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Abstract The study aims to investigate the potential of training efficient deep learning models by using 2.5D (2.5-Dimension) masks of sICH. Furthermore, it intends to evaluate and compare the predictive performance of a joint model incorporating four types of features with standalone 2.5D deep learning, radiomics, radiology, and clinical models for early expansion in sICH. A total of 254 sICH patients were enrolled retrospectively and divided into two groups according to whether the hematoma was enlarged or not. The 2.5D mask of sICH is constructed with the maximum axial, coronal and sagittal planes of the hematoma, which is used to train the deep learning model and extract deep learning features. Predictive models were built on clinic, radiology, radiomics and deep learning features separately and four type features jointly. The diagnostic performance of each model was measured using the receiver operating characteristic curve (AUC), Accuracy, Recall, F1 and decision curve analysis (DCA). The AUCs of the clinic model, radiology model, radiomics model, deep learning model, joint model, and nomogram model on the train set (training and Cross-validation) were 0.639, 0.682, 0.859, 0.807, 0.939, and 0.942, respectively, while the AUCs on the test set (external validation) were 0.680, 0.758, 0.802, 0.857, 0.929, and 0.926. Decision curve analysis showed that the joint model was superior to the other models and demonstrated good consistency between the predicted probability of early hematoma expansion and the actual occurrence probability. Our study demonstrates that the joint model is a more efficient and robust prediction model, as verified by multicenter data. This finding highlights the potential clinical utility of a multifactorial prediction model that integrates various data sources for prognostication in patients with intracerebral hemorrhage. The Critical Relevance Statement: Combining 2.5D deep learning features with clinic features, radiology markers, and radiomics signatures to establish a joint model enabling physicians to conduct better-individualized assessments the risk of early expansion of sICH.

This paper focuses on the stochastic stabilization of hidden semi-Markov jump nonlinear positive systems. First, a notion of stochastic stability is introduced for this class of systems. A criterion is addressed to ensure the stochastic stability using a stochastic copositive Lyapunov function. Then, an observed mode is proposed to estimate the emitted value of the hidden semi-Markov process and the mode-dependent controller is designed using an improved matrix decomposition approach. Some auxiliary variables are added to decouple the coupling terms in hidden semi-Markov jump nonlinear positive systems into a tractable condition. All conditions are described in terms of linear programming. Moreover, the proposed design is developed for systems with partially known emission probabilities. Two examples are provided to show the validity of the obtained results.

The biomedical application of self-healing materials in wet or (under)water environments is quite challenging because the insulation and dissociation effects of water molecules significantly reduce the reconstruction of material–interface interactions. Rapid closure with uniform tension of high-tension wounds is often difficult, leading to further deterioration and scarring. Herein, a new type of thermosetting water-resistant self-healing bioelastomer (WRSHE) was designed by synergistically incorporating a stable polyglycerol sebacate (PGS) covalent crosslinking network and triple hybrid dynamic networks consisting of reversible disulfide metathesis (SS), and dimethylglyoxime urethane (Dou) and hydrogen bonds. And a resveratrol-loaded WRSHE (Res@WRSHE) was developed by a swelling, absorption, and crosslinked network locking strategy. WRSHEs exhibited skin-like mechanical properties in terms of nonlinear modulus behavior, biomimetic softness, high stretchability, and good elasticity, and they also achieved ultrafast and highly efficient self-healing in various liquid environments. For wound-healing applications of high-tension full-thickness skin defects, the convenient surface assembly by self-healing of WRSHEs provides uniform contraction stress to facilitate tight closure. Moreover, Res@WRSHEs gradually release resveratrol, which helps inflammatory response reduction, promotes blood vessel regeneration, and accelerates wound repair.

Abstract In the context of globalization, the integration of cultural elements into scientific research, particularly through the incorporation of traditional Chinese cultural motifs in scientific illustrations, represents a novel frontier in enhancing the universality and appeal of scientific discoveries. This paper explores the innovative practice of embedding traditional Chinese cultural elements into scientific paper illustrations, highlighting its significant role in augmenting the global appeal of research findings, promoting diversity and innovation in scientific inquiry, and facilitating cross-cultural understanding. Through a series of case studies, including symbolic representations of ancient myths and the use of traditional themes to elucidate complex scientific phenomena, we demonstrate how this cultural integration not only makes scientific content more accessible and engaging but also fosters a deeper appreciation of Chinese heritage among international audiences. This approach not only bridges the gap between science and culture but also contributes to a more inclusive and interconnected global scientific community, underscoring the importance of cultural diversity in enriching scientific exploration and communication.

Abstract The present study aimed to explore the underlying mechanism of bile reflux-inducing chronic atrophic gastritis (CAG) with colonic mucosal lesion. The rat model of CAG with colonic mucosal lesion was induced by free-drinking 20 mmol/L sodium deoxycholate to simulate bile reflux and 2% cold sodium salicylate for 12 weeks. In comparison to the control group, the model rats had increased abundances of Bacteroidetes and Firmicutes but had decreased abundances of Proteobacteria and Fusobacterium. Several gut bacteria with bile acids transformation ability were enriched in the model group, such as Blautia, Phascolarctobacter, and Enterococcus. The cytotoxic deoxycholic acid and lithocholic acid were significantly increased in the model group. Transcriptome analysis of colonic tissues presented that the down-regulated genes enriched in T cell receptor signaling pathway, antigen processing and presentation, Th17 cell differentiation, Th1 and Th2 cell differentiation, and intestinal immune network for IgA production in the model group. These results suggest that bile reflux-inducing CAG with colonic mucosal lesion accompanied by gut dysbacteriosis, mucosal immunocompromise, and increased gene expressions related to repair of intestinal mucosal injury.

Abstract Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer with the worst prognosis. Radiotherapy (RT) is one of the core modalities for the disease; however, the ionizing radiation of RT has severe side effects. The consistent development direction of RT is to achieve better therapeutic effect with lower radiation dose. Studies have demonstrated that synergistic effects can be achieved by combining RT with non-ionizing radiation therapies such as light and magnetic therapy, thereby achieving the goal of dose reduction and efficacy enhancement. Methods In this study, we applied FeCo NPs with magneto thermal function and phototherapeutic agent IR-780 to construct an ionizing and non-ionizing radiation synergistic nanoparticle (INS NPs). INS NPs are first subjected to morphology, size, colloidal stability, loading capacity, and photothermal conversion tests. Subsequently, the cell inhibitory and cellular internalization were evaluated using cell lines in vitro. Following comprehensive assessment of the NPs’ in vivo biocompatibility, tumor-bearing mouse model was established to evaluate their distribution, targeted delivery, and anti-tumor effects in vivo. Results INS NPs have a saturation magnetization exceeding 72 emu/g, a hydrodynamic particle size of approximately 40 nm, a negatively charged surface, and good colloidal stability and encapsulation properties. INS NPs maintain the spectral characteristics of IR-780 at 808 nm. Under laser irradiation, the maximum temperature was 92 °C, INS NPs also achieved the effective heat temperature in vivo. Both in vivo and in vitro tests have proven that INS NPs have good biocompatibility. INS NPs remained effective for more than a week after one injection in vivo, and can also be guided and accumulated in tumors through permanent magnets. Later, the results exhibited that under low-dose RT and laser irradiation, the combined intervention group showed significant synergetic effects, and the ROS production rate was much higher than that of the RT and phototherapy-treated groups. In the mice model, 60% of the tumors were completely eradicated. Conclusions INS NPs effectively overcome many shortcomings of RT for TNBC and provide experimental basis for the development of novel clinical treatment methods for TNBC.

Abstract The use of nanomaterials in gene editing and synthetic biology has emerged as a pivotal strategy in the pursuit of refined treatment methodologies for pulmonary disorders. This review discusses the utilization of nanomaterial-assisted gene editing tools and synthetic biology techniques to promote the development of more precise and efficient treatments for pulmonary diseases. First, we briefly outline the characterization of the respiratory system and succinctly describe the principal applications of diverse nanomaterials in lung ailment treatment. Second, we elaborate on gene-editing tools, their configurations, and assorted delivery methods, while delving into the present state of nanomaterial-facilitated gene-editing interventions for a spectrum of pulmonary diseases. Subsequently, we briefly expound on synthetic biology and its deployment in biomedicine, focusing on research advances in the diagnosis and treatment of pulmonary conditions against the backdrop of the coronavirus disease 2019 pandemic. Finally, we summarize the extant lacunae in current research and delineate prospects for advancement in this domain. This holistic approach augments the development of pioneering solutions in lung disease treatment, thereby endowing patients with more efficacious and personalized therapeutic alternatives.

Abstract Background Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) exhibit potential as therapeutics for a variety of diseases. This observational and Mendelian randomization (MR) study aims to explore the relationship between omega-3 PUFAs and osteoarthritis (OA). Methods Excluding individuals under 20 years old and those with missing data on relevant variables in the National Health and Nutrition Examination Survey (NHANES) spanning from 2003 to 2016, a total of 22 834 participants were included in this cross-sectional study. Weighted multivariable-adjusted logistic regression was used to estimate the association between omega-3 PUFAs and OA in adults. Moreover, restricted cubic splines were utilized to examine the dose-response relationship between omega-3 PUFAs and OA. To further investigate the potential causal relationship between omega-3 PUFAs and OA risk, a two-sample MR study was conducted. Furthermore, the robustness of the findings was assessed using various methods. Results Omega-3 PUFAs intake were inversely associated with OA in adults aged 40 ∼ 59 after multivariable adjustment $$[\text{OR} (95\% \text{CI): }0.85 (0.73, 0.98), P = 0.027]$$ , with a nonlinear relationship observed between omega-3 PUFAs intake and OA $$\left(P \text{ for non-linearity}\text{ = 0.034}\right)$$ . The IVW results showed there was no evidence to suggest a causal relationship between omega-3 PUFAs and OA risk $$\text{[OR} (95\% \text{CI): }0.967 (0.863, 1.084), P = 0.568]$$ . Conclusions Omega-3 PUFAs were inversely associated with OA in adults aged 40 ∼ 59. However, MR studies did not confirm a causal relationship between the two.

BackgroundTranscutaneous Vagal Nerve Stimulation (tVNS) has been used as a promising noninvasive neuromodulation technique for the treatment of various systems.The aim of this study was to analyze the research hotspots and future directions of tVNS in the 21st century by using bibliometric methods.MethodsThe study object was the literature related to tVNS from the Web of Science database from 2000 to May 2024. In order to measure and analyze the number of literature issuance, institutions, authors, countries, keywords, co-citations, and journals of publication, we used VOSviewer, Citespace, Bibliometrix R-package, and Scimago Graphica software. A narrative review of the current research content of tVNS was conducted to gain a better understanding of the current state of the field.ResultsA total of 569 papers were included in the study. The results show that from 2000 to 2024, the number of publications shows an increasing trend year by year, involving a total of 326 research institutions. The United States, China, and Germany are the major research centers. The study identified 399 keywords, which roughly formed 11 natural clusters, revealing that the current hotspots of related research are mainly reflected in 3 areas: intervention efficacy on nervous system diseases, mechanism of action of tVNS, and stimulation mode of tVNS. The top 10 most cited references focus on research into the mechanism of action of tVNS.ConclusionThe efficacy and safety of tVNS have been confirmed in previous studies, but a standardized tVNS treatment protocol has not yet been developed, and most clinical studies have small sample sizes and lack multicenter and multidisciplinary collaboration. Currently, tVNS is used in the treatment of neurological diseases, psychiatric diseases, cardiovascular diseases, and some autoimmune diseases. It is expected that future research in this field will continue to focus on the application of tVNS in central nervous system diseases and the exploration of related mechanisms, and at the same time, with the rise of non-invasive neuromodulation technology, the application of tVNS in other diseases also has great potential for development.

BackgroundAcute coronary syndrome (ACS) is a leading cause of morbidity and mortality worldwide. In recent years, ACS has been reported to be associated with age, and the incidence has become more common in younger patients. Previous studies have identified various risk factors that contribute to the stratification of ACS patients. However, it remains unclear whether these risk factors, along with proteomic and clinical characteristics, are applicable to young ACS patients, as they are for middle-aged and elderly patients. This study aimed to investigate the proteomics, risk factors, and clinical characteristics of young ACS patients, as well as the differences between them and middle-aged and elderly ACS patients. By comparing these findings with those of middle-aged and elderly patients, we aimed to identify any discrepancies and these findings possibly may have implications for future management strategies of this specific population.MethodsThis observational study included a total of 187 participants diagnosed with ACS and 17 young healthy individuals as the control group. ACS patients were divided into three age groups:

Abstract Diabetic cardiomyopathy (DbCM) is characterized by diastolic dysfunction, which progresses into heart failure and aberrant electrophysiology in diabetic patients. Dyslipidemia in type 2 diabetic patients leads to the accumulation of lipid droplets (LDs) in cardiomyocytes and results in lipid toxicity which has been suggested to drive DbCM. It is aimed to explore potential pathways that may boost LDs degradation in DbCM and restore cardiac function. LDs accumulation resulted in an increase in lipid toxicity in DbCM hearts is confirmed. Microlipophagy pathway, rather than traditional macrolipophagy, is activated in DbCM hearts. RNA‐Seq data and Rab7‐CKO mice implicate that Rab7 is a major modulator of the microlipophagy pathway. Mechanistically, Rab7 is phosphorylated at Tyrosine 183, which allows the recruitment of Rab‐interacting lysosome protein (Rilp) to proceed LDs degradation by lysosome. Treating DbCM mice with Rab7 activator ML‐098 enhanced Rilp level and rescued the observed cardiac dysfunction. Overall, Rab7‐Rilp‐mediated microlipophagy may be a promising target in the treatment of lipid toxicity in DbCM is suggested.

IntroductionFospropofol disodium is a novel prodrug that has improved pharmacokinetic and pharmacodynamic properties when compared with propofol. This trial aims to compare the efficacy and safety of fospropofol versus propofol sedation for same-day bidirectional endoscopy in elderly patients.Methods and analysisThis is a prospective, single-center, double-blind, randomized, propofol-controlled, non-inferiority trial. A total of 256 patients aged 65 years or older, who are scheduled for same-day bidirectional endoscopy under sedation, will be randomly allocated, in a 1:1 ratio, to either fospropofol group or propofol group (n = 128 in each group). All patients will receive analgesic pre-treatment with sufentanil 5 μg. Two minutes later, an initial bolus dose of fospropofol 6.5 mg/kg or 1.5 mg/kg propofol and supplemental doses of fospropofol 1.6 mg/kg or 0.5 mg/kg propofol will be titrated as needed to achieve target sedation levels during the procedures. The primary outcome is the success rate of same-day bidirectional endoscopy. Secondary outcomes include the time to successful induction of sedation, duration, time to being fully alert, time to patient discharge, endoscopist satisfaction, patient satisfaction, and the top-up frequency and dosage of sedative medications. The safety endpoints consist of adverse events concerning cough reflex, gag reflexes, body movement, muscular tremor, and pain on injection. Sedation-related AEs, including episodes of desaturation, severe desaturation (SpO2 < 90%), hypotension, severe hypotension (decrease in MBP ≥30% of baseline), and bradycardia, will also be recorded. Data will be analyzed on an intention-to-treat basis.DiscussionWe hypothesize that the efficacy and safety of fospropofol sedation for elderly patients undergoing same-visit bidirectional endoscopy will not be inferior to that of propofol. Our findings will potentially provide a new sedation regimen for same-visit bidirectional endoscopy in elderly patients.Clinical Trial Registrationclinicaltrials.gov, identifier NCT02875639

Abstract Acute lung injury (ALI) is generally caused by severe respiratory infection and characterized by overexuberant inflammatory responses and inefficient pathogens-containing, the two major processes wherein alveolar macrophages (AMs) play a central role. Dysfunctional mitochondria have been linked with distorted macrophages and hence lung disorders, but few treatments are currently available to correct these defects. Plant-derive nanovesicles have gained significant attention because of their therapeutic potential, but the targeting cells and the underlying mechanism remain elusive. We herein prepared the nanovesicles from Artemisia annua, a well-known medicinal plant with multiple attributes involving anti-inflammatory, anti-infection, and metabolism-regulating properties. By applying three mice models of acute lung injury caused by bacterial endotoxin, influenza A virus (IAV) and SARS-CoV-2 pseudovirus respectively, we showed that Artemisia-derived nanovesicles (ADNVs) substantially alleviated lung immunopathology and raised the survival rate of challenged mice. Macrophage depletion and adoptive transfer studies confirmed the requirement of AMs for ADNVs effects. We identified that gamma-aminobutyric acid (GABA) enclosed in the vesicles is a major molecular effector mediating the regulatory roles of ADNVs. Specifically, GABA acts on macrophages through GABA receptors, promoting mitochondrial gene programming and bioenergy generation, reducing oxidative stress and inflammatory signals, thereby enhancing the adaptability of AMs to inflammation resolution. Collectively, this study identifies a promising nanotherapeutics for alleviating lung pathology, and elucidates a mechanism whereby the canonical neurotransmitter modifies AMs and mitochondria to resume tissue homeostasis, which may have broader implications for treating critical pulmonary diseases such as COVID-19.

Abstract Background A-to-I RNA editing is an abundant post-transcriptional modification event in hepatocellular carcinoma (HCC). Evidence suggests that adenosine deaminases acting on RNA 1 (ADAR1) correlates to oxidative stress that is a crucial factor of HCC pathogenesis. The present study investigated the effect of ADAR1 on survival and oxidative stress of HCC, and underlying mechanisms. Methods ADAR1 expression was measured in fifty HCC and normal tissues via real-time quantitative PCR, and immunohistochemistry. For stable knockdown or overexpression of ADAR1, adeno-associated virus vectors carrying sh-ADAR1 or ADAR1 overexpression were transfected into HepG2 and SMMC-7721 cells. Transfected cells were exposed to oxidative stress agonist tBHP or sorafenib Bay 43-9006. Cell proliferation, apoptosis, and oxidative stress were measured, and tumor xenograft experiment was implemented. Results ADAR1 was up-regulated in HCC and correlated to unfavorable clinical outcomes. ADAR1 deficiency attenuated proliferation of HCC cells and tumor growth and enhanced apoptosis. Moreover, its loss facilitated intracellular ROS accumulation, and elevated Keap1 and lowered Nrf2 expression. Intracellular GSH content and SOD activity were decreased and MDA content was increased in the absence of ADAR1. The opposite results were observed when ADAR1 was overexpressed. The effects of tBHP and Bay 43–9006 on survival, apoptosis, intracellular ROS accumulation, and Keap1/Nrf2 pathway were further exacerbated by simultaneous inhibition of ADAR1. Conclusions The current study unveils that ADAR1 is required for survival and oxidative stress of HCC cells, and targeting ADAR1 may sensitize HCC cells to oxidative stress via modulating Keap1/Nrf2 pathway.

Abstract Background The diameter of the ostial and proximal left main coronary artery can be greater than 5.0 mm. However, the diameters of the mostly available coronary drug-eluting stents (DESs) are ≤ 4.0 mm. Whether high-pressure dilatation can increase the diameter of stents from 4.0 to 5.0 mm and whether post-dilatation leads to longitudinal stent deformation (LSD) of 4.0-mm-diameter stents have rarely been studied. Therefore, this study aims to evaluate LSD and stent malapposition of six types of commercially available 4.0-mm-diameter stents in China in a 5.0-mm-diameter artificial blood vessel model by optical coherence tomography (OCT) in vitro. Methods The left main coronary artery was simulated by a truncated cone-shaped silicone tube. The internal diameters were 4.0 mm at one end of the silicone tube and 5.0 mm at the other end. Six different types of coronary stents widely used in China were selected for this study. Each stent was respectively implanted into the simulated blood vessel and dilated to a diameter of 4.2 mm according to the stent-balloon pressure compliance table. The stents were subjected to post-dilatation with a 5.0 × 15-mm noncompliant balloon. The LSD ratio of the longitudinal axis of each stent and stent malapposition were measured through OCT, and any fractures of the stents were determined. Results None of the six types of stents fractured following post-dilatation. The longitudinal axes of the BuMA and Excrossal stents were slightly shortened, while the other stents were elongated after high-pressure post-dilatation. All stents expanded to a diameter of 5.0 mm without incomplete stent apposition, except for the Nano Plus stent, which remained malapposed after high-pressure post-dilatation. Conclusion All 4.0-mm-diameter stents can be expanded to a diameter of 5.0 mm by noncompliant balloon post-dilatation without stent strut fracture. Most stents were found to be well apposed after high-pressure post-dilatation. However, LSD was observed after post-balloon dilatation. Stent malapposition might be positively correlated with the percentage change in stent length.

Polyoxymethylene dimethyl ethers (DMMx, CH3O(CH2O)xCH3, x = 1–8) are appealing oxygenated chemicals with potential applications mainly used as sustainable fuels and solvents. The growth of longer C-O chain for direct oxidation of dimethyl ether (DME) to DMMx is especially important, but the construction of the acid sites with different strengths and matched redox sites faces great difficulties. Herein, the gradient acidity and enhanced oxidizability have been successfully created by regulating coordination structure of titanium sulfate (Ti(SO4)x). The formation of a higher proportion of weak-medium acid sites and appropriate redox sites over a Ti(SO4)x/activated carbon (AC) catalyst with nitrogen treatment significantly promotes the synthesis of larger molecules, with DMM2–3 selectivity up to 42.2%. Combined with the characterizations, designed experiments and theoretical calculations, the configurations of Ti(SO4)x and their local chemical environment are revealed. The different distortions of Ti(SO4)x structure in nitrogen atmosphere result in the various coordination unsaturated Ti atoms located at the center of polyhedral, which is the main reason for the gradient acidity distribution and enhanced oxidative property.

BackgroundRepetitive transcranial magnetic stimulation (rTMS), as an emerging non-invasive neuromodulation technique, is now widely employed in rehabilitation therapy. The purpose of this paper is to comprehensively summarize existing evidence regarding rTMS intervention for lower limb motor function in patients at different stages of stroke.MethodsA systematic search was conducted to identify randomized controlled trials (RCTs) assessing the efficacy of rTMS for treating lower limb motor dysfunction after stroke. Multiple databases, including China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, VIP Database, PubMed, Embase, Web of Science, and Cochrane Library, were searched. The search period extended from the inception of the libraries to June 2024. Literature information was extracted, and methodological quality was evaluated using the risk of bias assessment tool in the Cochrane Handbook. Meta-analysis was performed using Stata 17.0 software.ResultsOverall, 49 appropriate studies (including 3,558 stroke subjects) were found. Meta-analysis results demonstrated that rTMS effectively improved lower limb motor function across all stages of stroke. The intervention was particularly more effective in patients in the subacute stage than in the acute or chronic stages. Subgroup analysis revealed that, for acute-stage patients, low-frequency stimulation targeting the M1 or DLPFC brain regions on the unaffected side with 20–40 sessions significantly improved FMA-LE scores. In subacute-phase patients, low-frequency stimulation targeting the M1 brain regions on the unaffected side with 18 sessions significantly improved FMA-LE scores. The results demonstrated that HF-rTMS was more effective than LF-rTMS in improving walking speed, with the greatest efficacy observed at 20 sessions. While for enhancing gait balance in stroke patients, LF-rTMS with the best therapeutic effect was observed at a frequency of 20–40 treatments.ConclusionThis study demonstrates the efficacy of rTMS in improving lower limb motor function, balance, and walking speed in stroke patients at various stages. The findings provide a valuable reference for the development of optimized rTMS treatment plans in clinical practice.Systematic review registration: PROSPERO: CRD42023466094.

Most colon cancer patients are diagnosed at an advanced stage, with a grim prognosis. In clinical, various combination therapies have been employed to enhance the efficacy of colon cancer treatment. The essence of combined treatment is the judicious selection and combination of various treatment units. Phototherapy (PT), sonodynamic therapy (SDT), and chemotherapy are treatment modalities that rely on the active molecules to treat tumors, and have been demonstrated to synergistically enhance tumor treatment efficacy. However, the differences in the metabolism of active molecules and hypoxic microenvironment of tumors have limited the synergistic effects of the aforementioned methods. To address this significant issue, in this study, we utilized polydopamine (PDA) as the encapsulated material to form a rigid shell that contains the therapeutic molecules IR-780 and methotrexate (MTX) on the surface of perfluorohexane (PFH) microdroplets through self-assembling method to develop an SDT/chemotherapy/PT combined nanoparticles (SCP NPs). Transmission electron microscopy (TEM) revealed that the nanoparticles exhibited a hollow shell structure, with an average size of approximately 100 nm. SCP NPs have excellent stability and biocompatibility in both in vitro and in vivo. The absorption and emission spectrum of the loaded IR-780 did not exhibit any significant shift, and the photothermal temperature rose to 92°C. Their ultrasonic cavitation effect was good and their cell inhibitory effect of MTX was maintained. SCP NPs can achieve multi-modal triggered release through ultrasound, laser irradiation, and pH, ensuring a simultaneous accumulation of therapeutic molecules in the tumor area and effectively alleviating tumor hypoxia. Additionally, both the near-infrared fluorescence (NIF) signal and the ultrasonic cavitation signal of the nanoparticles can be utilized for tracking and monitoring treatment efficacy. Most notably, SCP NPs exhibited outstanding synergistic treatment effects at low intervention levels, resulting in a 67% cure rate of tumors. These results provide an experimental basis for developing the new clinical treatments for colon cancer.

BackgroundAcupuncture, as an alternative and complementary therapy recommended by the World Health Organization for stroke treatment, holds potential in ameliorating neurofunctional deficits induced by ischemic stroke (IS). Understanding the immediate and long-term effects of acupuncture and their interrelation would contribute to a better comprehension of the mechanisms underlying acupuncture efficacy.MethodsActivation likelihood estimation (ALE) meta-analysis was used to analyze the brain activation patterns reported in 21 relevant functional neuroimaging studies. Among these studies, 12 focused on the immediate brain activation and 9 on the long-term activation. Single dataset analysis were employed to identify both immediate and long-term brain activation of acupuncture treatment in IS patients, while contrast and conjunction analysis were utilized to explore distinctions and connections between the two.ResultsAccording to the ALE analysis, immediately after acupuncture treatment, IS patients exhibited an enhanced cluster centered around the right precuneus (PCUN) and a reduced cluster centered on the left middle frontal gyrus (MFG). After long-term acupuncture treatment, IS patients showed an enhanced cluster in the left PCUN, along with two reduced clusters in the right insula (INS) and hippocampus (HIP), respectively. Additionally, in comparison to long-term acupuncture treatment, the right angular gyrus (ANG) demonstrated higher ALE scores immediately after acupuncture, whereas long-term acupuncture resulted in higher scores in the left superior parietal gyrus (SPG). The intersecting cluster activated by both of them was located in the left cuneus (CUN).ConclusionThe findings provide initial insights into both the immediate and long-term brain activation patterns of acupuncture treatment for IS, as well as the intricate interplay between them. Both immediate and long-term acupuncture treatments showed distinct patterns of brain activation, with the left CUN emerging as a crucial regulatory region in their association.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, CRD42023480834.

Summary: Obesity is a global health challenge with limited therapeutic solutions. Here, we demonstrate the engineering of an energy-dissipating hybrid tissue (EDHT) in the body for weight control. EDHT is constructed by implanting a synthetic gel matrix comprising immunomodulatory signals and functional cells into the recipient mouse. The immunomodulatory signals induce the host stromal cells to create an immunosuppressive niche that protects the functional cells, which are overexpressing the uncoupling protein 1 (UCP1), from immune rejection. Consequently, these endogenous and exogenous cells co-develop a hybrid tissue that sustainedly produces UCP1 to accelerate the host’s energy expenditure. Systematic experiments in high-fat diet (HFD) and transgenic (ob/ob) mice show that EDHT efficiently reduces body weight and relieves obesity-associated pathological conditions. Importantly, an 18-month observation for safety assessment excludes cell leakage from EDHT and reports no adverse physiological responses. Overall, EDHT demonstrates convincing efficacy and safety in controlling body weight.

Microplastics (MPs), emerging as significant pollutants, have been consistently detected in aquatic environments, with the Yangtze River experiencing a particularly severe level of microplastic pollution, exceeding all other watersheds in China. Polypropylene (PP), the plastic most abundantly found in the middle and lower reaches of the Yangtze River Basin, has less comprehensive research results into its toxic effects. Consequently, the present investigation employed zebrafish as a model organism to delve into the toxicological impacts of polypropylene microplastics (PP-MPs) with a diameter of 5 μm across varying concentrations (300 mg/L and 600 mg/L). Using histopathological, microbiota profiling, and transcriptomic approaches, we systematically evaluated the impact of PP-MPs exposure on the intestine and liver of zebrafish. Histopathological analysis revealed that exposure to PP-MPs resulted in thinner intestinal walls, damaged intestinal mucosa, and hepatic cellular damage. Intestinal microbiota profiling demonstrated that, the richness, uniformity, diversity, and homogeneity of gut microbes significantly increased after the PP-MPs exposure at high concentration. These alterations were accompanied by shifts in the relative abundance of microbiota associated with intestinal pathologies, suggesting a profound impact on the intestinal microbial community structure. Concurrently, hepatic transcriptome analysis and RT-qPCR indicated that the downregulation of pathways and genes associated with cell proliferation regulation and DNA damage repair mechanisms contributed to hepatic cellular damage, ultimately exerting adverse effects on the liver. Correlation analysis between the intestinal microbiota and liver transcriptome profiles further highlighted significant associations between intestinal microbiota and the downregulated hepatic pathways. Collectively, these results provide novel insights into the subacute toxicological mechanisms of PP-MPs in aquatic organisms and highlight the need for further research on the ecological and health risks associated with PP-MPs pollution.

Abstract The incidence rate of cancer is increasing year by year due to the aging of the population, unhealthy living, and eating habits. At present, surgery and medication are still the main treatments for cancer, without paying attention to the impact of individual differences in health management on cancer. However, increasing evidence suggests that individual psychological status, dietary habits, and exercise frequency are closely related to the risk and prognosis of cancer. The reminder to humanity is that the medical concept of the unified treatment plan is insufficient in cancer treatment, and a personalized treatment plan may become a breakthrough point. On this basis, the concept of “Humanistic Health Management” (HHM) is proposed. This concept is a healthcare plan that focuses on self‐health management, providing an accurate and comprehensive evaluation of individual lifestyle habits, psychology, and health status, and developing personalized and targeted comprehensive cancer prevention and treatment plans. This review will provide a detailed explanation of the relationship between psychological status, dietary, and exercise habits, and the regulatory mechanisms of cancer. Intended to emphasize the importance of HHM concept in cancer prevention and better prognostic efficacy, providing new ideas for the new generation of cancer treatment.

This paper investigates the regional control problem of switched positive systems with multiple equilibrium points. A proportional-integral-derivative controller is designed by combining the output, the error between the state and the equilibrium point, and the difference of output. A cone is introduced to design the final stable region. Two classes of copositive Lyapunov functions are constructed to achieve the stability and regional stability of subsystems and the whole systems, respectively. Then, a novel class of observers with multiple equilibrium points is proposed using a matrix decomposition approach. The observer-based proportional-integral-derivative control problem is thus solved and all states are driven to the designed cone region under the designed controller. All conditions are formulated in the form of linear programming. The novelties of this paper lie in that: (i) A proportional-integral-derivative control framework is introduced for the considered systems, (ii) Luenberger observer is developed for the observer with multiple equilibrium points, and (iii) Copositive Lyapunov functions and linear programming are employed for the analysis and design of controller and observer. Finally, the effectiveness of the proposed design is verified via two examples.

Abstract The CRISPR-Cas9 system offers substantial potential for cancer therapy by enabling precise manipulation of key genes involved in tumorigenesis and immune response. Despite its promise, the system faces critical challenges, including the preservation of cell viability post-editing and ensuring safe in vivo delivery. To address these issues, this study develops an in vivo CRISPR-Cas9 system targeting tumor-associated macrophages (TAMs). We employ bacterial protoplast-derived nanovesicles (NVs) modified with pH-responsive PEG-conjugated phospholipid derivatives and galactosamine-conjugated phospholipid derivatives tailored for TAM targeting. Utilizing plasmid-transformed E. coli protoplasts as production platforms, we successfully load NVs with two key components: a Cas9-sgRNA ribonucleoprotein targeting Pik3cg, a pivotal molecular switch of macrophage polarization, and bacterial CpG-rich DNA fragments, acting as potent TLR9 ligands. This NV-based, self-assembly approach shows promise for scalable clinical production. Our strategy remodels the tumor microenvironment by stabilizing an M1-like phenotype in TAMs, thus inhibiting tumor growth in female mice. This in vivo CRISPR-Cas9 technology opens avenues for cancer immunotherapy, overcoming challenges related to cell viability and safe, precise in vivo delivery.

Abstract Background Aberrant intracellular or intercellular signaling pathways are important mechanisms that contribute to the development and progression of cancer. However, the intercellular communication associated with the development of ccRCC is currently unknown. The purpose of this study was to examine the aberrant tumor cell-to-cell communication signals during the development of ccRCC. Methods We conducted an analysis on the scRNA-seq data of 6 ccRCC and 6 normal kidney tissues. This analysis included sub clustering, CNV analysis, single-cell trajectory analysis, cell–cell communication analysis, and transcription factor analysis. Moreover, we performed validation tests on clinical samples using multiplex immunofluorescence. Results This study identified eleven aberrantly activated intercellular signaling pathways in tumor clusters from ccRCC samples. Among these, two of the majors signaling molecules, MIF and SPP1, were mainly secreted by a subpopulation of cancer stem cells. This subpopulation demonstrated high expression levels of the cancer stem cell markers POU5F1 and CD44 (POU5F1hiCD44hiE.T), with the transcription factor POU5F1 regulating the expression of SPP1. Further research demonstrated that SPP1 binds to integrin receptors on the surface of target cells and promotes ccRCC development and progression by activating potential signaling mechanisms such as ILK and JAK/STAT. Conclusion Aberrantly activated tumor intercellular signaling pathways promote the development and progression of ccRCC. The cancer stem cell subpopulation (POU5F1hiCD44hiE.T) promotes malignant transformation and the development of a malignant phenotype by releasing aberrant signaling molecules and interacting with other tumor cells.

Data mining has achieved great success in air traffic management as a technology for learning knowledge from historical data that benefits people. However, data mining can rarely be embedded into the trajectory optimization process since regular optimization algorithms cannot utilize the functional and implicit knowledge extracted from historical data in a general paradigm. To tackle this issue, this research proposes a novel data mining-based trajectory generation method that is compatible with existing optimization algorithms. Firstly, the proposed method generates trajectories by combining various maneuvers learned from operation data instead of reconstructing trajectories with generative models. In such a manner, data mining-based trajectory optimization can be achieved by solving a combinatorial optimization problem. Secondly, the proposed method introduces a majorization–minimization-based adversarial training paradigm to train the generation model with more general loss functions, including non-differentiable flight performance constraints. A case study on Guangzhou Baiyun International Airport was conducted to validate the proposed method. The results illustrate that the trajectory generation model can generate trajectories with high fidelity, diversity, and flyability.

Real-time semantic segmentation is a challenging task in computer vision, especially in complex scenes. In this study, a novel three-branch semantic segmentation model is designed, aiming to effectively use boundary information to improve the accuracy of semantic segmentation. The proposed model introduces the concept of containment control in a pioneering way, which treats image interior elements as well as image boundary elements as followers and leaders in containment control, respectively. Based on this, we utilize two learnable feature fusion matrices in the high-level semantic information stage of the model to quantify the fusion process of internal and boundary features. Further, we design a dedicated loss function to update the parameters of the feature fusion matrices based on the criterion of containment control, which enables fine-grained communication between target features. In addition, our model incorporates a Feature Enhancement Unit (FEU) to tackle the challenge of maximizing the utility of multi-scale features essential for semantic segmentation tasks through the meticulous reconstruction of these features. The proposed model proves effective on the publicly available Cityscapes and CamVid datasets, achieving a trade-off between effectiveness and speed.

Objective: This study aimed to estimate the effects of the volume of preperitoneal balloon (PPB) on arterial and venous hemorrhage in a swine pelvic fracture model.Methods: Twenty-four swine were randomized into 0-mL, 500-mL, 800-mL, and 1000-mL intra-hematoma PPB groups. They were subjected to open-book pelvic fracture and reproducible injuries in the external iliac artery and vein. The pelvic binder and IH-PPBs with different volumes of fluid were applied to control the active hemorrhage after arterial and venous injuries. The survival time and rate during 60-min observation and digital subtraction angiography (DSA) images were the primary endpoints in this study. Secondary endpoints included survival rate within 70 min, peritoneal pressure, hemodynamics, blood loss, infusion fluid, blood pH, and lactate concentration.Results: Our results indicated that the 800-mL and 1000-mL groups had a higher survival rate (0%, 50%, 100% and 100% for 0, 500, 800, and 1000-mL groups respectively; p < 0.0001) and longer survival time (13.83 ± 2.64, 24.50 ± 6.29, 55.00 ± 6.33, and 60.00 ± 0.00 min for 0, 500, 800, and 1,000 groups respectively; p < 0.0005) than the 0-mL or 500-mL groups during the 60 min observation. Contrastingly, survival rate and time were comparable between 800-mL and 1000-mL groups during the 60-min observation. The IH-PPB volume was associated with an increase in the pressure of the balloon and the preperitoneal pressure but had no effect on the bladder pressure. Lastly, the 1000-mL group had a higher mean arterial pressure and systemic vascular resistance than the 800-mL group.Conclusion: IH-PPB volume-dependently controls vascular bleeding after pelvic fracture in the swine model. IH-PPB with a volume of 800 mL and 1000 mL efficiently managed pelvic fracture-associated arterial and venous hemorrhage and enhanced survival time and rate in the swine model without evidences of visceral injury.

Background: Heart failure (HF) and idiopathic pulmonary fibrosis (IPF) are global public health concerns. The relationship between HF and IPF is widely acknowledged. However, the interaction mechanisms between these two diseases remain unclear, and early diagnosis is particularly difficult. Through the integration of bioinformatics and machine learning, our work aims to investigate common gene features, putative molecular causes, and prospective diagnostic indicators of IPF and HF. Methods: The Gene Expression Omnibus (GEO) database provided the RNA-seq datasets for HF and IPF. Utilizing a weighted gene co-expression network analysis (WGCNA), possible genes linked to HF and IPF were found. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) were then employed to analyze the genes that were shared by HF and IPF. Using the cytoHubba and iRegulon algorithms, a competitive endogenous RNA (ceRNA) network was built based on seven basic diagnostic indicators. Additionally, hub genes were identified using machine learning approaches. External datasets were used to validate the findings. Lastly, the association between the number of immune cells in tissues and the discovered genes was estimated using the CIBERSORT method. Results: In total, 63 shared genes were identified between HF- and IPF-related modules using WGCNA. Extracellular matrix (ECM)/structure organization, ECM-receptor interactions, focal, and protein digestion and absorption, were shown to be the most enrichment categories in GO and KEGG enrichment analysis of common genes. Furthermore, a total of seven fundamental genes, including COL1A1, COL3A1, THBS2, CCND1, ASPN, FAP, and S100A12, were recognized as pivotal genes implicated in the shared pathophysiological pathways of HF and IPF, and TCF12 may be the most important regulatory transcription factor. Two characteristic molecules, CCND1 and NAP1L3, were selected as potential diagnostic markers for HF and IPF, respectively, using a support vector machine-recursive feature elimination (SVM-RFE) model. Furthermore, the development of diseases and diagnostic markers may be associated with immune cells at varying degrees. Conclusions: This study demonstrated that ECM/structure organisation, ECM-receptor interaction, focal adhesion, and protein digestion and absorption, are common pathogeneses of IPF and HF. Additionally, CCND1 and NAP1L3 were identified as potential diagnostic biomarkers for both HF and IPF. The results of our study contribute to the comprehension of the co-pathogenesis of HF and IPF at the genetic level and offer potential biological indicators for the early detection of both conditions.

Summary: Circular RNAs (circRNAs) play crucial biological functions in various tumors, including bladder cancer (BCa). However, the roles and underlying molecular mechanisms of circRNAs in the malignant proliferation of BCa are yet unknown. CircKDM1A was observed to be downregulated in BCa tissues and cells. Knockdown of circKDM1A promoted the proliferation of BCa cells and bladder xenograft growth, while the overexpression of circKDM1A exerts the opposite effect. The dual-luciferase reporter assay revealed that circKDM1A was directly bound to miR-889-3p, acting as its molecular sponge to downregulate CPEB3. In turn, the CPEB3 was bound to the CPE signal in p53 mRNA 3′UTR to stabilize its expression. Thus, circKDM1A-mediated CPEB3 downregulation inhibits the stability of p53 mRNA and promotes BCa malignant progression. In conclusion, circKDM1A functions as a tumor suppressor in the malignant proliferation of BCa via the miR-889-3p/CPEB3/p53 axis. CircKDM1A may be a potential prognostic biomarker and therapeutic target of BCa.

Recent studies have demonstrated that ferroptosis, a novel form of nonapoptotic regulated cell death plays an important role in doxorubicin (DOX)-induced cardiotoxicity (DoIC). Hydrogen sulfide (H2S) is emerging as the third important gaseous mediator in cardiovascular system. However, whether H2S has an effect on DOX-induced ferroptosis remains unknown. Here, we found that DOX not only triggered cardiomyocyte ferroptosis but also significantly inhibited the synthesis of endogenous H2S in the murine model of chronic DoIC. Application of NaHS, an H2S donor obviously activated the SLC7A11/GSH/GPx4 antioxidant pathway and thus alleviated DOX-induced ferroptosis and cardiac injury in mice. In contrast, cardiac-specific knockout of cystathionine γ-lyase gene (Cse) in mice (Csef/f/Cre+) to abolish the cardiac synthesis of endogenous H2S evidently exacerbated DOX-induced ferroptosis and cardiac dysfunction. A further suppression of SLC7A11/GSH/GPx4 pathway was obtained in Csef/f/Cre+ mice with DoIC, as compared to Csef/f/Cre− mice with DoIC. The aggravation caused by cardiac-specific Cse deficiency was remarkably rescued by exogenous supplementation of NaHS. Moreover, in DOX-stimulated H9c2 cardiomyocytes, pretreatment with NaHS dose-dependently enhanced the activity of SLC7A11/GSH/GPx4 pathway and subsequently mitigated ferroptosis and mitochondrial impairment. On the contrary, transfection with Cse siRNA in DOX-stimulated H9c2 cardiomyocytes markedly inhibited SLC7A11/GSH/GPx4 pathway, thus leading to aggravated ferroptosis and more damage to mitochondrial structure and function. In addition, the protective effect of NaHS on DOX-induced ferroptosis was closely related to the S-sulfhydrated Keap1, which in turn promoted nuclear translocation of Nrf2 and the transcription of SLC7A11 and GPx4. In conclusion, our findings suggest that H2S may exert protective effect on DoIC by inhibiting DOX-induced ferroptosis via Keap1/Nrf2-dependent SLC7A11/GSH/GPx4 antioxidant pathway.

Background: Environmental temperature is negatively associated with blood pressure (BP), and hypertension may exacerbate this association. The aim of this study is to investigate whether hypertensive individuals are more susceptible to acute BP increases following temperature decrease than non-hypertensive individuals. Methods: The study panel consisted of 126 hypertensive and 125 non-hypertensive (n = 251) elderly participants who completed 940 clinical visits during the winter of 2016 and summer of 2017 in Beijing, China. Personal-level environmental temperature (PET) was continuously monitored for each participant with a portable sensor platform. We associated systolic BP (SBP) and diastolic BP (DBP) with the average PET over 24 h before clinical visits using linear mixed-effects models and explored hourly lag patterns for the associations using distributed lag models. Results: We found that per 1 °C decrease in PET, hypertensive individuals showed an average (95 % confidence interval) increase of 0.96 (0.72, 1.19) and 0.28 (0.13, 0.42) mmHg for SBP and DBP, respectively; and non-hypertensive participants showed significantly smaller increases of 0.28 (0.03, 0.53) mmHg SBP and 0.14 (-0.01, 0.30) mmHg DBP. A lag pattern analysis showed that for hypertensive individuals, the increases in SBP and DBP were greatest following lag 1 h PET decrease and gradually attenuated up to lag 10 h exposure. No significant BP change was observed in non-hypertensive individuals associated with lag 1–24 h PET exposure. The enhanced increase in PET-associated BP in hypertensive participants (i.e., susceptibility) was more significant in winter than in summer. Conclusions: We found that a decrease in environmental temperature was associated with acute BP increases and these associations diminished over time, disappearing after approximately 10 hours. This implies that any intervention measures to prevent BP increases due to temperature drop should be implemented as soon as possible. Such timely interventions are particularly needed for hypertensive individuals especially during the cold season due to their increased susceptibility.

Transcutaneous vagus nerve stimulation (tVNS) is an emerging non-invasive technique designed to stimulate branches of the vagus nerve distributed over the body surface. Studies suggest a correlation between the brain-gut-microbiota (BGM) axis and the pathogenesis of Alzheimer’s disease (AD). The BGM axis represents a complex bidirectional communication system, with the vagus nerve being a crucial component. Therefore, non-invasive electrical stimulation of the vagus nerve might have the potential to modify—most of the time probably in a non-physiological way—the signal transmission within the BGM axis, potentially influencing the progression or symptoms of AD. This review explores the interaction between percutaneous vagus nerve stimulation and the BGM axis, emphasizing its potential effects on AD. It examines various aspects, such as specific brain regions, gut microbiota composition, maintenance of intestinal environmental homeostasis, inflammatory responses, brain plasticity, and hypothalamic–pituitary–adrenal (HPA) axis regulation. The review suggests that tVNS could serve as an effective strategy to modulate the BGM axis and potentially intervene in the progression or treatment of Alzheimer’s disease in the future.

Abstract Introduction The lumbar plexus originates from multiple segments of the spinal cord. Both single-level lumbar plexus block (LPB) and transmuscular quadratus lumborum block (TQLB) are commonly used to provide analgesia for the patients undergoing total hip arthroplasty (THA). However, neither of them can completely cover the lumbar plexus. Multiple-level LPB is also not recommended since this expert technique involves more potential risks. To achieve a better anesthetic effect and avoid risks, we propose to combine ultrasound-guided LPB with TQLB with Shamrock approach. We aim to assess the anesthetic efficacy of this combination technique and expect it will be an ideal alternative for conventional LPBs in THA. Methods and analysis In this prospective randomized controlled trial, 84 patients schedule for THA will be enrolled. The patients will be randomly assigned at a 1:1:1 ratio to receive LPB at L3 level (P group), T12 paravertebral block combined with LPB at L3 and L4 levels (TP group), or LPB combined with TQLB at L3 level (PQ group). Each method will be evaluated in terms of the successful rate of sensory blockade, postoperative pain, performance time of block, requirement for intraoperative sufentanil, cumulative doses of intraoperative vasoactive medications, and adverse events. Ethics and dissemination The study protocol has been approved by the institutional review board (IRB) at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, China (No.2020–031). The results will be disseminated in a peer-reviewed journal and the ClinicalTrials.gov registry. Trial registration ClinicalTrials.gov, NCT04266236 . Registered on 10 February 2020. ClinicalTrials.gov PRS: Record Summary NCT04266236 .

The objective of this study is to investigate the effectiveness of a multi-parameter intelligent fault diagnosis method based on a modified random forest algorithm (RFNB algorithm), so as to reduce the impact of blockage fault on the operation of a silage harvester, thus providing a reference for the intelligent control. In brief, the forward speed, cutting speed, engine speed and engine load were selected as the input variables. Then, a random forest (RF) was used to construct a naive Bayes classifier for each node of the decision tree, and finally the RFNB algorithm constituted based on the naive Bayes tree (NBTree). The results revealed that by improving the classification accuracy of a single decision tree, the fault diagnosis accuracy of the entire RF was improved. When the sample data were consistent, the accuracy of the RFNB algorithm was 97.9%, while that of the RF algorithm was only 93.27%. Besides, the performance of RFNB classifiers was significantly better than that of RF classifiers. In conclusion, the RFNB model can accurately identify the fault status of the silage harvester with its good robustness, which provides a new idea for the fault monitoring and early warning of large agricultural rotating machinery in the future.

Abstract Intraluminal lymphatic valves (LVs) and lymphovenous valves (LVVs) are critical to ensure the unidirectional flow of lymphatic fluid. Morphological abnormalities in these valves always cause lymph or blood reflux, and result in lymphedema. However, the underlying molecular mechanism of valve development remains poorly understood. We here report the implication of Efnb2-Ephb4-Rasa1 regulated Erk signaling axis in lymphatic valve development with identification of two new valve structures. Dynamic monitoring of phospho-Erk activity indicated that Erk signaling is spatiotemporally inhibited in some lymphatic endothelial cells (LECs) during the valve cell specification. Inhibition of Erk signaling via simultaneous depletion of zygotic erk1 and erk2 or treatment with MEK inhibitor selumetinib causes lymphatic vessel hypoplasia and lymphatic valve hyperplasia, suggesting opposite roles of Erk signaling during these two processes. ephb4b mutants, efnb2a;efnb2b or rasa1a;rasa1b double mutants all have defective LVs and LVVs and exhibit blood reflux into lymphatic vessels with an edema phenotype. Importantly, the valve defects in ephb4b or rasa1a;rasa1b mutants are mitigated with high-level gata2 expression in the presence of MEK inhibitors. Therefore, Efnb2-Ephb4 signaling acts to suppress Erk activation in valve-forming cells to promote valve specification upstream of Rasa1. Not only do our findings reveal a molecular mechanism of lymphatic valve formation, but also provide a basis for the treatment of lymphatic disorders.

Single-cell or low-input multi-omics techniques have revolutionized the study of pre-implantation embryo development. However, the single-cell or low-input proteomic research in this field is relatively underdeveloped because of the higher threshold of the starting material for mammalian embryo samples and the lack of hypersensitive proteome technology. In this study, a comprehensive solution of ultrasensitive proteome technology (CS-UPT) was developed for single-cell or low-input mouse oocyte/embryo samples. The deep coverage and high-throughput routes significantly reduced the starting material and were selected by investigators based on their demands. Using the deep coverage route, we provided the first large-scale snapshot of the very early stage of mouse maternal-to-zygotic transition, including almost 5,500 protein groups from 20 mouse oocytes or zygotes for each sample. Moreover, significant protein regulatory networks centered on transcription factors and kinases between the MII oocyte and 1-cell embryo provided rich insights into minor zygotic genome activation.

Abstract To analyze the relationship between the composition of urinary stones and various influencing factors in the Enshi region. We used FT-IR to examine the composition of 1092 stone samples. Combined with the relevant clinical materials, the data were analyzed using both one-dimensional statistical methods and multivariate statistical methods. The study included 1092 stone samples, classified as follows: 457 (41.8%) with a single component, 453 (41.5%) with two components, 149 (13.6%) with three components, and 33 (3.0%) with four components. Stones were categorized into five types: Calcium Oxalate (CaOx) (76.4%), carbapatite (CaP) (9.3%), Struvite (ST) (8.3%), Uric Acid (UA) (4.9%), and Others (1.0%). Age, gender, urinary tract infection (UTI), family history of urinary stones (FH), hyperuricemia (HUA) and stone location were significantly associated with stone type. Logistic regression revealed that females and UTI were relative risk factors for predicting CaP and ST, while FH and HUA were relative risk factors for predicting UA. Our study indicates that the overall composition of urinary tract stones in the Enshi region is consistent with that of the entire China. Additionally, the predisposing factors for stone formation vary in terms of gender, age, FH, UTI, hyperuricemia HUA, and stone location.

Abstract Resveratrol, curcumin, and quercetin are the secondary metabolites from medicinal food homology plants, that have been proven their potency in cancer treatment. However, the antitumor effect of a single component is weak. So, herein, we designed an antitumor compound named RCQ composed of resveratrol, curcumin, and quercetin. This study examined the effect on tumorigenesis and development of 4T1 breast cancer-bearing mice following administering RCQ by intragastric administration. RCQ increased the recruitment of T cells and reduced the accumulation of neutrophils and macrophages in the tumor microenvironment. Meanwhile, RCQ suppressed the development of tumor-infiltrating lymphocytes into immunosuppressive cell subpopulations, including CD4+ T cells to T helper Type 2 type (Th2), tumor-associated neutrophils (TANs) to the N2 TANs, and tumor-associated macrophages (TAMs) cells to M2 TAMs. RCQ reversed the predominance of immunosuppressive infiltrating cells in the tumor microenvironment and tipped the immune balance toward an immune activation state. In vitro the study showed that RCQ significantly increased reactive oxygen species (ROS), reduce mitochondrial membrane potentials in cancer cells, and modulate pro-apoptotic Bcl-2 family members. In conclusion, RCQ can promote the ROS apoptosis mechanism of tumor cells and alleviate immunosuppression of the tumor microenvironment to enhance the anti-tumor effect.

Abstract This paper investigates the proportional‐integral‐derivative (PID) control of positive systems in the discrete‐time case. First, a tuning parameter is introduced to construct the proportional‐integral‐derivative control framework of positive systems. The proportional‐integral‐derivative control problem is thus transformed into the control synthesis of positive systems with time‐delay. By virtue of a matrix decomposition approach, the gain matrices of proportional‐integral‐derivative controller are designed. Using co‐positive Lyapunov functions and linear programming, the positivity and stability of positive systems are achieved under the designed proportional‐integral‐derivative controller. Then, the proportional‐integral‐derivative control of positive systems with reference signal is solved. The main contribution of this paper lies in that linear programming associated to the matrix decomposition approach is first presented to handle the proportional‐integral‐derivative control of positive systems. Finally, two illustrative examples are provided to verify the effectiveness of the proposed design.

Liver disease is a significant global health issue that affects the liver and contributes to approximately 2 million deaths worldwide each year. Although treatment options including surgery and medication are available, effective treatment remains a challenge because of limitations of the traditional drug-delivery methods, such as uneven and nonspecific drug distribution, which lead to negative effects on healthy tissues and a reduction in drug bioavailability. Nanotechnology provides a promising solution for targeted drug delivery to the liver, which has unique anatomical and physiological structures that render it an ideal target for nanomedicine. Several categories of nanomaterials, including inorganic nanomaterials, polymer nanomaterials, and multifunctional nanoparticles (NPs), have been studied as potential agents for targeting this organ in the context of liver diseases. Using surface modification and functionalization, nanomaterials can be selectively targeted to liver tissue or hepatocytes, thus delivering drugs, and enhancing their efficacy while minimizing their side effects. Nanomaterials exhibit numerous benefits; however, their stability and toxicity pose potential risks to living organisms result in adverse effects, such as protein adsorption, and inflammation. Despite the challenges inherent to the development of nanomaterials, ongoing research and development have a great potential for the liver-targeted treatment of liver diseases through the use of nanotechnology. In this review, we first describe the nanomaterials used to target liver diseases, i.e., metallic NPs, ceramic nanomaterials, micelles, polysaccharides, liposomes, dendrimers, carbon nanotubes, and multifunctional NPs. Moreover, the mechanisms for nanomaterials target liver disease are discussed. Finally, this review discusses the current challenges and prospects for future research directions in this field.

The incidence of prostate pain is 90%–95% in prostatitis. The symptoms are persistent, which is prone to relapse and difficult to be cured. It seriously affects the survival and quality of life of patients. This study analyzed the correlation between pain and substance P (SP) and neurokinin-1 receptors (NK-1R) in the L5–S2 spinal cord of chronic nonbacterial prostatitis (CNP) rats, which may give a new way to explore the pathogenesis and treatment of pain in prostatitis. We randomly divided the rats into control group, 45 d group, 60 d group, and 90 d group. After making a rat model with autoimmune method, the paw withdrawal threshold (PWT) was measured, the histomorphological changes in the prostate was observed by transmission electron microscopy and light microscopy. The expression of SP and NK-1R was measured by immunohistochemistry, and the concentrations of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), and interleukin-10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA). Compared with the control group, the PWT was decreased by 34.21%, 41.90% and 64.79%, TNF-α was increased by 74.19%, 89.45% and 132.15%, IL-1β was increased by 148.88%, 181.95% and 250.74%, IL-2 was increased by 75.97%, 82.15% and 128.57% and IL-10 was increased by 31.04%, 63.28% and 212.99% in the 45 d group, 60 d group and 90 d group respectively. Microscope observation showed the structure of prostate tissue in control group was normal. However, the prostate tissue had obvious inflammatory response with the model extension. The expressions of SP and NK-1R in each model group were significantly higher than the control group. There was a significant correlation between pain and SP in L5–S2 spinal cord in CNP rats. These findings are indicative of a correlation between pain and the expression levels of SP and NK-1R in the L5–S2 spinal cord of CNP rats.

ABSTRACTUrinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) can lead to severe kidney injury. However, the molecular mechanisms underlying the pathological process of kidney injury are still incompletely understood. In the present study, we demonstrate that microRNA-146b (miR-146b) deficiency aggravates kidney injury during UTIs caused by UPEC. In a mouse kidney infection model utilizing urosepsis isolate CFT073, we found that miR-146b expression significantly increased in the early stages of UPEC infection. Also, miR-146b-deficient mice displayed exacerbated inflammation in the kidney injury with severe M1 macrophage infiltration. Additionally, the results showed that miR-146b targeted interferon regulatory factor 5-regulated M1 macrophage polarization during UTIs. The results suggested that miR-146b contributed significantly to the control of kidney damage during UTIs, highlighting that miR-146b might be used as a novel therapeutic target for treating kidney injury during UTIs.IMPORTANCEKidney injury during acute urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) is an important public health problem. However, how kidney injury develops during UPEC infection is still unclear. Although antibiotic therapy is currently an effective treatment for UTI, it cannot avoid kidney injury. MicroRNAs have gained extensive attention as essential molecules capable of regulating the autoimmune response. Among these, microRNA-146b (miR-146b) is involved in regulating inflammatory responses. In the present study, we demonstrated that miR-146b played an essential role in the development of kidney injury during UTIs caused by UPEC. The results showed that miR-146b may suppress M1 macrophage polarization and alleviate acute kidney injury. Furthermore, the miR-146b activator, agomir, in order to upregulate miR-146b, was effective in treating kidney damage by inhibiting the activation of M1 macrophages. In conclusion, our findings elucidated the mechanisms by which miR-146b alleviated kidney injury induced by UTIs, shed new light on the relationship between microRNA and bacterial infection, and provided a novel therapeutic target for treating this common bacterial infection.

Macrophages are highly heterogeneous and plastic, and have two main polarized phenotypes that are determined by their microenvironment, namely pro- and anti-inflammatory macrophages. Activation of pro-inflammatory macrophages is closely associated with metabolic reprogramming, especially that of aerobic glycolysis. Mitochondrial pyruvate dehydrogenase kinase (PDK) negatively regulates pyruvate dehydrogenase complex activity through reversible phosphorylation and further links glycolysis to the tricarboxylic acid cycle and ATP production. PDK is commonly associated with the metabolism and polarization of macrophages in metabolic and inflammatory diseases. This review examines the relationship between PDK and macrophage metabolism and discusses the mechanisms by which PDK regulates macrophage polarization, migration, and inflammatory cytokine secretion in metabolic and inflammatory diseases. Elucidating the relationships between the metabolism and polarization of macrophages under physiological and pathological conditions, as well as the regulatory pathways involved, may provide valuable insights into the etiology and treatment of macrophage-mediated inflammatory diseases.

The advancement of computer technology has led to an overwhelming amount of textual information, hindering the efficiency of knowledge intake. To address this issue, various text summarization techniques have been developed, including statistics, graph sorting, machine learning, and deep learning. However, the rich semantic features of text often interfere with the abstract effects and lack effective processing of redundant information. In this paper, we propose the Multi-Features Maximal Marginal Relevance BERT (MFMMR-BertSum) model for Extractive Summarization, which utilizes the pre-trained model BERT to tackle the text summarization task. The model incorporates a classification layer for extractive summarization. Additionally, the Maximal Marginal Relevance (MMR) component is utilized to remove information redundancy and optimize the summary results. The proposed method outperforms other sentence-level extractive summarization baseline methods on the CNN/DailyMail dataset, thus verifying its effectiveness.

Background: Vimentin, an intermediate filament protein, crucially contributes to the pathogenesis of inflammatory bowel disease (IBD) by interacting with genetic risk factors, facilitating pathogen infection, and modulating both innate and adaptive immune responses. This study aimed to demonstrate preclinical proof-of-concept for targeting vimentin therapeutically in IBD across diverse etiologies. Methods: The small molecule compound ALD-R491 was assessed for vimentin binding using microscale thermophoresis, off-target effects via Eurofins screening, and therapeutic effects in mice with dextran sulfate sodium (DSS)-induced acute colitis and in IL-10 KO with spontaneous colitis. Parameters measured included body weight, survival, disease activity, colon length, and histology. The study analyzed intestinal proinflammatory cytokines, Th17/Treg cells, and epithelial barrier molecules, along with gut microbiota profiling. Results: ALD-R491 specifically bound vimentin with a dissociation constant (KD) of 328 ± 12.66 nM and no off-target effects. In the DSS model, orally administered ALD-R491 exhibited dose-dependent therapeutic effects, superior to 5-ASA and Tofacitinib. In the IL-10 KO model, ALD-R491 significantly delayed colitis onset and progression, with near-zero disease activity index scores over a 15-week treatment. ALD-R491 consistently showed in both models a reduced proinflammatory cytokine expression, including TNF-α, IL-1β, IL-6, IL-17, IL-22, a rebalanced Th17/Treg axis by reducing RORγt while enhancing FoxP3 expression, and an improved epithelial barrier integrity by increasing intestinal expressions of Mucin-2, ZO-1 and Claudin5. The intestinal dysbiosis was restored with enriched presence of probiotics. Conclusions: Targeting vimentin exhibits significant therapeutic effects on various facets of IBD pathogenesis, representing a compelling approach for the development of highly effective treatments in IBD.

Investigating the sedimentary architecture and evolution of sand-rich submarine fans is vital for comprehending deep-water sedimentary processes and enhancing the success rate of hydrocarbon resource exploration. Recent drilling activities in the Qiongdongnan Basin, northern South China Sea, have unveiled significant gas hydrate and shallow gas potential. However, exploration in this area faces substantial challenges due to the limited understanding of sandy reservoirs. Leveraging extensive newly acquired extensive 3D seismic data (~9000 km2) and well data, our study reveals five distinct deep-water depositional systems in the Quaternary Ledong Formation, including a submarine fan system, mass transport deposits, deepwater channel-levee systems, slope fans, and hemipelagic sediments. Notably, the targeted sand-rich submarine fan lies within the abyssal plain, situated at a water depth of 1300-1700 m. This fan exhibits a unique tongue-shape configuration and a SW-NE flow direction within the plane and spans an expansive area of ~2800 km2 with maximum length and width reaching 140 km and 35 km, respectively. Vertically, the fan comprises five stages of distributary channel-lobe complexes, progressing from Unit 1 to Unit 5. Their distribution ranges steadily increase from Unit 1 to Unit 3, followed by a rapid decrease from Unit 4 to Unit 5. Our results suggest that the occurrence and evolution of the submarine fan are primarily controlled by sea level fluctuation, confined geomorphology, and sediment supply. Specifically, sea level fluctuation and sediment supply influenced the occurrence of the submarine fan. Concurrently, the confined geomorphology in the abyssal plain provided accumulation space for sediments and shaped the fan into its distinct tongue-like form. In contrast to the deepwater channels within the deepwater channel-levee systems, the distributary turbidite channels within the submarine fan are marked by lower erosion depth with “U” shapes, greater channel width, and higher ratios of width to depth. The comparative analysis identifies turbidite channels as the focal points for offshore gas hydrate and shallow gas exploration in the Qiongdongnan Basin. Furthermore, the temporal evolution of submarine fan offers valuable insights into Quaternary deep-water sedimentary processes and hydrocarbon exploration within shallow strata of marginal ocean basins.