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Abstract Unleashing the land sector’s potential for climate mitigation requires purpose-driven changes in land management. However, contributions of past management changes to the current global and regional carbon cycles remain unclear. Here, we use vegetation modelling to reveal how a portfolio of ecological restoration policies has impacted China’s terrestrial carbon balance through developing counterfactual ‘no-policy’ scenarios. Pursuing conventional policies and assuming no changes in climate or atmospheric carbon dioxide (CO2) since 1980 would have led China’s land sector to be a carbon source of 0.11 Pg C yr−1 for 2001–2020, in stark contrast to a sink of 175.9 Tg C yr−1 in reality. About 72.7% of this difference can be attributed to land management changes, including afforestation and reforestation (49.0%), reduced wood extraction (21.8%), fire prevention and suppression (1.6%) and grassland grazing exclusion (0.3%). The remaining 27.3% come from changes in atmospheric CO2 (42.2%) and climate (−14.9%). Our results underscore the potential of active land management in achieving ‘carbon-neutrality’ in China.

Abstract The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

Abstract G-protein coupled receptors (GPCRs), the largest family of membrane proteins in human body, involve a great variety of biological processes and thus have become highly valuable drug targets. By binding with ligands (e.g., drugs), GPCRs switch between active and inactive conformational states, thereby performing functions such as signal transmission. The changes in binding pockets under different states are important for a better understanding of drug-target interactions. Therefore it is critical, as well as a practical need, to obtain binding sites in human GPCR structures. We report a database (called GPCR-BSD) that collects 127,990 predicted binding sites of 803 GPCRs under active and inactive states (thus 1,606 structures in total). The binding sites were identified from the predicted GPCR structures by executing three geometric-based pocket prediction methods, fpocket, CavityPlus and GHECOM. The server provides query, visualization, and comparison of the predicted binding sites for both GPCR predicted and experimentally determined structures recorded in PDB. We evaluated the identified pockets of 132 experimentally determined human GPCR structures in terms of pocket residue coverage, pocket center distance and redocking accuracy. The evaluation showed that fpocket and CavityPlus methods performed better and successfully predicted orthosteric binding sites in over 60% of the 132 experimentally determined structures. The GPCR Binding Site database is freely accessible at https://gpcrbs.bigdata.jcmsc.cn . This study not only provides a systematic evaluation of the commonly-used fpocket and CavityPlus methods for the first time but also meets the need for binding site information in GPCR studies.

Multi-component alloys have been confirmed to be excellent reinforcing phases in high-entropy alloy-based composite. However, achieving a balance between strength and ductility by controlling the reinforcement content remains a major challenge in the design of high-entropy alloy-based composites. In this study, CoCrFeMnNi HEA/NiCoFeAlTi HER high-entropy alloy composites were prepared using SLM technology. Interestingly, gas-atomized NiCoFeAlTi high-entropy intermetallic (HER) powder was selected as the reinforcing phase, and the CoCrFeMnNi HEA matrix was used for comparison. The influence of the reinforcement content on the composite was investigated, and high-performance HEA/HER composites were obtained, with the strengthening mechanism elucidated. The results showed that the composite with 1 wt% HER reinforcement exhibited the optimal performance, with hardness, yield strength, ultimate tensile strength, and ductility at room temperature being approximately 226.9 HV, 562 MPa, 683 MPa, and 16%, respectively. The excellent mechanical properties at both room and elevated temperatures are attributed to the synergistic effects of heterogeneous microstructure strengthening, grain refinement, and precipitation strengthening. This work provides a foundation for the development of high-entropy alloy composites reinforced by high-entropy intermetallics.

Abstract High-throughput screening techniques are pivotal to unlocking the mysteries of biology. Yet, the promise of droplet microfluidics in enabling single-cell resolution, ultra-high-throughput screening remains largely unfulfilled. Droplet sorting errors caused by polydisperse droplet sizes that are often inevitable in multi-step assays have severely limited the effectiveness and utility of this technique, especially when screening large libraries. Even a relatively low 1% sorting error results in 10,000 false calls in a 1,000,000 droplet screen, imposing an unreasonably large burden on downstream validation. Here, we present NOVAsort (Next-generation Opto-Volume-based Accurate droplet sorter), a device capable of discerning droplets based on both size and fluorescence intensity. With a 1000- and 10,000-fold reduction in false positives and false negatives, respectively. NOVAsort addresses the challenges of conventional droplet sorting approaches and sets standards for accuracy and throughput in droplet microfluidic assays.

Background: Cataracts are a common eye disease and a major cause of blindness in China and worldwide. In China, the incidence of cataracts among people over 60 years old is as high as 80%. Surgery is the primary treatment for various types of cataracts, but such invasive procedures can affect corneal endothelial cells to some extent. Content: Cataract surgery can damage corneal endothelial cells, leading to complications such as corneal edema in mild cases. Severe damage can result in endothelial decompensation, necessitating secondary corneal endothelial transplantation. Preoperative thorough assessment of endothelial status, intraoperative endothelial protection measures, and postoperative active use of medications to prevent further damage to endothelial cells can reduce endothelial cell loss. Factors influencing endothelial cell status include whether the patient has related systemic diseases or ocular conditions, the hardness of the nucleus, the choice of surgical incision, the method of nuclear fragmentation, the type of viscoelastic agent used, the orientation of the phacoemulsification needle bevel, the duration and energy of ultrasound use, the choice of fluid control system, the use of protective auxiliary instruments, the application of intraocular lens scaffold technology, femtosecond laser assistance, and the use of certain medications. Conclusions: Actively regulating the factors affecting corneal endothelial cells to reduce damage related to cataract surgery is crucial. This paper reviews the existing literature on various factors affecting corneal endothelial cells during cataract surgery and explores future developments and research directions.

Abstract Background Gram-negative bacteria are the main bacterial pathogens infecting Chinese giant salamanders (Andrias davidianus; CGS) in captivity and the wild, causing substantial economic losses in the CGS industry. However, the molecular mechanisms underlying pathogenesis following infection remain unclear. Results Spleen-derived macrophages from healthy CGS were isolated, cultured, and identified using density gradient centrifugation and immunofluorescence. A macrophage transcriptome database was established 0, 6, and 12 h post lipopolysaccharide stimulation using RNA-sequencing. In the final database 76,743 unigenes and 4,698 differentially expressed genes (DEGs) were functionally annotated. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment results showed that DEGs were concentrated in toll-like receptor–nuclear factor kappa B-related immune pathways. Ten DEGs were validated 12 h after lipopolysaccharide (LPS) stimulation. Although the common LPS recognition receptor toll-like receptor 4 was not activated and the key adaptor protein MyD88 showed no significant response, we observed significant up-regulation of the following adaptors: toll/interleukin-1 receptor domain-containing adaptor inducing interferon-β, tumour necrosis factor receptor-associated factor 6, and transforming growth factor-β activated kinase 1, which are located downstream of the non-classical MyD88 pathway. Conclusions In contrast to that in other species, macrophage activation in CGS could depend on the non-classical MyD88 pathway in response to bacterial infection. Our study provides insights into the molecular mechanisms regulating CGS antibacterial responses, with implications for disease prevention and understanding immune evolution in amphibians.

Abstract Background Several tetraspanin (TSPAN) proteins have been implicated in tumorigenesis and disease progression. However, the precise function of tetraspanin 6 (TSPAN6) in glioma remains unclear. Methods Integrated raw data from the Tumor Genome Atlas (TCGA) and Gene Expression Profiling (GEO) databases were processed using R4.2.1. Bioinformatic methods were used to analyze the gene expression levels of TSPAN6 in both glioma and normal brain tissues, correlating them with clinical characteristics. Additionally, the predictive value of TSPAN6 in relation to the immune checkpoint blockade (ICB) therapy response was assessed. In vitro experiments were conducted to investigate the effects of TSPAN6 knockdown on glioma cell proliferation, migration, cell cycle regulation, and macrophage recruitment. Results TSPAN6 expression was significantly upregulated in glioma tissues compared to normal tissues. Elevated TSPAN6 expression is strongly correlated with unfavorable clinical characteristics in gliomas. Bioinformatic analyses revealed a significant correlation between elevated TSPAN6 expression and reduced overall survival. Additionally, TSPAN6 was co-expressed with several immune checkpoint genes and revealed a prognostic value in the context of ICB therapy. Functional enrichment analysis revealed the involvement of TSPAN6 in cell-cycle regulation. Furthermore, TSPAN6 expression positively correlated with macrophage and neutrophil infiltration. In vitro experiments confirmed that the downregulation of TSPAN6 inhibited U251 cell proliferation, disrupted the cell cycle, diminished migratory capabilities, and reduced the recruitment of macrophages. Conclusion Our findings emphasize its potential as both a diagnostic and therapeutic target as well as a predictor of immune therapy response in gliomas.

Abstract Background Coronary artery bypass grafting (CABG) is often performed with hypothermic cardiopulmonary bypass (CPB) to reduce metabolic demands and protect the myocardium. However, hypothermia can increase bleeding risks and other complications. Methods This is a prospective, multi-center, randomized controlled trial. From September 2023 to December 2024, a total of 336 eligible patients planning to undergo on-pump CABG will be enrolled. All participants will be randomly divided into mild hypothermia CPB group (target oxygenator arterial outlet blood temperature at 32–33℃) or normothermia CPB group (target oxygenator arterial outlet blood temperature at 35–36℃). The primary endpoint is Universal Definition of Perioperative Bleeding (UDPB) class 2–4. Secondary endpoints are class of UDPB, levels of coagulation and inflammatory factors, in-hospital mortality, perioperative related complications, ICU length of stay, and hospital length of stay. Discussion This clinical trial aims to compare the effects of different target temperature during CPB on postoperative bleeding and to explore optimal temperature strategy to provide new clinical evidence. Trial registration Chictr.org.cn : ChiCTR2300075405. The trial was prospectively registered on 4 September 2023.

Abstract Defective renal excretion and increased production of uric acid engender hyperuricemia that predisposes to gout. However, molecular mechanisms underlying defective uric acid excretion remain largely unknown. Here, we report a rare genetic variant of gout-unprecedented NUMB gene within a hereditary human gout family, which was identified by an unbiased genome-wide sequencing approach. This dysfunctional missense variant within the conserved region of the NUMB gene (NUMBR630H) underwent intracellular redistribution and degradation through an autophagy-dependent mechanism. Mechanistically, we identified the uric acid transporter, ATP Binding Cassette Subfamily G Member 2 (ABCG2), as a novel NUMB-binding protein through its intracellular YxNxxF motif. In polarized renal tubular epithelial cells (RTECs), NUMB promoted ABCG2 trafficking towards the apical plasma membrane. Genetic loss-of-function of NUMB resulted in redistribution of ABCG2 in the basolateral domain and ultimately defective excretion of uric acid. To recapitulate the clinical situation in human gout patients, we generated a NUMBR630H knock-in mouse strain, which showed marked increases of serum urate and decreased uric acid excretion. The NUMBR630H knock-in mice exhibited clinically relevant hyperuricemia. In summary, we have uncovered a novel NUMB-mediated mechanism of uric acid excretion and a functional missense variant of NUMB in humans, which causes hyperuricemia and gout.

Abstract Background Human Papillomavirus (HPV) DNA screening was a crucial element in the fight against cervical cancer and had been adopted in many countries, including China. However, the onset of the COVID-19 pandemic in March 2020 disrupted this program significantly. Methods The aim of this study is to investigate the prevalence and distribution of HPV genotypes among the population undergoing cervical cancer screening during the pandemic period. From January 2017 to December 2022, Peking Union Medical College Hospital gathered 45,496 cervical swabs from individuals undergoing cervical cancer screening. These samples were analyzed to detect fifteen high-risk HPV (HR-HPV) DNA types and a combination of two low-risk HPV (LR-HPV) types. Results The study revealed an overall infection rate of 11.24% (5,114/45,496), with 11.06% (5,032/45,496) of individuals infected with HR-HPV. The number of HPV screening patients and the infection rates of HPV, HR-HPV, LR-HPV, multiple genotype HPV (M-HPV), and single genotype HPV (S-HPV) during the pandemic were lower than those observed before the pandemic. Moreover, the age group with the highest percentage of infected individuals was under 45–49 years, with HPV52, HPV58, HPV16, and HPV51 being the most prevalent genotypes. Notably, HPV66 emerged as the fifth most commonly detected genotype during the pandemic. Additionally, among the eleven age groups examined, women under 25 exhibited the highest detection rate, with HPV52 and HPV16 infection rates exceeding those observed in the pre-pandemic period. Conclusions The findings of this study offer significant insights for shaping HPV prevention strategies and enhancing cervical cancer screening initiatives in China following the epidemic.

Abstract Background Working memory (WM), a core component of executive functions, relies on a dedicated brain system that maintains and stores information in the short term. While extensive neuroimaging research has identified a distributed set of neural substrates relevant to WM, their underlying molecular mechanisms remain enigmatic. This study investigated the neural correlates of WM as well as their underlying molecular mechanisms. Results Our voxel-wise analyses of resting-state functional MRI data from 502 healthy young adults showed that better WM performance (higher accuracy and shorter reaction time of the 3-back task) was associated with lower functional connectivity density (FCD) in the left inferior temporal gyrus and higher FCD in the left anterior cingulate cortex. A combination of transcriptome-neuroimaging spatial correlation and the ensemble-based gene category enrichment analysis revealed that the identified neural correlates of WM were associated with expression of diverse gene categories involving important cortical components and their biological processes as well as sodium channels. Cross-region spatial correlation analyses demonstrated significant associations between the neural correlates of WM and a range of neurotransmitters including dopamine, glutamate, serotonin, and acetylcholine. Conclusions These findings may help to shed light on the molecular mechanisms underlying the neural correlates of WM.

Radioactive nuclides such as 129I are produced during the operation of nuclear facilities. 129I is volatile and can induce radiation sickness. Capture of radioactive iodine can protect public health and facilitate the sustainable development of the nuclear industry. Preliminary studies on the synthesis and iodine adsorption properties of thorium based MOFs have shown that thorium-based MOFs usually have different structures and iodine adsorption performance when they contain different ligands. Quinoline derivatives containing both hydroxyl and carboxyl groups are a class of rigid ligands with strong coordination ability. Although these ligands have been used to synthesize transition metal complexes, their application in the preparation of thorium MOFs remains unexplored. To further investigate the effect of ligands on the structure and iodine adsorption performance of thorium-based MOFs, in this paper thorium-quinoline MOF (Th-HQCA) was synthesized using 2-hydroxyquinoline-4-carboxylic acid (HQCA) as the ligand via solvothermal method, and its structure, composition, thermal stability, spectral properties, and iodine adsorption performance were investigated through various characterization techniques, including single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), scanning electron microscope-energy dispersive X-ray spectroscopy (SEM-EDS), Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible (UV-Vis) spectroscopy, thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and fluorescence spectroscopy. Crystallographic analysis reveals that the coordination modes of thorium ions in the structure of Th-HQCA are the same, and each ion is coordinated with four carboxylate oxygen atoms from four HQCA and four hydroxyl oxygen atoms from another four HQCA. It is worth mentioning that thorium ions usually coordinate with carboxylate oxygen atoms in ligands, and rarely coordinate with hydroxyl group. The connections between thorium ions and HQCA ligands result in the formation of a novel 2,8-connected framework structure of Th-HQCA. The channels of the framework are filled with water molecules. Based on the crystallographic analysis, the ratio of thorium ions, HQCA, and water molecules is determined to be 1∶4∶1. However, further thermogravimetric analyses indicate that there may be twelve cocrystallized water molecules in the compound. Consequently, the chemical formula for Th-HQCA can be expressed as [Th(C9H5NOCOO)4]·12H2O. The solid-state fluorescence spectrum shows that Th-HQCA crystals emit blue light when they are excited by ultraviolet light. The adsorption experiments of Th-HQCA on gaseous iodine and iodine in cyclohexane solution show that their adsorption kinetic curves fit the pseudo-second-order kinetic equation, and the adsorption isotherm of the latter fits the Langmuir model. Through further calculations, the maximum adsorption capacity of Th-HQCA for iodine vapor is 535 mg/g, and the maximum adsorption capacity for iodine in cyclohexane solution is 295.63 mg/g. In summary, Th-HQCA is a thorium-quinoline MOF with a novel 2,8-connected topological structure, and it shows remarkable fluorescence properties and can effectively capture iodine in the gas phase and solution.

Abstract Background In small cell lung cancer (SCLC), the pathological N category is identical to it in non-small cell lung cancer (NSCLC) and remains unchanged over a decade. Here we verified the discriminability of number of involved nodal stations (nS) in SCLC and compared its efficacy in predicting survival with currently used pathological nodal (pN) staging. Methods We retrospectively analyzed the patients who received operations and were pathologically diagnosed as SCLC at Shanghai Pulmonary Hospital between 2009 and 2019. X-tile software was adopted to determine optimal cut-off values for nS groups. Kaplan–Meier method and Cox regression analysis were used to compare survival between different groups. Decision curve analysis (DCA) was employed to evaluate the standardized net benefit. Results A total of 369 patients were included. The median number of sampled stations was 6 (range 3–11), and the median number of positive stations was 1 (range 0–7). The optimal cutoff for nS groups was: nS0 (no station involved), nS1-2 (one or two stations involved), and nS ≥ 3 (three or more stations involved). Overall survival (OS) and relapse-free survival (RFS) were statistically different among all adjacent categories within the nS classification (p

Abstract Diabetic nephropathy affects a significant proportion of individuals with diabetes, and its progression often leads to cardiovascular disease and infections before the need for renal replacement therapy arises. Empagliflozin has been shown to have various protective effects in cardiovascular disease studies, such as improving diabetic myocardial structure and function, and reducing myocardial oxidative stress. However, the impact of empagliflozin on cardiac protein expression and signaling pathways has not been comprehensively analyzed. To address this gap, we conducted proteome analysis to identify specific protein markers in cardiac tissue from the diabetes model group, including Myh7, Wdr37, Eif3k, Acot1, Acot2, Cat, and Scp2, in cardiac tissue from the diabetes model group. In our drug model, empagliflozin primarily modulates the fat-related metabolic signaling pathway within the heart. Empagliflozin downregulated the protein expression levels of ACOX1, ACADVL and CPT1A in the model group. Overall, our findings demonstrate that empagliflozin provides cardiac protection by targeting metabolic signaling pathways, particularly those related to fat metabolism. Moreover, the identification of cardiac biomarkers in a mouse model of diabetic nephropathy lays the foundation for further exploration of disease biomarkers in cardiac tissue.

Abstract Bitter gourd wilt, a severe vascular disease triggered by the soilborne pathogen Fusarium oxysporum f. sp. momordicae (FOM), markedly constrains bitter gourd yield. In this study, a novel strain BF19 of Brevibacillus brevis was isolated and identified, exhibiting strong antimicrobial activity against FOM through in vivo and in vitro experiments. To comprehensively assess the biocontrol potential of strain BF19, we conducted phenotypic, phylogenetic, and comparative genomics analyses. Phenotypic analysis revealed that BF19 exhibited 53.33% biocontrol efficacy and significantly increased the average plant height, root fresh weight, and dry weight. Whole-genome sequencing and comparative genomic analysis revealed numerous potential genes associated with biocontrol mechanisms in BF19. Importantly, the integration of metabolic cluster prediction with liquid chromatography‒tandem mass spectrometry (LC‒MS/MS) revealed the presence of a macrobrevin antibiotic, a product of polyketide synthases (PKSs), predominantly in BF19 fermentation products. The effectiveness of the Br. brevis strain BF19 and its crude extract against bitter gourd wilt has also been confirmed. This study provides a genetic framework for future investigations on PKSs and establishes a scientific basis for optimizing field applications of microbial biopesticides derived from Br. brevis BF19.

Abstract Electrons and holes, fundamental charge carriers in semiconductors, dominate optical transitions and detection processes. Twisted van der Waals (vdW) heterostructures offer an effective approach to manipulate radiation, separation, and collection processes of electron-hole pairs by creating an atomically sharp interface. Here, we demonstrate that twisted interfaces in vdW layered black phosphorus (BP), an infrared semiconductor with highly anisotropic crystalline structure and properties, can significantly alter both recombination and separation processes of electron-hole pairs. On the one hand, the twisted interface breaks the symmetry of optical transition states resulting in infrared light emission of originally symmetry-forbidden optical states along the zigzag direction. On the other hand, spontaneous electronic polarization/bulk photovoltaic effect is generated at the twisted interface enabling effective separation of electron-hole pairs without external voltage bias. This is supported by first-principles calculations and repeated experiments at various twisted angles from 0 to 90°. Importantly, these phenomena can be observed in twisted heterostructures with thickness beyond two-dimensional. Our results suggest that the engineering of vdW twisted interfaces is an effective strategy for manipulating the optoelectronic properties of materials and constructing functional devices.

Abstract While high-entropy alloy (HEA) catalysts seem to have the potential to break linear scaling relationships (LSRs) due to their structural complexity, the weighted averaging of properties among multiple principal components actually makes it challenging to diverge from the symmetry dependencies imposed by the LSRs. Herein, we develop a ‘surface entropy reduction’ method to induce the exsolution of a component with weak affinity for others, resulting in the formation of few-atom-layer metal (FL-M) on the surface of HEAs. These exsolved FL-M surpass the confines of the original configurational space of conventional HEAs, and collaborate with the HEA substrate, serving as geometrically separated active sites for multiple intermediates in a complex reaction. This FL-M-covered HEA shows an outstanding performance for electrocatalytic reduction of nitrate to ammonia (NH3) with a Faradaic efficiency of 92.7%, an NH3 yield rate of 2.45 mmol h–1 mgcat. –1, and high long-term stability (>200 h). Our work achieves the precise manipulation of atomic arrangement, thereby expanding both the chemical space occupied by known HEA catalysts and their potential application scenarios.

Abstract Background Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors. Methods Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry. Results In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells. Conclusions Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.

Abstract Background Social engagement is closely related to well-being among older adults. However, studies on the changing trajectory and influencing factors (especially time-varying factors) of social engagement are limited. This study aimed to examine the social engagement trajectory of older Chinese adults and explore its time-fixed and time-varying factors, thus providing evidence for the development of strategies to promote a rational implementation for healthy aging. Methods This study included 2,195 participants from a subset of four surveys from the Chinese Longitudinal Healthy Longevity Survey conducted from 2008 to 2018 (with the latest survey completed in 2018), with follow-ups conducted approximately every three years. Growth mixture modeling was used to explore the social engagement trajectory of older adults and the effects of time-varying variables. In addition, multinomial logistic regression was employed to analyze the association between time-fixed variables and latent classes. Results Three distinct trajectories of social engagement among older adults in China were identified: slow declining (n = 204; 9.3%), which meant social engagement score decreased continuously, but social engagement level improved; slow rising (n = 1,039; 47.3%), marked by an increased score of social engagement, but with an depressed engagement level; and middle stabilizing (n = 952; 43.4%), which meant social engagement score and engagement level remained quite stable. A time-fixed analysis indicated that age, marital status, educational level, and annual family income had a significant impact on social engagement (P

Abstract Background Traditional topical drug delivery for treating inflammatory skin diseases suffers from poor skin penetration and long-term side effects. Metal nanoparticles show promising application in topical drug delivery for inflammatory skin diseases. Methods Here, we synthesized a new type of nanoparticles, azelamide monoethanolamine-functionalized gold nanoparticles (Au-MEA NPs), based on citrate-capped gold nanoparticles (Au-CA NPs) via the ligand exchange method. The physical and chemical properties of Au-CA NPs and Au-MEA NPs were characterized. In vivo studies were performed using imiquimod-induced psoriasis and LL37-induced rosacea animal models, respectively. For in vitro studies, a model of cellular inflammation was established using HaCaT cells stimulated with TNF-α. In addition, proteomics, gelatin zymography, and other techniques were used to investigate the possible therapeutic mechanisms of the Au-MEA NPs. Results We found that Au-MEA NPs exhibited better stability and permeation properties compared to conventional Au-CA NPs. Transcutaneously administered Au-MEA NPs exerted potent therapeutic efficacy against both rosacea-like and psoriasiform skin dermatitis in vivo without overt signs of toxicity. Mechanistically, Au-MEA NPs reduced the production of pro-inflammatory mediators in keratinocytes by promoting SOD activity and inhibiting the activity of MMP9. Conclusion Au-MEA NPs have the potential to be a topical nanomedicine for the effective and safe treatment of inflammatory skin diseases.

Abstract To address challenges in screening for chronic kidney disease (CKD), we devised a deep learning-based CKD screening model named UWF-CKDS. It utilizes ultra-wide-field (UWF) fundus images to predict the presence of CKD. We validated the model with data from 23 tertiary hospitals across China. Retinal vessels and retinal microvascular parameters (RMPs) were extracted to enhance model interpretability, which revealed a significant correlation between renal function and RMPs. UWF-CKDS, utilizing UWF images, RMPs, and relevant medical history, can accurately determine CKD status. Importantly, UWF-CKDS exhibited superior performance compared to CTR-CKDS, a model developed using the central region (CTR) cropped from UWF images, underscoring the contribution of the peripheral retina in predicting renal function. The study presents UWF-CKDS as a highly implementable method for large-scale and accurate CKD screening at the population level.

Abstract Objective This study aims to evaluate the real-world effectiveness of applying different levels of Enhanced Recovery After Surgery (ERAS) guidelines to video-assisted thoracic day surgery (VATS). The goal is to determine the optimal degree of ERAS protocols and management requirements to improve postoperative recovery outcomes. Methods It was designed as a single-centre, prospective pragmatic randomized controlled trial (PRCT), including patients who underwent VATS at the Day Surgery Center of West China Hospital, between January 2021 and November 2022. Patients were divided into Group A and Group B through convenience sampling to implement different levels of ERAS management protocols. Data collection included the baseline characteristics (gender, age, marital status, education level, BMI, PONV risk score, ASA classification), surgery-related indicators (type of surgery, pathological results, hospitalization costs, duration of surgery, intraoperative blood loss, intraoperative rehydration volume), postoperative recovery indicators (postoperative chest tube duration time, time to first postoperative ambulation and urination, postoperative complications, follow-up condition), pain-related indicators (pain threshold score, pain score at 6 h postoperatively, bedtime, and predischarge), psychological state indicators (anxiety level), Athens Insomnia Scale (AIS) scores, and social support scores. Propensity score matching (PSM) was utilized and statistical analyses were conducted using R version 4.4.1. Comparisons of categorical variables were performed using the χ² test, while comparisons of continuous variables were conducted using ANOVA or the Kruskal-Wallis rank-sum test. A significance level of α = 0.05 was set for statistical tests. Result A total of 340 patients were included, with 187 in Group A and 153 in Group B. After propensity score matching (PSM), there were 142 patients in Group A and 105 in Group B, with no significant baseline differences. Group A had a significantly higher proportion of chest tube removals within 24 h postoperatively (P

Abstract Background Acupuncture is an effective complementary therapy for nausea and vomiting during pregnancy (NVP). Nevertheless, the utilization of acupuncture for NVP has been minimally explored in current scholarly research, with a paucity of systematic randomized clinical trials (RCTs) in it. We aim to evaluate the effects of acupuncture on NVP after assisted reproductive techniques (ART) and explore the metabolism-related mechanism of the efficacy. Methods This single-blind, randomized, controlled trial will randomize 68 patients with NVP after ART to a traditional acupuncture (tACP) or a sham acupuncture (sACP) group. The tACP group will receive tACP thrice a week for 2 weeks with a day interval between sessions, while the sACP group will undergo the same number of nonpenetrative acupuncture at non-acupoints for the same period. Pregnancy-specific quantification of emesis will be used to evaluate symptom severity. Routine blood and urine tests, liver and kidney function tests, human chorionic gonadotropin, nuchal translucency thickness, and embryonic development measured using ultrasound will be used to evaluate safety during pregnancy. Non-targeted metabolomic analysis will be performed to explore the association between metabolic changes and clinical symptoms. Discussion This study will elucidate the effects and safety of acupuncture in treating NVP in women undergoing ART. The results of this study will contribute to optimizing acupuncture therapies by combining the body and auricular points and exploring the underlying therapeutic mechanism using a metabolomics approach. Trial registration Chinese Clinical Trial Registry, ChiCTR2300075259.

Abstract The aim of this study was to identify key genes and investigate the immunological mechanisms of atopic dermatitis (AD) at the molecular level via bioinformatics analysis. Gene expression profiles (GSE32924, GSE107361, GSE121212, and GSE230200) were obtained for screening common differentially expressed genes (co-DEGs) from the gene expression omnibus database. Functional enrichment analysis, protein–protein interaction network and module construction, and identification of common hub genes were performed. Hub genes were validated using receiver operating characteristic curve analysis based on GSE130588 and GSE16161. NetworkAnalyst was used to detect microRNAs (miRNAs) and transcription factors (TFs) associated with the hub genes. The immune cell infiltration was analyzed using the CIBERSORT algorithm to further analyze the correlation between hub genes and immune cells. A total of 146 co-DEGs were obtained, showing significant enrichment in cytokine–cytokine receptor interaction and JAK-STAT signaling pathway. Seven hub genes were identified by Cytoscape and validated with external datasets. Subsequent prediction of miRNAs and TFs targeting these hub genes revealed their regulatory roles. Analysis of immune cell infiltration and correlation revealed a significant positive correlation between CCL22 expression and the number of dendritic cells activated. The identified hub genes represent potential diagnostic and therapeutic targets in the immunological pathogenesis of AD.

Abstract Seed size, a key determinant of rice yield, is regulated by brassinosteroid (BR); however, the BR pathway in rice has not been fully elucidated. Here, we report the cloning and characterization of the quantitative trait locus Rice Big Grain 1 (qRBG1) from single-segment substitution line Z499. Our data show that qRBG1 Z is an unselected rare promoter variation that reduces qRBG1 expression to increase cell number and size, resulting in larger grains, whereas qRBG1 overexpression causes smaller grains in recipient Nipponbare. We demonstrate that qRBG1 encodes a non-canonical BES1 (Bri1-EMS-Suppressor1)/BZR1(Brassinazole-Resistant1) family member, OsBZR5, that regulates grain size upon phosphorylation by OsGSK2 (GSK3-like Kinase2) and binding to D2 (DWARF2) and OFP1 (Ovate-Family-Protein1) promoters. qRBG1 interacts with OsBZR1 to synergistically repress D2, and to antagonistically mediate OFP1 for grain size. Our results reveal a regulatory network controlling grain size via OsGSK2–qRBG1–OsBZR1–D2–OFP1 module, providing a target for improving rice yield.

Abstract Background The global rise in developmental delays underscores the critical need for a thorough understanding and timely interventions during early childhood. Addressing this issue, the Chinese Baby Connectome Project (CBCP)’s behavior branch is dedicated to examining language acquisition, social-emotional development, and environmental factors affecting Chinese children. The research framework is built around three primary objectives: developing a 0–6 Child Development Assessment Toolkit, implementing an Intelligent Coding System, and investigating environmental influence. Methods Utilizing an accelerated longitudinal design, the CBCP aims to enlist a minimum of 1000 typically developing Chinese children aged 0–6. The data collected in this branch constitutes parental questionnaires, behavioral assessments, and observational experiments to capture their developmental milestones and environmental influences holistically. The parental questionnaires will gauge children’s developmental levels in language and social-emotional domains, alongside parental mental well-being, life events, parenting stress, parenting styles, and family relationships. Behavioral assessments will involve neurofunctional developmental evaluations using tools such as the Griffiths Development Scales and Wechsler Preschool and Primary Scale of Intelligence. Additionally, the assessments will encompass measuring children’s executive functions (e.g., Head-Toe-Knee-Shoulder), social cognitive abilities (e.g., theory of mind), and language development (e.g., Early Chinese Vocabulary Test). A series of behavior observation. experiments will be conducted targeting children of different age groups, focusing primarily on aspects such as behavioral inhibition, compliance, self-control, and social-emotional regulation. To achieve the objectives, established international questionnaires will be adapted to suit local contexts and devise customized metrics for evaluating children’s language and social-emotional development; deep learning algorithms will be developed in the observational experiments to enable automated behavioral analysis; and statistical models will be built to factor in various environmental variables to comprehensively outline developmental trajectories and relationships. Discussion This study’s integration of diverse assessments and AI technology will offer a detailed analysis of early childhood development in China, particularly in the realms of language acquisition and social-emotional skills. The development of a comprehensive assessment toolkit and coding system will enhance our ability to understand and support the development of Chinese children, contributing significantly to the field of early childhood development research. Trial registration This study was registered with clinicaltrials.gov NCT05040542 on September 10, 2021.

Objective: To obtain the optimal enzyme and preparation process for Schisandra chinensis protein peptides and investigate its in vitro antioxidant activity. Methods: Seven proteases were used to hydrolyze Schisandra chinensis protein. Based on the degree of hydrolysis, free radical scavenging activity, polypeptide yield and content of different hydrolysates of Schisandra chinensis protein and the comprehensive evaluation of molecular weight in SDS-PAGE, the optimal protease was screened. The DPPH free radical scavenging rate was used as the index, and the optimal enzymatic hydrolysis process was determined by single factor test combined with response surface analysis. The scavenging ability of O2−·, ·OH, DPPH·, ABTS+·, Fe2+ chelating ability and Fe3+ reducing ability of Schisandrae chinensis protein peptides were analyzed and compared with Schisandra chinensis protein. Results: The optimum enzyme for the preparation of Schisandra chinensis protein peptides was alkaline protease. The optimum enzymatic hydrolysis parameters were as follows: substrate concentration 5%, enzyme-to-substrate ratio 1%, enzymatic hydrolysis time 3 h, enzymatic hydrolysis temperature 55 ℃, pH9.0. Under these conditions, the polypeptide content was 88.61%, the degree of hydrolysis was 24.21%, and the DPPH· scavenging rate was 86.96%. The free radical scavenging ability and reducing ability of Schisandrae chinensis protein peptides were better than those of Schisandrae chinensis protein. Conclusion: This study determined the optimum enzyme and hydrolysis process of Schisandrae chinensis protein peptides, and pointed out that Schisandrae chinensis protein peptides had better antioxidant activity in vitro and could be used as a natural antioxidant.

Abstract Background The ability of lignocellulose degradation for filamentous fungi is always attributed to their efficient CAZymes system with broader applications in bioenergy development. ADP-ribosylation factor GTPase-activating proteins (Arf-GAPs), pivotal in fungal morphogenesis, lack comprehensive studies on their regulatory mechanisms in lignocellulose utilization. Results Here, the orthologs (TgGlo3 and TgGcs1) of Arf-GAPs in S. cerevisiae were characterized in Trichoderma guizhouense NJAU4742. The results indicated that overexpression of Tggcs1 (OE-Tggcs1) enhanced the lignocellulose utilization, whereas increased expression of Tgglo3 (OE-Tgglo3) elicited antithetical responses. On the fourth day of fermentation with rice straw as the sole carbon source, the activities of endoglucanase, cellobiohydrolase, xylanase, and filter paper of the wild-type strain (WT) reached 8.20 U mL−1, 4.42 U mL−1, 14.10 U mL−1, and 3.56 U mL−1, respectively. Compared to WT, the four enzymes activities of OE-Tggcs1 increased by 7.93%, 6.11%, 9.08%, and 12.92%, respectively, while those decreased to varying degrees of OE-Tgglo3. During the nutritional growth, OE-Tgglo3 resulted in the hyphal morphology characterized by sparsity and constriction, while OE-Tggcs1 led to a notable increase in vacuole volume. In addition, OE-Tggcs1 exhibited higher transport efficiencies for glucose and cellobiose thereby sustaining robust cellular metabolic rates. Further investigations revealed that Tgglo3 and Tggcs1 differentially regulated the transcription level of a dynamin-like GTPase gene (Tggtp), eliciting distinct redox states and apoptotic reaction, thus orchestrating the cellular response to lignocellulose utilization. Conclusions Overall, these findings underscored the significance of TgArf-GAPs as pivotal regulators in lignocellulose utilization and provided initial insights into their differential modulation of downstream targets.

Abstract Background The aim of the present study was to investigate the function of novel circular RNA hsa_circ_0036683 (circ‐36683) in non‐small cell lung cancer (NSCLC). Methods RNA sequencing was used to screen out differentially expressed miRNAs. Expression levels of miR‐4664‐3p and circ‐36683 were evaluated in lung carcinoma cells and tissues by quantitative reverse transcription‐polymerase chain reaction (qRT‐PCR). The effects of miR‐4664‐3p and circ‐36683 on proliferation and migration were assessed using cell counting kit‐8 (CCK‐8), wound healing and transwell migration assays and xenograft experiments. The targeting relationship of circ‐36683/miR‐4664‐3p/CDK2AP2 was assessed by luciferase reporter assays, western blot, qRT‐PCR and argonaute2‐RNA immunoprecipitation (AGO2 RIP). Co‐immunoprecipitation (Co‐IP), 5‐ethynyl‐2′‐deoxyuridine (EdU) staining and CCK‐8 were used to validate the indispensable role of CDK2AP2 in suppressing cell proliferation as a result of CDK2AP1 overexpression. Results By RNA sequencing, miR‐4664‐3p was screened out as an abnormally elevated miRNA in NSCLC tissues. Transfection of miR‐4664‐3p could promote cell proliferation, migration and xenograft tumor growth. As a target of miR‐4664‐3p, CDK2AP2 expression was downregulated by miR‐4664‐3p transfection and CDK2AP2 overexpression could abolish the proliferation promotion resulting from miR‐4664‐3p elevation. Circ‐36683, derived from back splicing of ABHD2 pre‐mRNA, was attenuated in NSCLC tissue and identified as a sponge of miR‐4664‐3p. The functional study revealed that circ‐36683 overexpression suppressed cell proliferation, migration and resulted in G0/G1 phase arrest. More importantly, the antioncogenic function of circ‐36683 was largely dependent on the miR‐4664‐3p/CDK2AP2 axis, through which circ‐36683 could upregulate the expression of p53/p21/p27 and downregulate the expression of CDK2/cyclin E1. Conclusion The present study revealed the antioncogenic role of circ‐36683 in suppressing cell proliferation and migration and highlighted that targeting the circ‐36683/miR‐4664‐3p/CDK2AP2 axis is a promising strategy for the intervention of NSCLC.

Abstract Background This study aimed to investigate the epidemiological changes in scarlet fever before, during and after the COVID-19 pandemic (2005–2023) and predict the incidence of the disease in 2024 and 2025 in Chongqing Municipality, Southwest China. Methods Descriptive analysis was used to summarize the characteristics of the scarlet fever epidemic. Spatial autocorrelation analysis was utilized to explore the distribution pattern of the disease, and the seasonal autoregressive integrated moving average (SARIMA) model was constructed to predict its incidence in 2024 and 2025. Results Between 2005 and 2023, 9,593 scarlet fever cases were reported in Chongqing, which resulted in an annual average incidence of 1.6694 per 100,000 people. Children aged 3–7 were the primary victims of this disease, with the highest average incidence found among children aged 6 (5.0002 per 100,000 people). Kindergarten children were the dominant infected population, accounting for as much as 54.32% of cases, followed by students (34.09%). The incidence for the male was 1.51 times greater than that for the female. The monthly distribution of the incidence showed a bimodal pattern, with one peak occurring between April and June and another in November or December. The spatial autocorrelation analysis revealed that scarlet fever cases were markedly clustered; the areas with higher incidence were mainly concentrated in Chongqing’s urban areas and its adjacent districts, and gradually spreading to remote areas after 2020. The incidence of scarlet fever increased by 106.54% and 39.33% in the post-upsurge period (2015–2019) and the dynamic zero-COVID period (2020–2022), respectively, compared to the pre-upsurge period (2005–2014) (P

Abstract Background Esophageal squamous cell carcinoma (ESCC) is often diagnosed at advanced stages due to the inherent limitations of current screening methodologies. Central to evaluating tumor invasion and prognostic assessment in ESCC is the integrity of the basement membrane (BM). However, current research on the implications of BM-related genes (BMRGs) in diagnosing ESCC remains sparse. Methods We performed a comprehensive analysis using single-cell RNA-sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, alongside gene expression profiles acquired from GEO and The Cancer Genome Atlas (TCGA) databases. This identified differentially expressed BMRGs in ESCC. Employing LASSO, RF, and SVM-RFE, we selected potential BM biomarkers and crafted a diagnostic nomogram for ESCC, validated by ROC curves and AUC values. We also explored immune infiltration and biological mechanisms through consensus clustering and GSVA, and utilized single cell trajectory analysis and GSCALite to study gene distributions and pathways. In vitro experiments further elucidated the role of these genes in ESCC carcinogenesis. Results Here, we discovered that ESCC cell types exhibited markedly elevated BM-related scores. Our analysis pinpointed seven BM genes upregulated and linked to immune infiltration, showcasing unique gene expression profiles and varying immune cell densities across the BM-related subtypes. Furthermore, a robust positive correlation was observed between these genes expression and EMT activity. The knockdown of BGN significantly suppressed cell proliferation, migration, invasion, while also augmenting cell viability following chemotherapy drug treatment. Conclusion Our study identified seven key BMRGs (BGN, LAMB3, SPARC, MMP1, LUM, COL4A1, and NELL2) and established a diagnostic nomogram for ESCC. Of noteworthy significance is the discovery of BGN as a promising drug target, indicating a novel strategy for future clinical combination therapies in ESCC.

Abstract Myocardial ischemia-reperfusion injury (MIRI) is a significant complication following reperfusion therapy after myocardial infarction. Mitochondrial oxidative stress is a critical factor in MIRI, and Sirtuin 3 (SIRT3), as a major mitochondrial deacetylase, plays a key protective role, with its activity potentially regulated by O-GlcNAcylation. This study used the H9C2 cell line to establish a simulated ischemia/reperfusion (SI/R) model, we utilized co-immunoprecipitated to validate the relationship between O-GlcNAc transferase (OGT) and SIRT3, demonstrated SIRT3 O-GlcNAcylation sites through LC–MS/MS, and performed site mutations using CRISPR/Cas9 technology. The results were validated using immunoblotting. SIRT3 and superoxide dismutase 2 (SOD2) activities were detected using a fluorometric assay, while mitochondrial reactive oxygen species (MROS) levels and cellular apoptosis were assessed using immunofluorescence. We have identified an interaction between SIRT3 and OGT, where SIRT3 undergoes dynamic O-GlcNAcylation at the S190 site, facilitating SIRT3 deacetylase activity. During SI/R, elevated levels of O-GlcNAcylation activate SOD2 by promoting SIRT3 enzyme activity, thereby inhibiting excessive MROS production. This significantly mitigates the occurrence of malignant autophagy in myocardial cells during reperfusion, promoting their survival. Conversely, blocking SIRT3 O-GlcNAcylation at the S190 site exacerbates SI/R injury. We demonstrate that O-GlcNAcylation is a crucial post-translational modification (PTM) of SIRT3 during SI/R, shedding light on a promising mechanism for future therapeutic approaches.

Abstract Background Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle. Results Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. The genetically engineered self-assembled particles neoantigen-FNs with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly drainage to and continuously accumulate in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8+ T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier. Conclusions Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently drainage to lymph nodes and induce efficient antitumor immune responses. Graphical Abstract

Abstract Congenital myopathies (CMs) are a kind of non-progressive or slow-progressive muscle diseases caused by genetic mutations, which are currently defined and categorized mainly according to their clinicopathological features. CMs exhibit pleiotropy and genetic heterogeneity. Currently, supportive treatment and pharmacological remission are the mainstay of treatment, with no cure available. Some adeno-associated viruses show promising prospects in the treatment of MTM1 and BIN1-associated myopathies; however, such gene-level therapeutic interventions target only specific mutation types and are not generalizable. Thus, it is particularly crucial to identify the specific causative genes. Here, we outline the pathogenic mechanisms based on the classification of causative genes: excitation-contraction coupling and triadic assembly (RYR1, MTM1, DNM2, BIN1), actin-myosin interaction and production of myofibril forces (NEB, ACTA1, TNNT1, TPM2, TPM3), as well as other biological processes. Furthermore, we provide a comprehensive overview of recent therapeutic advancements and potential treatment modalities of CMs. Despite ongoing research endeavors, targeted strategies and collaboration are imperative to address diagnostic uncertainties and explore potential treatments.

Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, characterized by difficulties in early diagnosis, prone to distant metastasis, and high recurrence rates following surgery. Extracellular vesicles (EVs) are a class of cell-derived particles, including exosomes, characterized by a phospholipid bilayer. They serve as effective carriers for intercellular communication cargo, including proteins and nucleic acids, and are widely involved in tumor progression. They are being explored as potential tumor biomarkers and novel therapeutic avenues. We provide a brief overview of the biogenesis and characteristics of EVs to better understand their classification standards. The focus of this review is on the research progress of EV-associated proteins in the field of HCC. EV-associated proteins are involved in tumor growth and regulation in HCC, participate in intercellular communication within the tumor microenvironment (TME), and are implicated in events including angiogenesis and epithelial-mesenchymal transition (EMT) during tumor metastasis. In addition, EV-associated proteins show promising diagnostic efficacy for HCC. For the treatment of HCC, they also demonstrate significant potential including enhancing the efficacy of tumor vaccines, and as targeting cargo anchors. Facing current challenges, we propose the future directions of research in this field. Above all, research on EV-associated proteins offers the potential to enhance our comprehension of HCC and offer novel insights for developing new treatment strategies.

Objective: To extract Astragalus polysaccharides (APS) from Astragalus membranaceus using compound enzymes (including papain, pectinase and cellulase), and to analyze the effect of process conditions on APS extraction. Methods: Orthogonal experiments were conducted to determine the proportion of compound enzymes. The response surface method was used to optimize the conditions of extracting APS with compound enzymes. The optimal process condition was obtained, and the α-glucosidase-inhibiting effect of APS was evaluated by pNPG method. Results: For 5 g of Astragalus herbs, the optimal ratio of papain, pectinase and cellulase were 88000 U, 65000 U and 6000 U, respectively. The optimal extraction condition was as follows: time of 2.82 h, temperature at 60.34 ℃, pH of 5.11, and solid-liquid ratio of 1:34.46 g/mL. The yield of APS under the optimal condition was up to 22.79%±0.14%. The half-inhibition concentration (IC50) of APS for α-glucosidase was 7.42 μg/mL. Conclusion: The yield of APS by compound enzymes is significantly higher than that by single enzymes, and APS can effectively inhibit the activity of α-glucosidase.

Background: Streptococcus agalactiae is a recognized pathogen that primarily affects infants and pregnant women. However, its increasingly important role in causing invasive infections among non-pregnant adults has become a significant health concern due to the severity and variety of its clinical impacts. Methods: Nonduplicate S. agalactiae clinical strains associated with clinical infections (n = 139) were isolated from non-pregnant adults in Shandong, China. Antibiotic susceptibility testing, whole-genome sequencing and genomic analyses were conducted to characterize the genome and identify resistance features of these strains. Results: The strains exhibited universal susceptibility to penicillin, ampicillin, cefotaxime, meropenem, linezolid and vancomycin. Notably, high resistance rates were observed for erythromycin (91.4%), clindamycin (89.2%), levofloxacin (84.2%), tetracycline (54.0%) and, to a lesser extent, chloramphenicol (12.9%). Serotyping revealed seven serotypes and one non-typeable strain. Serotypes Ia, Ib, III and V predominated, representing 95.7% of the strains. Nineteen sequence types were categorized into seven clonal complexes, with CC10 being the most prevalent at 48.9%. The resistance genes mreA (100%), ermB (70.5%) and tetM (46.0%) were commonly detected. All the isolates carried at least one pilus backbone determinant and one alpha-like protein gene, with the PI-1+PI-2a and the bca gene being the most frequent at 84.2% and 54.7%, respectively. Conclusions: While S. agalactiae strains in non-pregnant adults retain sensitivity to β-lactam antibiotics, the elevated resistance to erythromycin, clindamycin, levofloxacin and tetracycline is concerning. Given the growing elderly population worldwide, the burden of S. agalactiae infections is significant. Continuous surveillance of serotype distribution and antibiotic resistance patterns is imperative for targeted prevention and therapeutic strategies.

Background With the gradual aging of China's population and the gradual rise of chronic disease co-morbidities, cardiometabolic co-morbidities (CMM) have become one of the most damaging co-morbidities. Current studies on prediction and intervention methods for CMM have focused on individual cardiovascular diseases and lifestyle, while studies on CMM as a whole are lacking. Objective To explore the association of Continuous Metabolic Syndrome Score (cMetS) and other obesity indicators with CMM, and to further confirm whether these indicators can be used as a simple indicator for screening CMM, as well as to estimate the threshold for prediction of CMM in the middle-aged and elderly population in Anhui Province. Methods The study included 131 390 participants from the Anhui Province Cardiovascular Disease High-Risk Population Early Screening and Comprehensive Intervention Project from 2017 to 2021, divided into CMM (779 males, 866 females) and non-CMM groups (53 020 males, 76 725 females). General patient information and biochemical markers were collected, and the waist-to-height ratio (WHtR), WHT.5R, body roundness index (BRI), and cMetS were calculated. Differences in CMM prevalence by gender and age group were compared using the Bonferroni method. Multivariate Logistic regression analysis was employed to investigate the factors influencing CMM. Receiver operating characteristic (ROC) curves for predicting CMM using cMetS and obesity indices were plotted, and the area under the ROC curve (AUC) was calculated. The value of different indices in predicting CMM status was assessed using paired sample tests. Results In the male cohort, the CMM group showed higher values for age, BMI, waist circumference (WC), mean arterial pressure (MAP), fasting plasma glucose (FPG), triglycerides (TG), diabetes, ischemic heart disease, stroke, WHtR, WHT.5R, BRI, and cMetS than the non-CMM group. Smoking and alcohol consumption, as well as total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C), were higher in the non-CMM group (P

The concentrated load endured by the locking system during the weapon mounting and release procedures may lead to mechanical wear in hinges and kinematic pairs, thereby influencing the functional reliability of the weapon rack mechanism system. This study aims to investigate the impact of kinematic pair wear evolution on the reliability of the locking system. Firstly, a rigid-flexible coupling multi-body dynamics model of the locking system was established to simulate the dynamic behaviors of the rack under different loading conditions. Moreover, the wear amounts of the main kinematic pairs were precisely calculated by the Archard wear model to provide data support for the subsequent reliability analysis. Subsequently, the response surface method was employed to design the orthogonal experiments for the reliability analysis of the locking system, and the reliability degradation law of the locking system within the design lifespan was obtained through the Monte Carlo method simulation. The research findings indicate that the wear of kinematic pairs has a significant effect on the motion function and accuracy of the mechanism. The motion reliability of the mechanism can be maintained above 99% within the design lifespan. Nevertheless, when the usage time exceeds twice the design lifespan, the reliability drops significantly to approximately 85%, and the influence degrees of different wear positions on the reliability were obtained through the sensitivity analysis. The research results not only provide a scientific basis for the optimal design of the locking system but also offer a novel perspective and method for the reliability assessment and maintenance strategy of the weapon rack locking system.

Abstract The two-dimensional nanomaterials are characterized by their ultra-thin structure, diverse chemical functional groups, and remarkable anisotropic properties. Since its discovery in 2004, graphene has attracted significant scientific interest due to its potential applications in various fields, including electronics, energy systems, and biomedicine. In medicine, graphene is used for designing smart drug delivery systems, especially for antibiotics, and biosensing. Skin trauma is a prevalent dermatological condition that increasingly contributes to morbidities and mortalities, thus representing a significant health burden. During tissue damage, rapid skin repair is crucial to prevent blood loss and infection. Therefore, drugs used for skin trauma must possess antimicrobial and anti-inflammatory properties. Two-dimensional (2D) nanomaterials possess remarkable physical, chemical, optical, and biological characteristics due to their uniform shape, increased surface area, and surface charge. Graphene and its derivatives, transition-metal dichalcogenides (TMDs), black phosphorous (BP), hexagonal boron nitride (h-BN), MXene, and metal-organic frameworks (MOFs) are among the commonly used 2D nanomaterials. Moreover, they exhibit antibacterial and anti-inflammatory properties. This review presents a comprehensive discussion of the clinical approaches employed for wound healing treatment and explores the applications of commonly used 2D nanomaterials to enhance wound healing outcomes.

As one of the most common primary glomerulopathies, immunoglobulin A nephropathy（IgAN） is a major cause of end-stage renal disease （ESRD）. Its proper treatment has remained rather challenging. Disease progression may be delayed if associated risk factors are intervened. Hyperuricemia is a common clinical feature of IgAN and it is correlated with disease progression. However, the relationship has been elusive between hyperuricemia, pathological injury and disease progression in IgAN. This review focused upon the prevalence of hyperuricemia in IgAN, related pathogenesis and the relationship with the progression of IgAN and therapeutic targets.

In the wake of the largest-ever recorded outbreak of mpox in terms of magnitude and geographical spread in human history since May 2022, we innovatively developed an automated online sewage virus enrichment and concentration robot for disease tracking. Coupled with an artificial intelligence (AI) model, our research aims to estimate mpox cases based on the concentration of the monkeypox virus (MPXV) in wastewater. Our research has revealed a compelling link between the levels of MPXV in wastewater and the number of clinically confirmed mpox infections, a finding that is reinforced by the ability of our AI prediction model to forecast cases with remarkable precision, capturing 87 % of the data’s variability. However, it is worth noting that this high precision in predictions may be related to the relatively high frequency of data acquisition and the relatively non-mobile isolated environment of the hospital itself. In conclusion, this study represents a significant step forward in our ability to track and respond to mpox outbreaks. It has the potential to revolutionize public health surveillance by utilizing innovative technologies for disease surveillance and prediction.

Abstract Rosacea patients show facial hypersensitivity to stimulus factors (such as heat and capsaicin); however, the underlying mechanism of this hyperresponsiveness remains poorly defined. Here, we show capsaicin stimulation in mice induces exacerbated rosacea-like dermatitis but has no apparent effect on normal skin. Nociceptor ablation substantially reduces the hyperresponsiveness of rosacea-like dermatitis. Subsequently, we find that γδ T cells express Ramp1, the receptor of the neuropeptide CGRP, and are in close contact with these nociceptors in the skin. γδ T cells are significantly increased in rosacea skin lesions and can be further recruited and activated by neuron-secreted CGRP. Rosacea-like dermatitis is reduced in T cell receptor δ-deficient (Tcrd−/−) mice, and the nociceptor-mediated aggravation of rosacea-like dermatitis is also reduced in these mice. In vitro experiments show that CGRP induces IL17A secretion from γδ T cells by regulating inflammation-related and metabolism-related pathways. Finally, rimegepant, a CGRP receptor antagonist, shows efficacy in the treatment of rosacea-like dermatitis. In conclusion, our findings demonstrate a neuron-CGRP-γδT cell axis that contributes to the hyperresponsiveness of rosacea, thereby showing that targeting CGRP is a potentially effective therapeutic strategy for rosacea.

Abstract Relapse remains the main cause of treatment failure in patients with myeloid malignancies even after allogeneic hematopoietic stem cell transplantation (allo‐HSCT). We observed a particularly low incidence of relapse in patients prepared with fludarabine, busulfan and melphalan in our previous study and this multicenter retrospective analysis aimed to confirm the feasibility of the regimen and to identify the potential prognostic factors. This study was performed using registry data from adults patients with myeloid malignancies who underwent their first allo‐HSCT following fludarabine(≥100 mg/m2), busulfan (≥3.2 mg/kg) and melphalan (≥100 mg/m2) based conditioning at nine transplantation centers in China between Jan. 2020 and Mar. 2022. A total of 221 consecutive patients (AML n = 171, MDS‐IB‐1 or 2 n = 44, CMML n = 6) with median age of 46 were enrolled in this study. The median follow‐up was 507 days for survivors. The 2‐year NRM, CIR, OS and DFS were 10.6% ± 2.2%, 14.8% ± 3.3%, 79.4% ± 3.7% and 74.6% ± 3.7%, respectively. In multivariate analyses, high HCT‐CI (≥3) was the only independent factor for higher NRM [hazard ratio (HR), 2.96; 95% confidence interval (CI), 1.11 to 7.90; p = 0.030] and ECOG score ≥2 was the only independent factor for inferior OS (HR, 2.43; 95%CI, 1.15 to 5.16; p = 0.020) and DFS (HR, 2.12; 95%CI, 1.13 to 4.02; p = 0.020). AML diagnosis and positive measurable residual disease (MRD) at transplantation were predictors for higher CIR (HR = 7.92, 95%CI 1.05‐60.03, p = 0.045; HR = 3.64, 95%CI 1.40‐9.44, p = 0.008; respectively), while post‐transplantation cyclophosphamide based graft‐versus‐host disease prophylaxis was associated with lower CIR (HR = 0.24 95%CI 0.11‐0.54, p = 0.001). The intensity of conditioning regimen did not impact CIR, NRM, DFS and OS. These results supported that double alkylating agents of busulfan and melphalan based conditioning regimens were associated with low relapse rate and acceptable NRM in adult patients with myeloid malignancies. The optimal dose remained to be confirmed by further prospective studies.

Abstract Background We aimed to explore the impact of adherence to Life’s Simple 7 (LS7) metrics on risk of obstructive sleep apnea (OSA), and the impact of inflammation on the association, in adults in the United States. Methods Data from 13,825 community-dwelling adults aged ≥ 20 years recruited in the National Health and Nutrition Examination Surveys (NHANES) 2005–2008, 2015–2018 was analyzed. The LS7 score was calculated based on the AHA definition of LS7 metrics. The diagnosis of OSA was based on self-reported symptoms of sleep disturbance using a standard questionnaire. The Multivariable Apnea Prediction (MAP) Index score was also calculated to assess the risk of OSA. Log-binominal regression and negative binomial regression were performed to estimate the associations between LS7 and OSA and MAP index, with odds ratios (ORs) and prevalence ratios (PRs) and their 95% confidence intervals (CIs) calculated. Mediation analysis was performed to estimate the mediating effects of inflammatory indicators on the associations. Results A total of 4473 participants (32.4%) had OSA, and the mean MAP index was 0.39. In fully adjusted log-binominal regression models, with total score 8, respectively (P for trend 8, respectively (P for trend

Abstract Intertidal algae may adapt to environmental challenges by acquiring genes from other organisms and relying on symbiotic microorganisms. Here, we obtained a symbiont-free and chromosome-level genome of Pyropia haitanensis (47.2 Mb), a type of intertidal algae, by using multiple symbiont screening methods. We identified 286 horizontal gene transfer (HGT) genes, 251 of which harbored transposable elements (TEs), reflecting the importance of TEs for facilitating the transfer of genes into P. haitanensis. Notably, the bulked segregant analysis revealed that two HGT genes, sirohydrochlorin ferrochelatase and peptide-methionine (R)-S-oxide reductase, play a significant role in the adaptation of P. haitanensis to heat stress. Besides, we found Pseudomonas, Actinobacteria, and Bacteroidetes are the major taxa among the symbiotic bacteria of P. haitanensis (nearly 50% of the HGT gene donors). Among of them, a heat-tolerant actinobacterial strain (Saccharothrix sp.) was isolated and revealed to be associated with the heat tolerance of P. haitanensis through its regulatory effects on the genes involved in proline synthesis (proC), redox homeostasis (ggt), and protein folding (HSP20). These findings contribute to our understanding of the adaptive evolution of intertidal algae, expanding our knowledge of the HGT genes and symbiotic microorganisms to enhance their resilience and survival in challenging intertidal environments.

Abstract Background The triglyceride glucose (TyG) index is a cutting-edge and highly effective marker of insulin resistance, a crucial factor in the development and exacerbation of diabetic kidney disease (DKD). To date, there has been limited research on how the triglyceride-glucose (TyG) index affects the outlook for patients suffering from DKD. Methods In this multicenter retrospective cohort study, the analysis recruited 2,203 DKD patients from the National Health and Nutrition Examination Survey (NHANES) dataset, which covers the US from 2001 to 2018. The research applied a Cox proportional hazards model with multiple variables to investigate the association of the TyG index with mortality outcomes. Restricted cubic splines (RCS) and methods for analyzing threshold effects were employed to identify possible non-linear relationships. Results Over nearly 19 years of follow-up, this study captured data on 753 all-cause and 231 cardiovascular disease-specific fatalities. Sophisticated statistical methods, including RCS and smoothing curve adjustments via penalized splines, helped identify distinctive patterns: The baseline TyG index was observed to have a U-shaped pattern related to overall mortality and an L-shape with cardiovascular diseases(CVD) mortality among individuals with DKD. Notably, TyG index below 9.15 for overall mortality and 9.27 for CVD mortality were linked to reduced death rates (HR = 0.65, 95% CI = 0.52–0.82 for all-cause; HR = 0.58, 95% CI = 0.43–0.83 for CVD). On the other hand, TyG index exceeding these benchmarks (greater than 9.15 for all-cause and 9.27 for CVD) correlated with increased all-cause mortality risks (HR = 1.21, 95% CI = 1.02–1.43) and showed a non-significant change in CVD mortality risks (HR = 1.07, 95% CI = 0.83–1.38). Conclusions This study emphasizes the non-linear linkage involving the TyG index and death rates due to CVD and other factors in patients with DKD, demonstrating its effectiveness in estimating potential adverse events within this demographic.

Abstract Background CD74 is ectopically expressed in many tumors and can regulate tumor immunity. However, there are many gaps in the study of the prognostic value of CD74 expression and immune infiltration in hepatocellular carcinoma (HCC). Methods An online tumor database was searched to obtain data on gene/protein expression. Immune infiltration analysis was performed using the Tumor Immune Estimation Resource and Comprehensive Analysis on Multi-Omics of Immunotherapy in Pan-cancer databases. Single-cell data were obtained from the Tissue-specific Gene Expression and Regulation, Single-cell Transcriptomes of Tumor Immune Microenvironment and Tumor Immune Single-cell Hub 2 databases. Results CD74 was highly expressed in HCC patients. HCC patients with high CD74 expression who consumed alcohol or were negative for hepatitis virus had a better prognosis than patients with low CD74 expression. CD74 was mainly enriched in immune response regulation pathways. Both copy number variations in CD74 and CD74 expression patterns affected the infiltration levels of immune cells. Interestingly, CD74 regulated the differentiation of myeloid cells. CD74 in macrophages and dendritic cells (DCs) forms complex networks with malignant cells and hepatic progenitor cell (HPC)-like cells, respectively. High CD74 expression in HPC-like cells and malignant cells significantly decreased the fraction of C-type lectin domain family 9 A (CLEC9A)-cDC1+ DCs and IL-1B+ macrophages, respectively. Their crosstalk subsequently shaped the tumor microenvironment of HCC, possibly through the CD74-MIF axis. Importantly, patients with high CD74 expression presented higher immune scores and achieved good outcomes after receiving immunotherapy. Conclusion High CD74 expression is associated with the abundance of a variety of immune cell types, mediating interactions among tumor and immune cells and shaping the malignant behavior of HCC. In summary, CD74 may be a hallmark for determining the prognosis and immune cell infiltration levels of HCC patients.