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Background: Cognitive impairments are prevalent among stroke patients, impacting independent living. While intermittent theta burst stimulation (iTBS) shows potential for rehabilitation, the efficacy of the commonly-used doses remains unsatisfactory. Objective: To investigate the efficacy, dose-dependent effect, and safety of high-dose iTBS targeting the individualized frontoparietal cognitive network (FCN) for post-stroke cognitive recovery. Methods: In a randomized, sham-controlled, three-arm trial, patients with post-stroke cognitive impairment (PSCI) received 15 days of high-dose (3600 pulses/day), standard low-dose (1200 pulses/day) as an active control, or sham iTBS targeting the individualized FCN, alongside cognitive training. Primary outcome measured changes in global cognition via the Montreal Cognitive Assessment (MoCA). Secondary measures included MoCA response rates and score changes in the Wechsler Memory Scale, Wechsler Adult Intelligence Scale, and Mini-Mental State Examination. Results: Of forty-five randomized participants, forty-one (8 women; mean [SD] age, 58.63 [8.64] years) were analyzed. Personalized targeting improved focality by 33.0 % over the standard F3 target in E-field analysis. Both high-dose and standard low-dose groups showed significant improvements in MoCA. Importantly, the high-dose group demonstrated superior cognitive recovery over both the active control group (estimated difference = 2.50, p = 0.0339, 95 % CI = 0.15–4.84) and the sham control group (estimated difference = 4.29, p = 0.0001, 95 % CI = 1.99–6.60), indicating a superior effect of high-dose stimulation for cognitive recovery. Similar high-dose and dose-dependent effects were observed in other secondary outcomes, suggesting consistent effects on the memory, intelligence, and mental state. No serious adverse events occurred. Conclusions: This study highlights the efficacy and safety of high-dose iTBS targeting the individualized FCN for post-stroke cognitive recovery.

Abstract Background Sepsis often led to multiple organ dysfunction (MODS) and even death. Although a variety of medicine were used to treat sepsis in clinic, there was still no specific and effective clinical medicine treatment. Exercise had been shown to work on MODS. However, in preclinical studies, there was no systematic evidence to summarize the effects of exercise training on sepsis. Objectives To investigate the effects of exercise training on sepsis in preclinical studies and explore possible mechanisms to provide reliable preclinical evidence for the use of exercise training in sepsis. Method Preclinical studies were retrieved from electronic databases (Pubmed, Embase, Cochrane Library, Scopus, Medline, Web of science) as of June 25, 2024. Our review included in vivo English studies evaluating the radioprotective effects of exercise training on sepsis. The quality of each study was assessed using the Center for Systematic Evaluation of Experimental Animal Studies (SYCLE) Animal Research Bias Risk Tool. All results were described comprehensively. Results 17 in vivo studies were included. Our comprehensive descriptive analysis showed that exercise could improve the general condition, lung injury, liver injury, kidney injury, heart and aortic injury, spleen and thymus injury, and other injuries in animals with sepsis. And its possible mechanisms were involved improving the general condition of sepsis animals, pathological and cell number of organs, anti-inflammation, anti-oxidative stress, anti-DNA damage, and so on. Conclusion Exercise training could protect sepsis by anti-inflammatory, anti-oxidative stress, increased antibacterial ability, reduced cell death, improved metabolism, vital signs and MODS.

The real-time road surface friction coefficient (RSFC) is a critical parameter for evaluating skid resistance and making safe driving decisions in driver assistance systems and autonomous vehicles, especially under adverse weather conditions. RSFC estimation depends on the interaction between the road surface and tires. However, accurate estimation is challenging due to varying road environments and sensor errors that can cause significant distortions. To obtain high-accuracy RSFC, this study proposes a novel real-time RSFC detection method that integrates a diffusion model with the Transformer-in-Transformer(TNT) model to detect RSFC from vehicle video pictures. The method consists of three steps. First, we created labeled friction coefficient image datasets representing asphalt concrete surfaces under four moisture conditions. Second, we used a diffusion model to enhance the dataset, increasing sample diversity. Finally, we trained a TNT model on the extended dataset to recognize friction coefficients. The approach was tested across various datasets and compared to four state-of-the-art (SOTA) methods. The results show that the proposed method significantly improves accuracy, achieving a 22.89% increase compared to the unenhanced dataset and a 5.59% improvement over SOTA methods. The primary contribution of this study is the integration of generative artificial intelligence and computer vision algorithms to enhance RSFC recognition accuracy. Furthermore, the recognition method meets the real-time performance requirements, processing frames in just two milliseconds. This method can be an effective tool for perceiving road surface environmental parameters and holds significant value in improving driving safety under adverse weather conditions.

Pseudomonas aeruginosa causes high morbidity and mortality in nosocomial infections, and newly approved antibiotics have been declining for decades. A green and universal deprotonation-driven strategy is used to screen the guanylic acid-metal ion coordination polymer nanoparticles (GMC), instead of the failure of binding occurs when specific metal ion participation. We find that the precise pH-dependent oxidase-like activity of GMC-2 orchestrates a duple symphony of immune modulation for Pseudomonas aeruginosa biofilm infections. Specifically, GMC-2-mediated reactive oxygen species (ROS) regulation triggers mitochondrial dysfunction and releases damage-associated molecular patterns, engaging pattern recognition receptors and resulting in endogenous innate immune activation. Meanwhile, GMC-2-triggered ROS generation in a mildly acidic biofilm environment destroys the biofilm, exposing exogenous pathogen-associated molecular patterns. GMC-2 cannot cause resistance for Pseudomonas aeruginosa compared with conventional antibiotics. In an infected implant mouse model, Pseudomonas aeruginosa biofilms were effectively eliminated by GMC-2-mediated triggering of innate and adaptive immunity. These findings provide a universal approach for facilitating the binding of biomolecules with metal ions and highlight the precise ROS-regulating platform plays a critical role in initiating endogenous and exogenous immune activation targeted for bacterial biofilm infection.

Abstract Objective To investigate the predictive value of machine learning-based PET/CT radiomics and clinical risk factors in predicting interim efficacy in patients with follicular lymphoma (FL). Methods This study retrospectively analyzed data from 97 patients with FL diagnosed via histopathological examination between July 2012 and November 2023. Lesion segmentation was performed using LIFEx software, and radiomics features were extracted through the uAI Research Portal (uRP) platform, including first-order features, shape features, and texture features. Fourteen filters were applied to the raw images to extract higher-order features from the derived images. Univariate analysis was employed to identify clinical risk factors, and correlation coefficients, MRMR, and LASSO algorithms were used for dimensionality reduction and selection of radiomics features. Finally, a logistic regression machine learning model was developed to predict the interim efficacy of FL using a five-fold cross-validation strategy. Model performance was assessed using the area under the receiver operating characteristic (ROC) curve, accuracy, and the Delong test to compare AUC differences. Result Among the 97 patients, 42 (43.30%) achieved complete response (CR) for interim efficacy, while 55 (56.70%) had non-complete response (non-CR). A total of 2264 radiomics features were extracted from the images. Seven clinical risk factors and ten radiomics features associated with interim efficacy were selected to construct the clinical, radiomics, and radiomics-clinical combined models. Among the three logistic regression machine learning models developed, the radiomics-clinical combined model demonstrated the best performance, achieving a mean AUC of 0.849 (95% CI, 0.676–1.000) and an accuracy of 0.795, outperforming the other two models. Conclusion Our preliminary results demonstrate that a radiomics-clinical combined model, based on baseline [18F]FDG PET/CT radiomics features and clinical risk factors, may contribute to predicting interim efficacy in FL patients.

Abstract The involvement of B lymphocytes in the pathogenesis of rheumatoid arthritis (RA) is well-established, with their early and aberrant activation being a crucial factor. However, the mechanisms underlying this abnormal activation in RA remain incompletely understood. In this study, we identified a significant reduction in MAPK4 expression in both RA patients and collagen-induced arthritis (CIA) mouse models, which correlates with disrupted B cell activation. Using MAPK4 knockout (KO) mice, we demonstrated that MAPK4 intrinsically promotes the differentiation of marginal zone (MZ) B cells. Loss of MAPK4 in KO mice enhances proximal BCR signaling and activates the PI3K-AKT-mTOR pathway, leading to heightened B cell proliferation. Notably, B cells from MAPK4 KO mice produce significantly higher levels of IL-6, a key pro-inflammatory cytokine in RA. Furthermore, MAPK4 KO mice exhibit impaired T cell-independent humoral immune responses. Mechanistically, MAPK4 inhibits the activation of the PI3K signaling pathway in B cells by activating the IRF4-SHIP1 pathway. Treatment with the MAPK4 agonist Vacquinol-1 enhances MZ B cell differentiation in WT mice and reduces IL-6 secretion in CIA mouse models. In summary, this study reveals the diverse roles of MAPK4 in regulating of B cell functions, with potential implications for developing therapeutic strategies for RA and related autoimmune diseases.

Abstract Background The Family Vitiligo Impact Scale (FVIS) is the first reliable and valid instrument to evaluate the psychological and social impact on family members with vitiligo. However, the FVIS has not yet been validated in China. Objective This study aimed to adapt the FVIS across cultures and utilize a cross-sectional design to validate its reliability and validity in evaluating the quality of life of family members with vitiligo in China. Methods The original version scale was first translated into Chinese using Brislin back- translation method. This study was conducted among adult individuals in China (N = 348). The participants were aged 18 to 70 years, with a mean age of 33.6 years (SD = 11.3). The sample consisted of 50.9% females (n = 177) and 49.1% males (n = 171). Respondents completed the Chinese versions of the FVIS and Family Dermatology Life Quality Index (FDLQI). Exploratory factor analysis (EFA) and confrmatory factor analysis (CFA) were used to test the construct validity of the scale, and the content validity of the scale was assessed through the content validity index. The internal consistency of the scale was assessed by calculating Cronbach’s alpha coefcient, Omega coefcient, split-half reliability, and test-retest reliability. Results EFA supported a three-factor structure, explaining 79.208% of cumulative variance. CFA demonstrated satisfactory construct validity for the FVIS, with excellent model fit: chi-square degree of freedom (χ2/df) = 2.019, root mean square error of approximation (RMSEA) = 0.072, standardized root mean square residual (SRMR) = 0.0145, Comparative Fit Index (CFI) = 0.983, and Tucker Lewis Index (TLI) = 0.978. The content validity index of the scale was 0.979. The Cronbach’s alpha coefcient was 0.975, Omega coefcient was 0.964, the split-half reliability coefcient was 0.977, and the test–retest reliability was 0.959. Conclusion The Chinese FVIS showed satisfactory reliability and validity for assessing vitiligo’s psychosocial impact on family membersin Chinese clinical and research settings.

Abstract In the framework of sustainable development and environmental preservation, this research aims to improve the stability and frost resistance of sulfate saline soil by utilizing industrial solid waste. Geopolymer materials containing fly ash (FA) activated by different NaOH concentrations were studied for study on stabilized soil with saline soil, with NaOH concentrations used ranged from 0.1 to 0.9. This study investigates the impact of the molar concentration of NaOH and the number of freeze-thaw cycles on the microstructure and strength of stabilized soil incorporating FA geopolymer. The XRD, FTIR, and TG studies of NaOH-excited FA stabilized soil revealed that the FA gel material grew with increasing concentration. The strength and frost resistance of stabilized soil increased and then declined as NaOH concentration increased, with an optimum excitation concentration of 0.5 M. After 28 days of curing at 20 °C, its UCS and splitting strength were 7.18 MPa and 1.89 MPa, respectively. The residual values of UCS and splitting strength after 5 freeze-thaw cycles (12 hours of freezing followed by 12 hours of thawing at +20 °C) at the optimal concentration were 46.35% and 39.92%, respectively.

This study investigated the interaction between arachin and eight common polyphenols—ferulic acid, resveratrol, hesperidin, catechin, quercetin, curcumin, gallic acid, and myricetin. The interaction patterns of these polyphenols with arachin were analyzed using UV-visible and fluorescence spectroscopy, with a focus on their effects on protein structure, surface hydrophobicity and solubility. UV-visible spectroscopy revealed that the polyphenols altered the microenvironment surrounding the amino acid residues of arachin, leading to changes in its molecular conformation. Fluorescence spectroscopy identified static quenching as the quenching mechanism of polyphenols on arachin, with resveratrol and catechin demonstrating the highest binding affinity. Additionally, catechin, myricetin, and gallic acid were observed to form high-molecular-weight polymers with arachin through covalent cross-linking, verified by SDS-PAGE. Fourier infrared spectroscopy showed that polyphenols induced various conformational changes in arachin, notably increasing the proportion of α-helix, with the maximum rise reaching 36.33%. The polyphenols decreased the surface hydrophobicity and solubility of arachin, with the lowest levels dropping to 19.92 µg and 51.7%, respectively. In conclusion, the interaction between the eight polyphenols and arachin induced diverse alterations to the conformation and physicochemical properties of arachin. This study offers a scientific basis and theoretical guidance for the further processing and utilization of polyphenols and arachin.

Abstract In this study, the effects of six operating conditions on the performance of a 3 kW- ORC (organic Rankine cycle) system were investigated. The results of experiments show that, despite differences in the physical parameters of the three working fluids used, the performance of the ORC system was similar. Further, the cooling water temperature (CWT) was strictly controlled, but the experimental results were affected by the condensation temperature, however the experimental system can maintain stable operation. Since generators are affected by different factors, the variation in generator generation fluctuates over a wide range during steady state operation of the system. The theoretical shaft work of the expander and generator power generation of the system using R245fa exceeds that of the other two working fluids due to the density. It had a maximum generator power conversion efficiency of 64.651% under C1 condition, maximum exergy efficiency of 27.346% under C3 condition; the system has a maximum cycle efficiency of 9.543% and a cold energy utilization efficiency of 5.633%, under C6 conditions; although maximum power generation (1.019 kW) and maximum net work (1.321 kW), the total exergy loss of the system also reached its maximum value (13.756kw) under C5 condition.

Abstract The molecular mechanism underlying the role of hippocampal hilar interneuron degeneration in temporal lobe epilepsy (TLE) remains unclear. Especially, very few studies have focused on the role of neuronal nitric oxide synthase (nNOS, encoded by Nos1) containing hilar interneurons in TLE. In the present study, Nos1 conditional knockout mice were constructed, and we found that selective deletion of Nos1 in hilar interneurons rather than dentate granular cells (DGCs) triggered epileptogenesis. The level of nNOS was downregulated in patients and mice with TLE. Nos1 deletion led to excessive epilepsy-like excitatory input circuit formation and hyperexcitation of DGCs. Replenishment of hilar nNOS protein blocked epileptogenic development and memory impairment in pilocarpine-induced TLE mice. Moreover, chronic treatment with DETA/NONOate, a slowly released exogenous nitric oxide (NO) donor, prevented aberrant neural circuits of DGCs and the consequent epileptogenesis without acute antiseizure effects. Therefore, we concluded that NO donor therapy may be a novel anti-epileptogenesis strategy, different from existing antiseizure medications (ASMs), for curing TLE.

Abstract Cisplatin (CDDP) is the primary drug used in the initial treatment of esophageal cancer (EC). However, its side effects and resistance can limit its effectiveness in clinical therapy. Curcumin (Cur)-mediated glutathione (GSH) depletion can reverse resistance, enhance the chemosensitivity of CDDP, and further improve the efficacy of platinum-containing chemotherapy in the treatment of esophageal cancer. However, it is also faced with problems of poor water solubility and low bioavailability in vivo, which severely hinders cancer treatments. In order to address these issues, we developed a novel nanotherapeutic system called CDCZA, combining Cur/CDDP/Cu/ZIF8@Au to enhance chemotherapy through GSH depletion and chemodynamic therapy through self-produced H2O2. Cu and CDDP were precisely co-loaded into Cu/ZIF8 nanoparticles using a one-pot method, then ultra-small gold nanoparticles mimicking glucose oxidase (Au nanoparticles) were embedded in the outer shell to create the CDCZA nano system. The released Cur could notably decrease intracellular GSH content and thus improve the chemosensitivity of CDDP, resulting in severe cellular apoptosis. And the Au nanoparticles effectively enabled chemodynamic therapy enhancement by accelerating the depletion of β-D-glucose into H2O2. As a result, the CDCZA nanoparticles showed increased tumor accumulation and improved antitumor effectiveness in a model of EC. Taken together, this work provides a new idea for the clinical design of efficient treatment reagents for EC.

Abstract The impregnated layer solution combustion synthesis (SCS) technique was employed to synthesize CaO-based sorbents supported by inert stabilizers so as to improve the cyclic CO2 uptake stability. Four different inert stabilizers were evaluated for their impact on the cyclic CO2 uptake stability of sorbents. It found that the Mg-based inert stabilizer significantly outperforms the other three in improving cyclic CO2 sorption capabilities of sorbents synthesized by the impregnated layer SCS method. Moreover, MgO-supported sorbent pellets were prepared via graphite hydrophobic layer-assisted casting, with the magnesia load within the pellets being regulated between 15 and 45 wt %. It is the addition of MgO stabilizer that significantly improves the performance of CaO-based sorbents, with the improvements being notably more pronounced at higher MgO loads. The calcium-based sorbent pellets containing 45 wt % MgO show extremely stable CO2 sorption performance; after 17 cycles, the carbonation conversion rate is 73.6%, about three times the rate of pellets without MgO loading. The uniform dispersion of MgO inert stabilizer inside pellets improves high-temperature sintering resistance and, concurrently, enhances the mechanical property. Furthermore, the use of waste cigarette butts as impregnated layer templates, rather than other organic additives, will significantly reduce the cost of synthesizing MgO-supported CaO-based sorbents. Graphical Abstract

With the rapid development of uncrewed aerial vehicle (UAV) technology, detecting aerial images has found significant applications across various domains. However, existing algorithms overlook the impact of illumination on target detection, resulting in less satisfactory detection performance under low-light conditions. We propose EfficientFuseDet, a visible and infrared image fusion detection network to overcome this issue. First, an effective multilevel cross-modal fusion network called EfficientFuse is presented to combine complementary information from both modalities better. EfficientFuse captures local dependencies and global contextual information in shallow and deep layers, seamlessly combining complimentary local and global features throughout the network. The generated fused images can exhibit clear target contours and abundant texture information. Second, we propose a detection network called AFI-YOLO, which employs an inverted residual vision transformer backbone (IRViT) to effectively address the challenges associated with background interference in fused images. We design an efficient feature pyramid network (EFPN) that efficiently integrates multiscale information, enhancing multiscale detection capability using aerial images. A reparameterization decoupling head (RepHead) is proposed to further improve target classification and localization precision. Finally, experiments on the DroneVehicle dataset indicate that the detection accuracy using fused images can reach 47.2 %, which is higher than that observed with visible light images of 45 %. Compared to state-of-the-art detection algorithms, EfficientFuseDet exhibits a slight decrease in speed. However, it demonstrates superior detection capabilities and effectively enhances the detection accuracy using aerial images under low-light conditions.

Lactic acid bacteria and coagulase-negative staphylococci play an important role in the production of fermented sausages, such as inhibiting the growth of undesirable bacteria and antioxidant. In this study, the effects of inoculation with different starter cultures (Lactiplantibacillus plantarum HN108 and Staphylococcus simulans NJ209) on the free amino acids (FAAs), biogenic amines (BAs) and volatile compounds of fermented sausages were investigated using an amino acid analyzer, ultra performance liquid chromatography and gas chromatography-ion mobility spectrometry, respectively. The pH and carbonyl content of the inoculated group was significantly lower than those in the control group (P < 0.05). L. plantarum HN108 significantly reduced the content of FAAs and BAs in fermented sausage production (P < 0.05), while S. simulans NJ209 promoted the formation of FAAs (especially bitter amino acids) and exhibited slight BAs-reducing activity. In addition, L. plantarum HN108 promoted the formation of volatile compounds such as ketones, alcohols and alkenes in sausages. In conclusion, L. plantarum HN108 could contribute to reducing the content of putrescine and tyramine and forming the desirable flavor compounds in fermented sausages. Thus, L. plantarum HN108 is expected to be a starter culture that can improve the safety and flavor of fermented sausages.

In recent decades, pentazolate salts have gained considerable attention as high energy density materials (HEDMs). Using the machine-learning accelerated structure searching method, we predicted four pentazolate salts stabilized with tetravalent metals (Ti-N and Zr-N). Specifically, the ground state MN20 (M = Ti, Zr) adopts the space-group P4/mcc under ambient conditions, transforming into the I-4 phase at higher pressure. Moreover, the I-4-MN20 becomes energetically stable at moderate pressure (46.8 GPa for TiN20, 38.7 GPa for ZrN20). Anharmonic phonon spectrum calculations demonstrate the dynamic stabilities of these MN20 phases. Among them, the P4/mcc phase can be quenched to 0 GPa. Further ab-initio molecular dynamic simulations suggest that the N5 rings within these MN20 systems can still maintain integrity at finite temperatures. Calculations of the projected crystal orbital Hamilton population and reduced density gradient revealed their covalent and noncovalent interactions, respectively. The aromaticity of the N5 ring was investigated by molecular orbital theory. Finally, we predicted that these MN20 compounds have very high energy densities and exhibit good detonation velocities and pressures, compared to the HMX explosive. These calculations enrich the family of pentazolate compounds and may also guide future experiments.

Abstract Machine-learned potentials (MLPs) have exhibited remarkable accuracy, yet the lack of general-purpose MLPs for a broad spectrum of elements and their alloys limits their applicability. Here, we present a promising approach for constructing a unified general-purpose MLP for numerous elements, demonstrated through a model (UNEP-v1) for 16 elemental metals and their alloys. To achieve a complete representation of the chemical space, we show, via principal component analysis and diverse test datasets, that employing one-component and two-component systems suffices. Our unified UNEP-v1 model exhibits superior performance across various physical properties compared to a widely used embedded-atom method potential, while maintaining remarkable efficiency. We demonstrate our approach’s effectiveness through reproducing experimentally observed chemical order and stable phases, and large-scale simulations of plasticity and primary radiation damage in MoTaVW alloys.

Abstract Background Triple-negative breast cancer (TNBC) is currently the most aggressive subtype of breast cancer, characterized by high heterogeneity and strong invasiveness, and currently lacks effective therapies. PRMT5, a type II protein arginine methyltransferase, is upregulated in numerous cancers, including TNBC, and plays a critical role, marked it as an attractive therapeutic target. PROTAC (Proteolysis Targeting Chimeras) is an innovative drug development technology that utilizes the ubiquitin-proteasome system (UPS) to degrade target proteins, which is characterized by higher activity, enhanced safety, lower resistance, and reduced toxicity, offering significant value for clinical translation. Methods This study utilizes the PROTAC technology to develop potential degraders targeting PRMT5 in vitro and in vivo. Results Through the design, synthesis and screening of a series of targeted compounds, we identified YZ-836P as an effective compound that exerted cytotoxic effects and reduced the protein levels of PRMT5 and its key downstream target protein KLF5 in TNBC after 48 h. Its efficacy was significantly superior to the PRMT5 PROTAC degraders that had been reported. YZ-836P induced G1 phase cell cycle arrest and significantly induced apoptosis in TNBC cells. Additionally, we demonstrated that YZ-836P promoted the ubiquitination and degradation of PRMT5 in a cereblon (CRBN)-dependent manner. Notably, YZ-836P exhibited pronounced efficacy in inhibiting the growth of TNBC patient-derived organoids and xenografts in nude mice. Conclusions These findings position YZ-836P as a promising candidate for advancing treatment modalities for TNBC. Trial registration Ethics Committee of Yunnan Cancer Hospital, KYCS2023-078. Registered 7 June 2023.

Abstract Background Myofibroblasts constitute a significant component of the tumor microenvironment (TME) and play a pivotal role in the progression of hepatocellular carcinoma (HCC). Integrin α5 (ITGA5) is a crucial regulator in myofibroblasts of malignant tumors. Therefore, the potential of ITGA5 as a novel target for the therapeutic strategy of HCC should be investigated. Methods Digital scanning and analysis of the HCC tissue microarray were performed to locate the distribution of ITGA5 and conduct the prognosis analysis. CRISPR Cas9-mediated ITGA5 knockout was performed to establish the ITGA5-KO myofibroblast cell line. Extracellular vesicles (EVs) derived from LX2 were extracted for the treatment of HCC cells. Subsequently, the sphere-forming ability and the stemness markers expression of the treated HCC cells were examined. An orthotopic HCC mouse model with fibrotic injury was constructed to test the outcomes of ITGA5-targeting therapy and its efficacy in the programmed death-ligand 1 (PD-L1) treatment. Co-immunoprecipitation/mass spectrometry and transcriptome data were integrated to delve into the mechanism. Results The tissue microarray results revealed that ITGA5 was highly enriched in the stromal myofibroblasts of HCC tissues and contributed to enhanced tumor progression and poor prognosis. Notably, ITGA5 transmission via extracellular vesicles (EVs) from myofibroblasts to HCC cells induced the acquisition of cancer stem cell-like properties. Mechanistically, ITGA5 directly bind to YES1, facilitating the activation of YES1 and its downstream pathways, thereby enhancing the stemness of HCC cells. Furthermore, the blockade of ITGA5 impeded tumor progression driven by ITGA5+ myofibroblasts and enhanced the efficacy of treatment with PD-L1 in a mouse model of HCC. Conclusions Our findings elucidated a novel mechanism by which the EV-mediated transfer of ITGA5 from myofibroblasts to tumor cells augmented HCC stemness. ITGA5-targeting therapy helped prevent the progression of HCC and improved the efficacy of PD-L1 treatment. Graphical Abstract

Abstract Background Functional disability significantly burdens healthcare services, negatively affecting older adults’ social interaction and quality of life. This study aims to identify the association between functional disability and mental health, and examine the moderating effects of social participation and physical exercise on the association. Methods The data were drawn from 2018 wave of Chinese Longitudinal Healthy Longevity Survey, and ordinary least squares regression model was exploited to explore the association between functional disability and mental health. Results Activity of daily living (ADL) disability negatively predicted mini-mental state examination (MMSE) score. Furthermore, social participation and physical exercise moderated the association between ADL disability and MMSE score. Conclusion The results highlight the importance of social participation and physical exercise for the older adults with ADL disability.

Abstract Angiogenesis is well known to play a critical role in breast cancer. We previously reported that TNFAIP2 activates Rac1 to promote triple-negative breast cancer (TNBC) cell proliferation, migration, and chemoresistance. However, the potential contribution of TNFAIP2 to tumor angiogenesis remains unknown. In this study, we demonstrated that TNFAIP2 promotes TNBC angiogenesis by activating the Rac1-ERK-AP1-HIF1α signaling axis. Under hypoxia, TNFAIP2 activates Rac1 and ERK sequentially. Following that, ERK activates the AP-1 (c-Jun/Fra1) transcription factor. By employing chromatin immunoprecipitation and luciferase reporter assays, we showed that AP-1 directly interacts with the HIF1α gene promoter, thereby enhancing its transcription. The combined application of ERK inhibitors, U0126 or trametinib, with the VEGFR inhibitor Apatinib, additively suppresses angiogenesis and tumor growth of HCC1806 in nude mice. These findings provide new therapeutic strategies for TNBC.

Abstract Background During the COVID-19 pandemic, non-therapeutic interventions (NPIs), such as traffic restrictions, work stoppages, and school suspensions, have led to a sharp decline in the concentration of air pollutants in the epidemic sites. However, few studies focused on the impact of air pollutant changes on the risk of nonaccidental death. Method We selected Yancheng City, China, as the study site and applied a Generalized Additive Model (GAM) based on the quasi-Poisson distribution to evaluate the impact of atmospheric pollutants exposure on the nonaccidental death of local residents. The time span of this study was set from January 1, 2013, to December 21, 2022, that is, before and after the outbreak of COVID-19. Results The concentration of some air pollutants has greatly varied after the outbreak of COVID-19, with a significant decline for PM2.5 (− 43.4%), PM10 (− 38.5%), SO2 (− 62.9%), and NO2 (− 22.6%), but an increase for O3 (+ 4.3%). Comparative analysis showed that PM2.5 contributed to an increased risk of nonaccidental death after the outbreak of COVID-19. With an increase in PM2.5 by 10 µg/m³, the excess relative risks (ER) of nonaccidental death of residents increased by 1.01% (95%CI: 0.19%,1.84%). The stratified analysis revealed that air pollutants impacted nonaccidental deaths in both men and women before the outbreak of COVID-19. After the outbreak of COVID-19, PM10 had a significant effect on male nonaccidental deaths. The concentrations of PM2.5, PM10, and SO2 increased by 10 µg/m³, the ER of PM2.5, PM10, and SO2 on female nonaccidental death increased by 1.52% (0.38%,2.67%), 0.58% (0.02%,1.13%), and 15.09% (5.73%,25.28%), respectively. Before the outbreak of COVID-19, five air pollutants had an impact on the death of residents from cardiovascular disease (CVD). After the outbreak of COVID-19, only PM10 significantly affected the death risk of CVD. In addition, we discovered that PM2.5, PM10, and SO2 significantly impacted the risk of death due to respiratory diseases before and after the outbreak of COVID-19. Conclusions Air pollutants have different effects on nonaccidental deaths before and after the COVID-19 outbreak. A decrease in air pollutant concentration due to the NPIs for COVID-19 had a significant effect on the reduction of the risk of nonaccidental death.

Abstract The Hewlett Packard Enterprise–Cray EX Frontier is the world’s first and fastest exascale supercomputer, hosted at the Oak Ridge Leadership Computing Facility in Tennessee, United States. Frontier is a significant electricity consumer, drawing 8–30 MW; this massive energy demand produces significant waste heat, requiring extensive cooling measures. Although harnessing this waste heat for campus heating is a sustainability goal at Oak Ridge National Laboratory (ORNL), the 30 °C–38 °C waste heat temperature poses compatibility issues with standard HVAC systems. Heat pump systems, prevalent in residential settings and some industries, can efficiently upgrade low-quality heat to usable energy for buildings. Thus, heat pump technology powered by renewable electricity offers an efficient, cost-effective solution for substantial waste heat recovery. However, a major challenge is the absence of benchmark data on high-performance computing (HPC) heat generation and waste heat profiles. This paper reports power demand and waste heat measurements from an ORNL HPC data centre, aiming to guide future research on optimizing waste heat recovery in large-scale data centres, especially those of HPC calibre.

Abstract Dysregulation of brain homeostasis is associated with neuropsychiatric conditions such as major depressive disorder. However, underlying neural-circuit mechanisms remain not well-understood. We show in mice that chronic restraint stress (CRS) and social defeat stress (SDS) are both associated with disruption of excitation (E)-inhibition (I) balance, with increased E/I ratios, in medial preoptic area (MPOA) circuits, but through affecting different neuronal types. CRS results in elevated activity in glutamatergic neurons, and their suppression mitigates CRS-induced depressive-like behaviors. Paraventricular hypothalamic input to these neurons contributes to induction but not expression of depressive-like behaviors. Their projections to ventral tegmental area and periaqueductal gray/dorsal raphe suppress midbrain dopaminergic and serotonergic activity, respectively, and mediate expression of divergent depressive-like symptoms. By contrast, SDS results in reduced activity of GABAergic neurons, and their activation alleviates SDS-induced depressive-like behaviors. Thus, E/I imbalance with relatively increased excitation in MPOA circuits may be a general mechanism underlying depression caused by different etiological factors.

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.

Abstract Aiming at the multi-objective vehicle path planning problem with time windows (VRPTW), a Spark-based parallel Adaptive Large Neighborhood Search algorithm (Spark-ALNS) is proposed to solve it. The main design of the 4-point strategy: (1) Design a new simulated annealing algorithm cooling strategy to achieve a better jump out of the local optimal solution. (2) Adopt CW initialization to accelerate the convergence speed. (3) Use three destruction operators and three repair operators to implement local path optimization. (4) A new parallel strategy is proposed to improve the algorithm’s accuracy and reduce the running time. To illustrate the algorithm’s effectiveness, the arithmetic example in Solomon is used as an example. The experimental results show that the proposed Spark-ALNS can find better solutions, get the known optimal solutions for 41 out of 56 instances, and find new optimal solutions for 31 algorithms, which outperforms other evolutionary algorithms. The runtime is 3–5 times better than other parallel algorithms and is able to solve VRPTW effectively.

Abstract Vascular calcification (VC) arises from the accumulation of calcium salts in the intimal or tunica media layer of the aorta, contributing to higher risk of cardiovascular events and mortality. Despite this, the mechanisms driving VC remain incompletely understood. We previously described that nesfatin-1 functioned as a switch for vascular smooth muscle cells (VSMCs) plasticity in hypertension and neointimal hyperplasia. In this study, we sought to investigate the role and mechanism of nesfatin-1 in VC. The expression of nesfatin-1 was measured in calcified VSMCs and aortas, as well as in patients. Loss- and gain-of-function experiments were evaluated the roles of nesfatin-1 in VC pathogenesis. The transcription activation of nesfatin-1 was detected using a mass spectrometry. We found higher levels of nesfatin-1 in both calcified VSMCs and aortas, as well as in patients with coronary calcification. Loss-of-function and gain-of-function experiments revealed that nesfatin-1 was a key regulator of VC by facilitating the osteogenic transformation of VSMCs. Mechanistically, nesfatin-1 promoted the de-ubiquitination and stability of BMP-2 via inhibiting the E3 ligase SYTL4, and the interaction of nesfatin-1 with BMP-2 potentiated BMP-2 signaling and induced phosphorylation of Smad, followed by HDAC4 phosphorylation and nuclear exclusion. The dissociation of HDAC4 from RUNX2 elicited RUNX2 acetylation and subsequent nuclear translocation, leading to the transcription upregulation of OPN, a critical player in VC. From a small library of natural compounds, we identified that Curculigoside and Chebulagic acid reduced VC development via binding to and inhibiting nesfatin-1. Eventually, we designed a mass spectrometry-based DNA-protein interaction screening to identify that STAT3 mediated the transcription activation of nesfatin-1 in the context of VC. Overall, our study demonstrates that nesfatin-1 enhances BMP-2 signaling by inhibiting the E3 ligase SYTL4, thereby stabilizing BMP-2 and facilitating the downstream phosphorylation of SMAD1/5/9 and HDAC4. This signaling cascade leads to RUNX2 activation and the transcriptional upregulation of MSX2, driving VC. These insights position nesfatin-1 as a potential therapeutic target for preventing or treating VC, advancing our understanding of the molecular mechanisms underlying this critical cardiovascular condition.

Nonalcoholic steatohepatitis (NASH) may soon become the leading cause of end-stage liver disease worldwide with limited treatment options. Liver fibrosis, which is driven by chronic inflammation and hepatic stellate cell (HSC) activation, critically determines morbidity and mortality in patients with NASH. Pyruvate kinase M2 (PKM2) is involved in immune activation and inflammatory liver diseases; however, its role and therapeutic potential in NASH-related fibrosis remain largely unexplored. Bioinformatics screening and analysis of human and murine NASH livers indicated that PKM2 was upregulated in nonparenchymal cells (NPCs), especially macrophages, in the livers of patients with fibrotic NASH. Macrophage-specific PKM2 knockout (PKM2FL/FLLysM-Cre) significantly ameliorated hepatic inflammation and fibrosis severity in three distinct NASH models induced by a methionine- and choline-deficient (MCD) diet, a high-fat high-cholesterol (HFHC) diet, and a western diet plus weekly carbon tetrachloride injection (WD/CCl4). Single-cell transcriptomic analysis indicated that deletion of PKM2 in macrophages reduced profibrotic Ly6Chigh macrophage infiltration. Mechanistically, PKM2-dependent glycolysis promoted NLR family pyrin domain containing 3 (NLRP3) activation in proinflammatory macrophages, which induced HSC activation and fibrogenesis. A pharmacological PKM2 agonist efficiently attenuated the profibrotic crosstalk between macrophages and HSCs in vitro and in vivo. Translationally, ablation of PKM2 in NPCs by cholesterol-conjugated heteroduplex oligonucleotides, a novel oligonucleotide drug that preferentially accumulates in the liver, dose-dependently reversed NASH-related fibrosis without causing observable hepatotoxicity. The present study highlights the pivotal role of macrophage PKM2 in advancing NASH fibrogenesis. Thus, therapeutic modulation of PKM2 in a macrophage-specific or liver-specific manner may serve as a novel strategy to combat NASH-related fibrosis.

Abstract Background Paraplegia after spinal cord ischemia is a devastating condition in the clinic. Here, we develop an awake rabbit model of spinal cord ischemia with delayed paraplegia and explore the influence of ambient temperature on the outcomes after injury. Methods A total of 47 male rabbits were involved in the present study. Transient spinal cord ischemia was induced by occluding the infrarenal abdominal aorta of awake rabbits at different ambient temperatures. To find the optimal conditions for developing delayed paraplegia, hindlimb motor function after ischemia was evaluated between experiments. Results The onset and magnitude of ischemic injury varied with the ambient temperature maintained during the peri‐ischemia period. More serious spinal cord injury occurred when ischemia was induced at higher temperatures. At 18°C, 25‐minute ischemia resulted in 74% of rabbits developing delayed paraplegia. At a temperature of 28°C or higher, most of the animals developed acute paraplegia immediately. While at 13°C, rabbits usually regained normal motor function without paraplegia. Conclusion This awake rabbit model is highly reproducible and will be helpful in future studies of delayed paraplegia after spinal cord ischemia. The ambient temperature must be considered while using this model during investigation of therapeutic interventions.

Abstract Background Atrial fibrillation (AF) has emerged as a notable public health issue in China due to the aging population and rapid urbanization. This study aimed to describe the characteristics of patients with AF (paroxysmal and nonparoxysmal) and investigate the association between left ventricular ejection fraction (LVEF) levels and AF subtypes to facilitate early prevention in patients with AF. Method Patients with AF who presented at the cardiology department of the First People’s Hospital of Yancheng were recruited in this study. In univariate and multivariate logistic regression analyses, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the relationships between each dependent variable and nonparoxysmal AF. The restricted cubic splines (RCS) curve was employed to explore the linear relationship between LVEF and nonparoxysmal AF on a continuous scale. Subgroup analysis was applied to examine the stability of the results. Results The study included a total of 2054 patients who were diagnosed with AF. 652 (31.74%) patients had paroxysmal AF, and 1402 (68.26%) had nonparoxysmal AF. Multivariate logistic regression analyses indicated that compared to those with paroxysmal AF, patients with nonparoxysmal AF tended to have a higher prevalence of coronary artery disease, lower levels of LVEF, and an elevated heart rate. Additionally, RCS curves also showed that LVEF was negatively and linearly associated with the nonparoxysmal AF. Furthermore, the association between LVEF and nonparoxysmal AF was stronger among patients with hypertension and obesity (P for interaction