate pillar, No. 6 and No. 8 gobs were connected. Extraction of two SLL panels acted as one supercritical panel. The maximum possible subsidence was reached which lowers the likelihood of potential future secondary subsidence as underground gob fractures and voids have closed. Therefore, SLL is more favorable for post-mining land reuse as gobs are more consolidated underground.

Abstract Background Acute necrotizing encephalopathy (ANE) and myocarditis are both acute, life-threatening conditions that can be triggered by COVID-19. We report a case of sequential ANE and myocarditis following a COVID-19 infection. Case presentation A 27-year-old female patient was brought to the emergency department due to episodes of fever for two days and a 9-h altered state of consciousness. Her condition rapidly developed into stuporous and hemodynamic instability within serval hours. Veno-arterial extracorporeal membrane oxygenation (ECMO) was rapidly initiated with other supportive treatments. The following-up MRI showed bilateral, symmetrically distributed lesions in the brainstem, bilateral hippocampal regions, and bilateral basal ganglia, consistent with ANE. The diagnosis was confirmed through the detection of SARS-CoV-2 and the exclusion of other potential causes. After weeks of medical treatment, her condition stabilized, and she was transferred for further rehabilitation treatment. Conclusions This case study indicates that COVID-19 may simultaneously and rapidly affect the central nervous system and cardiovascular system, leading to poor outcomes. Accurate diagnosis and timely invasive bridging therapy, when necessary, can be lifesaving. Further exploration of potential mechanisms underlying COVID-19 central nervous system (CNS) and cardiovascular system manifestations will be important.

Abstract Within the evolving landscape of fifth‐generation (5G) wireless networks, the introduction of network‐slicing protocols has become pivotal, enabling the accommodation of diverse application needs while fortifying defences against potential security breaches. This study endeavours to construct a comprehensive network‐slicing model integrated with an attack detection system within the 5G framework. Leveraging software‐defined networking (SDN) along with deep learning techniques, this approach seeks to fortify security measures while optimizing network performance. This undertaking introduces network slicing predicated on SDN with the OpenFlow protocol and Ryu control technology, complemented by a neural network model for attack detection using deep learning methodologies. Additionally, the proposed convolutional neural networks‐long short‐term memory approach demonstrates superiority over conventional ML algorithms, signifying its potential for real‐time attack detection. Evaluation of the proposed system using a 5G dataset showcases an impressive accuracy of 99%, surpassing previous studies, and affirming the efficacy of the approach. Moreover, network slicing significantly enhances quality of service by segmenting services based on bandwidth. Future research will concentrate on real‐world implementation, encompassing diverse dataset evaluations, and assessing the model's adaptability across varied scenarios.

Abstract Background Epigenetic clocks were known as promising biomarkers of aging, including original clocks trained by individual CpG sites and principal component (PC) clocks trained by PCs of CpG sites. The effects of genetic and environmental factors on epigenetic clocks are still unclear, especially for PC clocks. Methods We constructed univariate twin models in 477 same-sex twin pairs from the Chinese National Twin Registry (CNTR) to estimate the heritability of five epigenetic clocks (GrimAge, PhenoAge, DunedinPACE, PCGrimAge, and PCPhenoAge). Besides, we investigated the longitudinal changes of genetic and environmental influences on epigenetic clocks across 5 years in 134 same-sex twin pairs. Results Heritability of epigenetic clocks ranged from 0.45 to 0.70, and those for PC clocks were higher than those for original clocks. For five epigenetic clocks, the longitudinal stability was moderate to high and was largely due to genetic effects. The genetic correlations between baseline and follow-up epigenetic clocks were moderate to high. Special unique environmental factors emerged both at baseline and at follow-up. PC clocks showed higher longitudinal stability and unique environmental correlations than original clocks. Conclusions For five epigenetic clocks, they have the potential to identify aging interventions. High longitudinal stability is mainly due to genetic factors, and changes of epigenetic clocks over time are primarily due to changes in unique environmental factors. Given the disparities in genetic and environmental factors as well as longitudinal stability between PC and original clocks, the results of studies with original clocks need to be further verified with PC clocks.

Abstract The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

Purpose: The poor retention and ambiguous differentiation of stem cells (SCs) within corpus cavernosum (CC) limit the cell application in erectile dysfunction (ED). Herein, the effects and mechanism of microRNA-145 (miR-145) gene modification on modulating the traits and fate of bone marrow-derived mesenchymal stem cells (BMSCs) were investigated. Materials and Methods: The effects of miR-145 on cell apoptosis, proliferation, migration, and differentiation were determined by flow cytometry, cell counting kit-8, transwell assays and myogenic induction. Then, the age-related ED rats were recruited to four groups including phosphate buffer saline, BMSC, vector-BMSC, overexpressed-miR-145-BMSC groups. After cell transplantation, the CC were harvested and prepared to demonstrate the retention and differentiation of BMSCs by immunofluorescent staining. Then, the target of miR-145 was verified by quantitative real-time polymerase chain reaction and immunohistochemical. After that, APTO-253, as an inducer of Krüppel-like factor 4 (KLF4), was introduced for rescue experiments in corpus cavernosum smooth muscle cells (CCSMCs) under the co-culture system. Results: In vitro, miR-145 inhibited the migration and apoptosis of BMSCs and promoted the differentiation of BMSCs into smooth muscle-like cells with stronger contractility. In vivo, the amount of 5-ethynyl-2'-deoxyuridine (EdU)+ cells within CC was significantly enhanced and maintained in the miR-145 gene modified BMSC group. The EdU/CD31 co-staning was detected, however, no co-staining of EdU/α-actin was observed. Furthermore, miR-145, which secreted from the gene modified BMSCs, dampened the expression of KLF4. However, the effects of miR-145 on CCSMCs could be rescued by APTO-253. Conclusions: Overall, miR-145 modification prolongs the retention of the transplanted BMSCs within the CC, and this effect might be attributed to the modulation of the miR-145/KLF4 axis. Consequently, our findings offer a promising and innovative strategy to enhance the local stem cell-based treatments.

Research on inflammatory response, liver injury, and immune regulation has demonstrated that the intricate interactions among immune cells constitute a critical regulatory network. Alcohol consumption alters the liver microenvironment, triggering inflammation and immune responses. Elucidating the inhibitory, cooperative, and synergistic effects among lymphocytes and myeloid cells may reveal the core mechanisms of alcohol-associated liver disease (ALD) pathogenesis and identify promising therapeutic targets. This review seeks to elucidate the intricate and multifaceted interactions among immune cells, encompassing both direct cellular interactions and the secretion of various effector molecules. It is essential to underscore that these interactions have broader and more complex roles in ALD than the activities of individual immune cell types. These interactions play a crucial role in mutually regulating one another, thereby preserving the homeostasis of the inflammatory and immune response in the liver environment. Targeting these immune cell interactions is anticipated to offer a novel approach to the prevention and treatment of ALD.

This is an article in the field of mining engineering. Aiming at problems of high cost and high comminution rate in the iron enriched sludge pelletizing process, a new kind of low cost binder was developed. In this paper, the effects of water content, pressure and drying temperature on the falling strength and comminution rate of the pellets were studied. The results show that when the binder ratio is 1.5%, the falling strength of the raw pellets is more than 5 times/m, the falling strength of dried ball is more than 28 times/2 m, the comminution rate is less than 2%, which meets the requirements of production. At the same time， the binder cost of per ton pellet is reduced by 35% compared with the previous binder.

Abstract Background Telomeres consist of repetitive DNA sequences at the chromosome ends to protect chromosomal stability, and primarily maintained by telomerase or occasionally by alternative telomere lengthening of telomeres (ALT) through recombination-based mechanisms. Additional mechanisms that may regulate telomere maintenance remain to be explored. Simultaneous measurement of telomere length and transcriptome in the same human embryonic stem cell (hESC) revealed that mRNA expression levels of UBQLN1 exhibit linear relationship with telomere length. Methods In this study, we first generated UBQLN1-deficient hESCs and compared with the wild-type (WT) hESCs the telomere length and molecular change at RNA and protein level by RNA-seq and proteomics. Then we identified the potential interacting proteins with UBQLN1 using immunoprecipitation-mass spectrometry (IP-MS). Furthermore, the potential mechanisms underlying the shortened telomeres in UBQLN1-deficient hESCs were analyzed. Results We show that Ubiquilin1 (UBQLN1) is critical for telomere maintenance in human embryonic stem cells (hESCs) via promoting mitochondrial function. UBQLN1 deficiency leads to oxidative stress, loss of proteostasis, mitochondria dysfunction, DNA damage, and telomere attrition. Reducing oxidative damage and promoting mitochondria function by culture under hypoxia condition or supplementation with N-acetylcysteine partly attenuate the telomere attrition induced by UBQLN1 deficiency. Moreover, UBQLN1 deficiency/telomere shortening downregulates genes for neuro-ectoderm lineage differentiation. Conclusions Altogether, UBQLN1 functions to scavenge ubiquitinated proteins, preventing their overloading mitochondria and elevated mitophagy. UBQLN1 maintains mitochondria and telomeres by regulating proteostasis and plays critical role in neuro-ectoderm differentiation.

ABSTRACT Background MiRNA let7d‐5p has been recently reported to be abnormally expressed in diabetes‐associated atherosclerosis (AS). However, it still remains unknown how let7d‐5p contributes to the process of atherosclerosis. Methods Twenty fresh tissues and a total of 28 wax block specimens from carotid endarterectomy procedures were obtained from the Luoyang Central Hospital affiliated to Zhengzhou University. The expression of let7d‐5p was assessed using quantitative RT‐PCR (qRT‐PCR). A series of in vitro experiments was used to determine the roles of let7d‐5p knockdown and overexpression in vascular smooth muscle cells (VSMCs). Results We discovered that the carotid plaques from diabetic patients had lower expression levels of miR let7d‐5p. In VSMCs, the expression of miRNA let7d‐5p was significantly lower in high glucose conditions compared with low glucose situations. The proliferation and migration of VSMCs were also inhibited by the overexpression of let7d‐5p, whereas the opposite was true when let7d‐5p was inhibited, according to gain and loss of function studies. Mechanically, let7d‐5p might activate the GSK3β/β‐catenin signaling pathway via binding to the high mobility group AT‐Hook 2 (HMGA2) mRNA in VSMCs. Additionally, GLP‐1RA liraglutide may prevent the migration and proliferation of VSMCs by raising let7d‐5p levels. Conclusions High glucose stimulated the proliferation and migration of VSMCs by regulating the let7d‐5p/HMGA2/GSK3β/β‐catenin pathway, and liraglutide may slow atherosclerosis by increasing the levels of miR let7d‐5p.

Per- and polyfluoroalkyl substances (PFASs) can disrupt lipid metabolism, and changes in cord blood fatty acid composition have been observed in small newborns. Emerging evidence suggests that exposure to PFASs during pregnancy is linked to decreased newborn size, although the evidence is not consistent. The modifying effect of fatty acids on the associations of gestational PFAS exposure with newborn size is still unknown. Here we show that the nutritional status of the fetus, as indicated by the level of fatty acids in the cord blood, mitigates the adverse effects of gestational PFAS exposure on the size of the newborn. Our study confirms the adverse developmental effects of PFASs and identifies emerging short-chain PFASs as the primary drivers of reduced newborn size, despite their lower exposure burden compared to legacy PFASs. Additionally, we find the protective role of cord blood fatty acids, suggesting potential strategies for mitigating the detrimental effects of emerging environmental exposures on human health. Our findings provide new evidence of the potential toxicity of emerging PFASs and call for further toxicity evaluations of these pollutants for regulatory purposes. Future studies should consider the complex interaction between exposure and nutrition within the human body, particularly during the first thousand days of life, to promote lifelong health.

Milk production traits play an important role in dairy cattle breeding, and single nucleotide polymorphisms can be used as effective molecular markers for milk production trait marker-assisted breeding in dairy cattle. Based on the results of the preliminary GWAS, candidate genes SPP1 and NCAPG associated with milk production traits were screened. In this study, the aim was to screen and characterize the SNPs of SPP1 and NCAPG genes about milk production traits. Two SNPs and one haplotype block of the SPP1 gene and four SNPs and one haplotype block of the NCAPG gene were obtained by amplification, sequencing and association analysis, and all six SNPs were located in the exon region. Association analysis showed that all six SNPs were significantly associated with milk protein percentage. Linkage disequilibrium analysis showed that 2 SNPs of SPP1 (g. 36,700,265 C > T and g. 36,693,596 C > A) constituted a haplotype that correlated with milk protein percentage, and the dominant haplotype was H2H2, which was CCTT. 4 SNPs of NCAPG (g. 37,342,705 C > A, g. 37,343,379 G > T, g. 37,374,314 C > A and g. 37,377,857 G > A) constituted a haplotype associated with milk protein percentage, 305-days milk protein yield and 305 days milk yield. Tissue expression profiling results revealed that SPP1 and NCAPG had the highest expression in mammary tissue. Interference with SPP1 and NCAPG inhibited the proliferation of Bovine mammary epithelial cells. (BMECs), down-regulated the expression of PCNA, CDK2 and CCND1, up-regulated the expression of BAX and BAD, and promoted apoptosis. Reduced triglyceride synthesis in BMECs, down-regulated the expression of DGAT1, DGAT2, LPIN1, and AGPAT6.SPP1 and NCAPG are involved in the synthesis of milk proteins, and interfering with SPP1 and NCAPG decreased the secretion of β-casein, κ-casein, and αs1-casein, as well as up-regulated the CSN2 and CSN3 expression. The above results indicate that the SNP loci of SPP1 and NCAPG can be used as potential molecular markers to improve milk production traits in dairy cows, laying the foundation for marker-assisted selection. It also proves that SPP1 and NCAPG can be used as candidate key genes for milk production traits in dairy cows, providing new insights into the physiological mechanisms of lactation regulation in dairy cows.

ABSTRACT Background In the era of novel agents, the clinical outcomes of induction treatment and the impact of the number of high‐risk cytogenetic abnormalities (HRA) in newly diagnosed multiple myeloma (NDMM) need to be explored. Objective Through this study, we aim to analyze the effectiveness of different induction treatments and explore the survival outcomes of patients with varying numbers of HRA. Methods A total of 734 patients from seven medical centers were included in our study. Results Patients in the CD38 monoclonal antibody or IMiDs plus proteasome inhibitors (PI) groups had significantly superior overall survival (OS) and progression‐free survival (PFS) compared to those receiving IMiDs or PI alone. Additionally, the CD38 monoclonal antibody conferred a PFS advantage over IMiDs plus PI. Patients with ≥ 2 high‐risk cytogenetic abnormalities (HRA) exhibited an extremely poor prognosis and should be considered ultra‐high‐risk individuals in multiple myeloma (MM). The CD38 monoclonal antibody, transplantation, and achieving minimal residual disease (MRD) negativity only partly mitigated the poor prognosis in patients with HRA. Furthermore, patients with 1q21 gain/amplification (1q21+) only had a significantly worse prognosis compared to patients without HRA, and those with 1q21+ plus del17p or t(4;14) exhibited an inferior prognosis compared to those with 1q21+ alone. Conclusion Our results suggested that double‐hit multiple myeloma was associated with extremely poor survival outcomes, and more effective treatments needed to be explored for this particular subtype of MM.

ABSTRACT Children diagnosed with severe tonsillar hypertrophy display discernible craniofacial features distinct from those with adenoid hypertrophy, prompting illuminating considerations regarding microbiota regulation in this non-inflammatory condition. The present study aimed to characterize the salivary microbial profile in children with tonsillar hypertrophy and explore the potential functionality therein. A total of 112 children, with a mean age of 7.79 ± 2.41 years, were enrolled and divided into the tonsillar hypertrophy (TH) group (n = 46, 8.4 ± 2.5 years old), adenoid hypertrophy (AH) group (n = 21, 7.6 ± 2.8 years old), adenotonsillar hypertrophy (ATH) group (n = 23, 7.2 ± 2.1 years old), and control group (n = 22, 8.6 ± 2.1 years old). Unstimulated saliva samples were collected, and microbial profiles were analyzed by 16S rRNA sequencing of V3–V4 regions. Diversity and composition of salivary microbiome and the correlation with parameters of overnight polysomnography and complete blood count were investigated. As a result, children with tonsillar hypertrophy had significantly higher α-diversity indices (P＜0.05). β-diversity based on Bray–Curtis distance revealed that the salivary microbiome of the tonsillar hypertrophy group had a slight separation from the other three groups (P＜0.05). The linear discriminant analysis effect size (LEfSe) analysis indicated that Gemella was most closely related to tonsillar hypertrophy, and higher abundance of Gemella, Parvimonas, Dialister, and Lactobacillus may reflect an active state of immune regulation. Meanwhile, children with different degrees of tonsillar hypertrophy shared similar salivary microbiome diversity. This study demonstrated that the salivary microbiome in pediatric tonsillar hypertrophy patients had different signatures, highlighting that the site of upper airway obstruction primarily influences the salivary microbiome rather than hypertrophy severity.IMPORTANCETonsillar hypertrophy is the most frequent cause of upper airway obstruction and one of the primary risk factors for pediatric obstructive sleep apnea (OSA). Studies have discovered that children with isolated tonsillar hypertrophy exhibit different craniofacial morphology features compared with those with isolated adenoid hypertrophy or adenotonsillar hypertrophy. Furthermore, characteristic salivary microbiota from children with OSA compared with healthy children has been identified in our previous research. However, few studies provided insight into the relationship between the different sites of upper airway obstruction resulting from the enlargement of pharyngeal lymphoid tissue at different sites and the alterations in the microbiome. Here, to investigate the differences in the salivary microbiome of children with tonsillar hypertrophy and/or adenoid hypertrophy, we conducted a cross-sectional study and depicted the unique microbiome profile of pediatric tonsillar hypertrophy, which was mainly characterized by a significantly higher abundance of genera belonging to phyla Firmicutes and certain bacteria involving in the immune response in tonsillar hypertrophy, offering novel perspectives for future related research.

In Holstein cows, β-casein, one of the most critical proteins in milk, exists in two main genotypes, A1 and A2. Herein, 45 Holstein cows [categorized into three groups based on β-casein A1A1, A1A2, and A2A2 genotypes (N = 15)] with the same feeding management and litter size were enrolled to explore differences in rumen microflora and metabolites across various β-casein genotypes. Rumen fluids were collected for metagenomics and metabolomics analyses. Metabolomics and weighted gene co-expression network analysis (WGCNA) revealed that arachidonic acid (AA), adrenic acid (AdA), glycocholic acid (GCA), and taurocholic acid (TCA) were significantly and positively correlated with milk fat % in dairy cows (p

Strong evidence indicates that environmental stressors are the risk factors for male testosterone deficiency (TD). However, the mechanisms of environmental stress-induced TD remain unclear. Based on our all-cause male reproductive cohort, we found that serum ferrous iron (Fe2⁺) levels were elevated in TD donors. Then, we explored the role and mechanism of ferroptosis in environmental stress-reduced testosterone levels through in vivo and in vitro models. Data demonstrated that ferroptosis and lipid droplet deposition were observed in environmental stress-exposed testicular Leydig cells. Pretreatment with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, markedly mitigated environmental stress-reduced testosterone levels. Through screening of core genes involved in lipid droplets formation, it was found that environmental stress significantly increased the levels of perilipins 4 (PLIN4) protein and mRNA in testicular Leydig cells. Further experiments showed that Plin4 siRNA reversed environmental stress-induced lipid droplet deposition and ferroptosis in Leydig cells. Additionally, environmental stress increased the levels of METTL3, METTL14, and total RNA m6A in testicular Leydig cells. Mechanistically, S-adenosylhomocysteine, an inhibitor of METTL3 and METTL14 heterodimer activity, restored the abnormal levels of Plin4, Fe2⁺ and testosterone in environmental stress-treated Leydig cells. Collectively, these results suggest that Plin4 exacerbates environmental stress-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

Diminished testosterone levels have been documented as a key factor in numerous male health disorders. Both human and animal studies have consistently demonstrated that cadmium (Cd), a pervasive environmental heavy metal, results in decreased testosterone levels. However, the exact mechanism through which Cd interferes with testosterone synthesis remains incompletely elucidated. This research sought to examine the impact of cellular senescence on Cd-suppressed testosterone synthesis. We also investigated the related m6A modification mechanism. The results demonstrated that Cd (100 mg/L) led to a decrease in testosterone levels, along with downregulated expression of testosterone synthase in C57BL/6 N male mice. Furthermore, Cd significantly increased β-galactosidase staining intensity, senescence-related proteins, and senescence-related secretory phenotypes in mouse testicular Leydig cells. Subsequent investigations revealed that Cd decreased the mRNA and protein levels of NAD-dependent deacetylase Sirtuin-1 (SIRT1) in Leydig cells. Mechanistically, mice treated with resveratrol (50 mg/kg), a specific SIRT1 activator, mitigated Leydig cell senescence and reversed Cd-reduced testosterone levels in mouse testes. These effects were also restored by SIRT1 overexpression in Leydig cells. Additionally, we found that Cd increased the level of methyltransferase enzyme METTL3 and Sirt1 m6A modification in Leydig cells. Mettl3 siRNA effectively restored Cd-enhanced Sirt1 m6A level and reversed Cd-downregulated Sirt1 mRNA expression in Leydig cells. Overall, our findings suggest that Cd exposure inhibits testosterone synthesis via Sirt1 m6A modification-mediated senescence in mouse testes. These results offer an experimental basis for investigating the causes and potential treatments of hypotestosteronemia induced by environmental factors.

Pomelo flowers emit a strong fragrance and give aromatic odors. Volatile compounds from pomelo flowers were analyzed at three developmental stages and in the main organs by molecular sensory science. A total of 134 volatiles including 25 odorants, were analyzed by gas chromatography–mass spectrometry/pulsed flame photometric detector (GC–MS/PFPD) and multidimensional GC–MS/olfactory (MDGC–MS/O). The total volatile content varied among pomelo flowers at different developmental stages (stage-III > stage-II > stage-I) and among different organs of pomelo flowers (petal > pistil > stamen). Linalool was an important odorant with a high OAV, and floral/fruity comprised the predominant aroma profile. Four odorants, ethyl 2-methylbutanoate, linalool, β-myrcene, and 2-butenal, were selected based on variable importance in projection (VIP) values and contributed mainly to the discrimination of pomelo flowers at three different developmental stages. Linalool, β-myrcene, d-limonene, and ethyl hexanoate were potential markers for evaluating flavor differences in pomelo floral organs.

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p

Dyslipidemia is one of the cardiometabolic risk factors that influences mortality globally. Unraveling the causality between blood lipids and metabolites and the complex networks connecting lipids, metabolites, and other cardiometabolic traits can help to more accurately reflect the body’s metabolic disorders and even cardiometabolic diseases. We conducted targeted metabolomics of 248 metabolites in 437 twins from the Chinese National Twin Registry. Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) analysis was used for causal inference between metabolites and lipid parameters. Bidirectional mediation analysis was performed to explore the linkages between blood lipids, metabolites, and other seven cardiometabolic traits. We identified 44, 1, and 31 metabolites associated with triglyceride (TG), total cholesterol (TC), and high-density lipoprotein-cholesterol (HDL-C), most of which were gut microbiota-derived metabolites. There were 9, 1, and 14 metabolites that showed novel associations with TG, TC, and HDL-C, respectively. ICE FALCON analysis found that TG and HDL-C may have a predicted causal effect on 23 and six metabolites, respectively, and one metabolite may have a predicted causal effect on TG. Mediation analysis discovered 14 linkages connecting blood lipids, metabolites, and other cardiometabolic traits. Our study highlights the significance of gut microbiota-derived metabolites in lipid metabolism. Most of the identified cross-sectional associations may be due to the lipids having a predicted causal effect on metabolites, but not vice versa, nor are they due to family confounding. These findings shed new light on lipid metabolism and personalized management of cardiometabolic diseases.

Abstract Mechanotherapy has emerged as a promising treatment for tissue injury. However, existing robots for mechanotherapy are often designed on intuition, lack remote and wireless control, and have limited motion modes. Herein, through topology optimization and hybrid fabrication, wireless magneto‐active soft robots are created that can achieve various modes of programmatic deformations under remote magnetic actuation and apply mechanical forces to tissues in a precise and predictable manner. These soft robots can quickly and wirelessly deform under magnetic actuation and are able to deliver compressing, stretching, shearing, and multimodal forces to the surrounding tissues. The design framework considers the hierarchical tissue‐robot interaction and, therefore, can design customized soft robots for different types of tissues with varied mechanical properties. It is shown that these customized robots with different programmable motions can induce precise deformations of porcine muscle, liver, and heart tissues with excellent durability. The soft robots, the underlying design principles, and the fabrication approach provide a new avenue for developing next‐generation mechanotherapy.

Summary: Pancreatic cancer is associated with an oncogenic KRAS mutation in approximately 90% of cases. However, a non-negligible proportion of pancreatic cancer cases harbor wild-type KRAS (KRAS-WT). This study establishes genetically engineered mouse models that develop spontaneous pancreatic cancer in the context of KRAS-WT. The Trp53loxP/loxP;Smad4loxP/loxP;Pdx1-Cre (PPSSC) mouse model harbors KRAS-WT and loss of Trp53/Smad4. The Trp53loxP/loxP;Tgfbr2loxP/loxP;Pdx1-Cre (PPTTC) mouse model harbors KRAS-WT and loss of Trp53/Tgfbr2. We identify that either Trp53/Smad4 loss or Trp53/Tgfbr2 loss can induce spontaneous pancreatic tumor formation in the absence of an oncogenic KRAS mutation. The Trp53/Smad4 loss and Trp53/Tgfbr2 loss mouse models exhibit distinct pancreatic tumor histological features, as compared to oncogenic KRAS-driven mouse models. Furthermore, KRAS-WT pancreatic tumors with Trp53/Smad4 loss reveal unique histological features of pancreatic adenosquamous carcinoma (PASC). Single-cell RNA sequencing (scRNA-seq) analysis reveals the distinct tumor immune microenvironment landscape of KRAS-WT (PPSSC) pancreatic tumors as compared with that of oncogenic KRAS-driven pancreatic tumors.

This study synthesized biochar adsorbents from chemically activated sugarcane bagasse using ZnCl 2 at pyrolysis temperatures of 400, 500, and 600°C. The modified bagasse biochar was used to remove methylene blue (MB) and acid red (AR) dyes. The surface characteristics of the modified bagasse biochars were analyzed using Scanning Electron Microscope (SEM), Fourier Transform infrared spectroscopy (FTIR), and Brunauer-Emmett-Teller (BET) analysis. Batch adsorption experiments were conducted to assess the impact of various parameters on adsorption performance. Among the different bagasse biochar samples, Zn-BC-600 exhibited superior adsorption capacities for MB and AR with values of 182.225 and 43.324 mg/g, respectively. The adsorption efficiency was significantly influenced by pH, with optimal conditions at pH = 6.0 for MB and pH = 2.0 and 10.0 for AR. The adsorption process for MB and AR on Zn-BCs followed a pseudo-second-order kinetic model, indicating chemisorption as the primary mechanism. Adsorption isotherm studies revealed that Zn-BCs conform to the Freundlich model, proposing a multilayer adsorption due to the heterogeneity of the biochar surface. Regeneration experiments indicated that Zn-BCs could be reused for multiple adsorption cycles. In conclusion, the modified bagasse biochar showed strong adsorption affinity for both MB and AR, particularly for MB, making it a promising adsorbent for treating printing and dyeing wastewater.

This study introduces an alternate spatial-temporal modeling-assisted InSAR time-series analysis method for mine subsidence mapping, aiming to address the large deformation gradients and decorrelation issues. The approach employs the iterative Modeling-Assisted Phase Unwrapping (MA-PU) algorithm for spatial phase unwrapping, and integrates it with temporal models to derive the deformation time-series. Four different inversion procedures are implemented to derive the time-series based on pixel types. The MA-PU method’s effectiveness in handling phase gradients is validated with simulations and real data analysis, showing superiority over non-model-based methods. The incorporation with temporal modeling and time-series inversion demonstrates advantages over time-series inversion alone in dealing with rank-deficiency issues within subsidence zones. The approach is applied to the West Cliff Colliery, Australia, using 23 ALOS-1 data. Results have been compared with GNSS data for validation. Obtained accuracy is approximately 16 mm, with a correlation of 0.99 between the two measurements, showing generally better performances compared to other methods. The comparison result suggest that this approach provides a more robust solution for monitoring mine subsidence in complex scenarios.

High-performance wide-bandgap (WBG) perovskite solar cells are used as top cells in perovskite/silicon or perovskite/perovskite tandem solar cells, which possess the potential to overcome the Shockley-Queisser limitation of single-junction perovskite solar cells (PSCs). However, WBG perovskites still suffer from severe nonradiative recombination and large open-circuit voltage (Voc) losses, which restrict the improvement of PSC performance. Herein, we introduce 3,3′-diethyl-oxacarbo-cyanine iodide (DiOC2(3)) and multifunctional groups (C=N, C=C, C-O-C, C-N) into perovskite precursor solutions to simultaneously passivate deep level defects and reduce recombination centers. The multifunctional groups in DiOC2(3) coordinate with free Pb2+ at symmetric sites, passivating Pb vacancy defects, effectively suppressing nonradiative recombination, and maintaining considerable stability. The results reveal that the power conversion efficiency (PCE) of the 1.68 eV WBG perovskite solar cell with an inverted structure increases from 18.51% to 21.50%, and the Voc loss is only 0.487 V. The unpackaged device maintains 95% of its initial PCE after 500 h, in an N2 environment at 25°C.

Lung cancer, one of the most prevalent cancers worldwide, stands as the primary cause of cancer-related deaths. As is well-known, the utmost crucial risk factor contributing to lung cancer is smoking. In recent years, remarkable progress has been made in treating lung cancer, particularly non-small cell lung cancer (NSCLC). Nevertheless, the absence of effective and accurate biomarkers for diagnosing and treating lung cancer remains a pressing issue. Interleukin 22 (IL-22) is a member of the IL-10 cytokine family. It exerts biological functions (including induction of proliferation and anti-apoptotic signaling pathways, enhancement of tissue regeneration and immunity defense) by binding to heterodimeric receptors containing type 1 receptor chain (R1) and type 2 receptor chain (R2). IL-22 has been identified as a pro-cancer factor since dysregulation of the IL-22-IL-22R system has been implicated in the development of different cancers, including lung, breast, gastric, pancreatic, and colon cancers. In this review, we discuss the differential expression, regulatory role, and potential clinical significance of IL-22 in lung cancer, while shedding light on innovative approaches for the future.

In this study, a systematic analysis was conducted to investigate the efficiency and mechanism of methylene blue (MB) removal from water using blue coke-based activated carbon (AC) as an adsorbent. The investigation encompassed several critical parameters, including adsorbent dosage, contact time, pH, temperature, initial MB concentration, and the regeneration capacity of the adsorbent. The adsorption mechanism of MB by AC was elucidated through instrumental analysis and theoretical models such as adsorption kinetics, isotherm models, and thermodynamic analysis. The experimental results demonstrated several key findings: the removal efficiency of MB increased with the adsorbent dosage, although the unit adsorption capacity decreased; the removal rate of MB rose rapidly with increasing contact time and reached equilibrium after 90 min; the highest removal efficiency was achieved at pH 6; the adsorption capacity increased with higher initial MB concentrations. The adsorption kinetics conformed to the pseudo-second-order model, indicating that chemical adsorption was the predominant control step. The adsorption process was identified as a spontaneous reaction, with the Langmuir model suggesting a maximum adsorption capacity of 2040.696 mg/g at 318 K. Furthermore, AC exhibited an abundant mesoporous structure and surface functional groups, contributing to the efficient removal of MB. The adsorption mechanism involved pore-filling, hydrogen bonding, π-π interactions, and electrostatic attraction. Additionally, AC demonstrated excellent regeneration performance. These findings suggest that AC prepared from blue coke holds significant potential for industrial applications in MB removal, owing to its high removal efficiency, low cost, and good regenerative properties, making it highly valuable for practical use.

Accumulative roll bonding (ARB) is an effective approach to improve the strength of metal sheets. This work studied the evolution of microstructure and texture and their influence on the strength of an ARBed Al-Sc-Zr-Er-Ti alloy, produced by multi-microalloying Sc, Zr, Er, and Ti into pure Al. A high-quality interface and a fine microstructure with an average grain size of ∼0.6 μm were achieved as by the ARB process. The Dillamore {4411} and the Copper {112} components were sharpened in final texture as is common in ARB. However, after the 5th cycle, there was a new texture component along the α-fiber, at (φ1, Φ, φ2) ≡ (60°, 45°, 0°) in Euler space. The yield strength (YS) and tensile strength (UTS) increased with increasing the number of ARB cycles. The 7th ARBed Al-Sc-Zr-Er-Ti alloy had increased YS by 45% and UTS by 57%, respectively, compared to the initial cold rolled sheet. Strengthening was mainly attributed to dislocation strengthening, grain refinement strengthening and precipitation strengthening. There was little texture strengthening because of a strengthening and softening alternation with the change of ARB cycle.

Abstract Background Alzheimer’s Disease (AD) is a progressive memory disorder that causes irreversible cognitive decline. Given that there is currently no cure, it is critical to detect AD in its early stage during the disease progression. Recently, many statistical learning methods have been presented to identify cognitive decline with temporal data, but few of these methods integrate heterogeneous phenotype and genetic information together to improve the accuracy of prediction. In addition, many of these models are often unable to handle incomplete temporal data; this often manifests itself in the removal of records to ensure consistency in the number of records across participants. Results To address these issues, in this work we propose a novel approach to integrate the genetic data and the longitudinal phenotype data to learn a fixed-length “enriched” biomarker representation derived from the temporal heterogeneous neuroimaging records. Armed with this enriched representation, as a fixed-length vector per participant, conventional machine learning models can be used to predict clinical outcomes associated with AD. Conclusion The proposed method shows improved prediction performance when applied to data derived from Alzheimer’s Disease Neruoimaging Initiative cohort. In addition, our approach can be easily interpreted to allow for the identification and validation of biomarkers associated with cognitive decline.

Abstract Background Myocardial ischemia-reperfusion injury (MIRI) is caused by reperfusion after ischemic heart disease. LncRNA Snhg1 regulates the progression of various diseases. N6-methyladenosine (m6A) is the frequent RNA modification and plays a critical role in MIRI. However, it is unclear whether lncRNA Snhg1 regulates MIRI progression and whether the lncRNA Snhg1 was modified by m6A methylation. Methods Mouse cardiomyocytes HL-1 cells were utilized to construct the hypoxia/reoxygenation (H/R) injury model. HL-1 cell viability was evaluated utilizing CCK-8 method. Cell apoptosis, mitochondrial reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were quantitated utilizing flow cytometry. RNA immunoprecipitation and dual-luciferase reporter assays were applied to measure the m6A methylation and the interactions between lncRNA Snhg1 and targeted miRNA or target miRNAs and its target gene. The I/R mouse model was constructed with adenovirus expressing lncRNA Snhg1. HE and TUNEL staining were used to evaluate myocardial tissue damage and apoptosis. Results LncRNA Snhg1 was down-regulated after H/R injury, and overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization. Besides, lncRNA Snhg1 could target miR-361-5p, and miR-361-5p targeted OPA1. Overexpressed lncRNA Snhg1 suppressed H/R-stimulated cell apoptosis, mitochondrial ROS level and polarization though the miR-361-5p/OPA1 axis. Furthermore, WTAP induced lncRNA Snhg1 m6A modification in H/R-stimulated HL-1 cells. Moreover, enforced lncRNA Snhg1 repressed I/R-stimulated myocardial tissue damage and apoptosis and regulated the miR-361-5p and OPA1 levels. Conclusion WTAP-mediated m6A modification of lncRNA Snhg1 regulated MIRI progression through modulating myocardial apoptosis, mitochondrial ROS production, and mitochondrial polarization via miR-361-5p/OPA1 axis, providing the evidence for lncRNA as the prospective target for alleviating MIRI progression.

Abstract Oligonucleotide synthesis is vital for molecular experiments. Bioinformatics has been employed to create various algorithmic tools for the in vitro synthesis of nucleotides. The main approach to synthesizing long-chain DNA molecules involves linking short-chain oligonucleotides through ligase chain reaction (LCR) and polymerase chain reaction (PCR). Short-chain DNA molecules have low mutation rates, while LCR requires complementary interfaces at both ends of the two nucleic acid molecules or may alter the conformation of the nucleotide chain, leading to termination of amplification. Therefore, molecular melting temperature, length, and specificity must be considered during experimental design. POSoligo is a specialized offline tool for nucleotide fragment synthesis. It optimizes the oligonucleotide length and specificity based on input single-stranded DNA, producing multiple contiguous long strands (COS) and short patch strands (POS) with complementary ends. This process ensures free 5′- and 3′-ends during oligonucleotide synthesis, preventing secondary structure formation and ensuring specific binding between COS and POS without relying on stabilizing the complementary strands based on Tm values. POSoligo was used to synthesize the linear RBD sequence of SARS-CoV-2 using only one DNA strand, several POSs for LCR ligation, and two pairs of primers for PCR amplification in a time- and cost-effective manner.