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Abstract Background The deformation of oral and maxillofacial region leads to not only the damage of morphology and function, but also a series of aesthetic and psychological problems, severely affecting the quality of life of patients. Oral tissue engineering refers to developing biomaterials for repair or regeneration, with the application of tissue engineering technologies. This has become an area of increasing prominence. Current biologically inert materials are insufficient to fulfill clinical requirements. Therefore, tissue-engineered biomaterials with bioactive, even bionic properties are desperately needed. Main body The complexity of the anatomy and the diversity of tissue types of oral and maxillofacial region pose great challenges to the regeneration, in the aspects of both biomaterials and manufacturing technologies. Biomaterials in clinical practice or research have evolved from natural materials to synthetic materials, from homogeneous materials to multiple composite materials. And now composite materials have increasingly demonstrated their advantages in terms of physicochemical and biological properties over conventional materials. In terms of manufacturing, traditional coating, sintering, and milling technologies can no longer satisfy the requirements for high-precision bionic structures of oral-tissue-engineering biomaterials. Scientists have turned to biofabrication technologies such as microfluidics and additive manufacturing. Short conclusion This review aims to summarize the noteworthy advancements made in biomaterials of oral tissue engineering. We outlined the current biomaterials and manufacturing technologies and focused on various applications of these materials that may be connected to clinical treatment and research. We also suggested the future direction of development for biomaterials in oral tissue engineering. In future, biomaterials characterized by precision, functionalization, and individualization will be manufactured through digital, microfluidic, and 3D printing technologies. Graphical abstract

Abstract Recent years have seen ticagrelor, a potent P2Y12 inhibitor, emerge as a significant advancement in the peri-thrombolytic management of patients with ST-segment elevation myocardial infarction (STEMI), offering a promising alternative to traditional antiplatelet drugs like clopidogrel. This review critically examines the efficacy and safety of ticagrelor during the peri-thrombolytic phase in STEMI patients, drawing on evidence from key clinical trials such as TREAT and MIRTOS, as well as other relevant studies. These investigations underscore ticagrelor’s superior platelet inhibition capabilities, which are crucial for minimizing thrombotic complications post-thrombolysis without increasing bleeding risks. Despite its potential, clopidogrel remains the guideline-recommended choice for such patients, leaving the appropriateness of ticagrelor in this context open to debate. By summarizing the current evidence and identifying gaps in our understanding, this study advocates for targeted research to clarify the long-term benefits and optimal deployment of ticagrelor, highlighting its evolving significance in cardiovascular care.

Abstract Background There are no clear recommendations for optimal transfusion thresholds for patients with coronary artery disease who undergo noncardiac surgery. By comparing restrictive and liberal transfusion strategies for coronary artery disease combined with hip surgery, this study hopes to provide recommendations for transfusion strategies in this special population. Methods A total of 805 patients from the FOCUS trial (Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair) with coronary artery disease combined with hip surgery were divided into two groups based on transfusion thresholds: restricted transfusion (a hemoglobin level of 8 g/deciliter) and liberal transfusion (a hemoglobin threshold of 10 g/deciliter). The primary outcome of this study was a composite endpoint including in-hospital death, myocardial infarction, unstable angina, and acute heart failure. The secondary endpoints included other in-hospital adverse events and 30- and 60-day follow-up events. Analyses were performed by intention to treat. Results Except for the proportion of congestive heart failure patients, the baseline levels of the two groups were comparable. The median number of transfusion units in the liberal transfusion group was 2 units, and the median transfusion volume in the restricted transfusion group was 0 units. The primary outcome was not significantly different between the two groups (9.2% vs. 9.4%, p = 0.91). The incidence of in-hospital myocardial infarction events was lower in the liberal transfusion group than in the restricted transfusion group (3.2% vs. 6.2%) (OR = 0.51, P = 0.048). The remaining in-hospital endpoint events, except for myocardial infarction, were not significantly different between the two groups. The 30-day and 60-day endpoints of death and inability to walk independently were not significantly different between the two groups, with ORs (95% CI) of 1.00 (0.75–1.31) and 1.06 (0.80–1.41), respectively. We also found no interaction between transfusion strategies and factors such as age, sex, or multiple underlying comorbidities at the 60-day follow-up. Conclusions There was no significant difference in the in-hospital, 30-day or 60-day outcome endpoints between the two groups. However, this study demonstrated that a liberal transfusion strategy tends to reduce the incidence of in-hospital myocardial infarction events in patients with coronary artery disease combined with hip surgery compared to a restrictive transfusion strategy. More high-quality studies should be designed to investigate the optimal transfusion threshold in patients with coronary artery disease treated without cardiac surgery.

Highlights We propose the novel concept of a tough hydrogel scaffold within the realm of tissue engineering. This scaffold combines exceptional strength (6.66 MPa), customization capabilities, and superior biocompatibility in a manner not previously achieved in existing research. These tough hydrogel scaffolds possess functional surface structures and can effectively enhance cell-guided growth and prompt regeneration of muscle tissue in vivo. This is a universal manufacturing method for tough hydrogel scaffolds in tissue engineering.

Abstract. Background:. Breast cancer (BC) risk-stratification tools for Asian women that are highly accurate and can provide improved interpretation ability are lacking. We aimed to develop risk-stratification models to predict long- and short-term BC risk among Chinese women and to simultaneously rank potential non-experimental risk factors. Methods:. The Breast Cancer Cohort Study in Chinese Women, a large ongoing prospective dynamic cohort study, includes 122,058 women aged 25–70 years old from the eastern part of China. We developed multiple machine-learning risk prediction models using parametric models (penalized logistic regression, bootstrap, and ensemble learning), which were the short-term ensemble penalized logistic regression (EPLR) risk prediction model and the ensemble penalized long-term (EPLT) risk prediction model to estimate BC risk. The models were assessed based on calibration and discrimination, and following this assessment, they were externally validated in new study participants from 2017 to 2020. Results:. The AUC values of the short-term EPLR risk prediction model were 0.800 for the internal validation and 0.751 for the external validation set. For the long-term EPLT risk prediction model, the area under the receiver operating characteristic curve was 0.692 and 0.760 in internal and external validations, respectively. The net reclassification improvement index of the EPLT relative to the Gail and the Han Chinese Breast Cancer Prediction Model (HCBCP) models for external validation was 0.193 and 0.233, respectively, indicating that the EPLT model has higher classification accuracy. Conclusions:. We developed the EPLR and EPLT models to screen populations with a high risk of developing BC. These can serve as useful tools to aid in risk-stratified screening and BC prevention.

Background: The breeding of high-quality, high-yield, and disease-resistant varieties is closely related to food security. The investigation of breeding results relies on the evaluation of seed phenotype, which is a key step in the process of breeding. In the global digitalization trend, digital technology based on optical sensors can perform the digitization of seed phenotype in a non-contact, high throughput way, thus significantly improving breeding efficiency. Aim of review: This paper provides a comprehensive overview of the principles, characteristics, data processing methods, and bottlenecks associated with three digital technique types based on optical sensors: spectroscopy, digital imaging, and three-dimensional (3D) reconstruction techniques. In addition, the applicability and adaptability of digital techniques based on the optical sensors of maize seed phenotype traits, namely external visible phenotype (EVP) and internal invisible phenotype (IIP), are investigated. Furthermore, trends in future equipment, platform, phenotype data, and processing algorithms are discussed. This review offers conceptual and practical support for seed phenotype digitization based on optical sensors, which will provide reference and guidance for future research. Key scientific concepts of review: The digital techniques based on optical sensors can perform non-contact and high-throughput seed phenotype evaluation. Due to the distinct characteristics of optical sensors, matching suitable digital techniques according to seed phenotype traits can greatly reduce resource loss, and promote the efficiency of seed evaluation as well as breeding decision-making. Future research in phenotype equipment and platform, phenotype data, and processing algorithms will make digital techniques better meet the demands of seed phenotype evaluation, and promote automatic, integrated, and intelligent evaluation of seed phenotype, further helping to lessen the gap between digital techniques and seed phenotyping.

This study investigates the hot compression behavior of a molybdenum- Rhenium (Mo–Re) alloy, focusing on deformation mechanisms and instability. Utilizing electron backscattered diffraction (EBSD) and transmission electron microscope (TEM), we characterized the microstructure, grain orientation, and deformation behavior across temperatures (650, 750, 850, and 950 °C) and strain rates (0.01, 0.1, 1, and 10s-1). The study reveals that Mo–Re alloys exhibit high hot deformation resistance, necessitating optimal processing conditions for effective plastic deformation. Key findings by EBSD and TEM include the formation of dislocation networks and substructures enhancing grain plasticity. We established a constitutive equation and processing maps, providing valuable insights for industrial applications and future alloy development.

In this study, the keyhole dynamic behavior and molten pool flow were investigated to elucidate the effects of oscillating laser on porosity in narrow-gap oscillating laser-MIG hybrid welding of aluminum alloys. A weld with a porosity of 0.08% was produced at the laser oscillating frequency of 600 Hz and diameter of 1 mm, while 2.27% without oscillating laser. Compared to non-oscillating laser, keyhole opening size increased by about 2.3 times and keyhole depth fluctuation was suppressed. The forces acted on the interface between keyhole wall and molten pool became more balanced. The increased vapor recoil pressure overcame the combined closure effect of gravity and molten pool pressure. While applying oscillating laser, the vortex in molten pool was eliminated and the liquid metal flow was more stable. The combined impact force caused by droplets transfer and liquid metal convection due to constraining effect of narrow gap was buffered, which had less effect on molten pool and keyhole stability. The liquid metal tended to flow from the molten pool inside to surface, which favored the escape of bubbles from the molten pool.

Objective: Chronic atrophic gastritis (CAG) is a complex and burdensome disease. However, side effects and compliance issues cannot be ignored due to the long treatment cycle. Numerous studies have confirmed the effectiveness of rutaecarpine (RUT) for treating digestive dysfunction. However, the potential mechanism of action of RUT in the context of CAG treatment remains unclear. This study aimed to explore the therapeutic effects and mechanisms of RUT in 1-methyl-3-nitro-1-nitrosoguanidine-induced CAG using network pharmacology, metabolomics, and traditional pharmacological approaches. Materials and Methods: Pathological tests and ELISA assays were used to observe the therapeutic effects of RUT treatment on CAG. Differential metabolites were identified using ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolism-related target genes were enriched. The same target genes were identified between RUT and CAG diseases. The intersectional target genes were uploaded to Cytoscape for enrichment, and the nucleotide-binding oligomerization domain (NOD)-like receptor signaling pathway was selected to validate the mechanisms of the study. Finally, cell pyroptosis status was evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and the expressions of associated proteins of the NOD-like receptor signaling pathway were assessed by Western blotting and immunohistochemistry. Results: RUT alleviated gastric mucosal damage and significantly downregulated indicators associated with inflammation and gastric atrophy. A total of 29 intersection target genes was identified, and core pathways were obtained. The NOD-like receptor signaling pathway and pyroptosis status were selected to validate the mechanisms of RUT treatment in CAG rats. The expression of NOD-related proteins and downstream factors was downregulated in the RUT group. Conclusions: RUT exerts a pharmacological effect on relieving gastric damage in CAG rats by inhibiting NOD-like receptors and inflammasomes.

Abstract The minimally invasive injection of tissue engineering scaffolds is of interest as it requires a smaller incision and quickens recovery. However, the engineering of scaffolds capable of injection remains a challenge. Here, we report on a shrunken scaffold inspired by the shrinking of puffed food in a humid environment. A scaffold is freeze-dried to remove water then placed in a humid atmosphere. The humidity causes the dry scaffold to shrink by up to 90%. In addition, the humidity treatment reduces the scaffolds modulus minimizing the foreign body response after implantation. The scaffolds can rapidly swell into their original size and shape after application. A tool for the delivery of the minimally invasive scaffolds is developed and we demonstrate the potential for minimally invasive delivery using this shrinking technique.

Abstract Metabolic disorders are currently threatening public health worldwide. Discovering new targets and developing promising drugs will reduce the global metabolic-related disease burden. Metabolic disorders primarily consist of lipid and glucose metabolic disorders. Specifically, metabolic dysfunction-associated steatosis liver disease (MASLD) and alcohol-associated liver disease (ALD) are two representative lipid metabolism disorders, while diabetes mellitus is a typical glucose metabolism disorder. In this review, we aimed to summarize the new drug candidates with promising efficacy identified in clinical trials for these diseases. These drug candidates may provide alternatives for patients with metabolic disorders and advance the progress of drug discovery for the large disease burden.

Low back pain is among the most grave public health concerns worldwide and the major clinical manifestation of intervertebral disc degeneration (IVDD). The destruction of annulus fibrosus (AF) is the primary cause of IVDD. A sustainable and stable treatment system for IVDD is lacking because of the special organizational structure and low nutrient supply of AF. We here found that IVDD results in the impaired mitochondrial function of AF tissue, and mitochondrial autophagy (mitophagy) plays a protective role in this process. We therefore reported a thread-structural microneedle (T-MN) matching the ring structure of AF. Based on the adsorption effect of laminin, our T-MN could load with bone marrow mesenchymal stem cell-derived exosomes to envelope the regulating mitophagy microRNA (miRNA 378), named as T-MN@EXO@miR−378. In general, we offered in situ locking in the defect site of AF to prevent nucleus pulposus leakage and promoted AF repair. The design of the thread structure was aimed at bionically matching the layered AF structure, thereby providing stronger adhesion. The T-MN@EXO@miR−378 effectively attached to AF and slowly released therapeutic engineered exosomes, and prevented IVDD progression by restoring mitophagy, promoting AF cell proliferation and migration, and inhibiting the pathological remodeling of the extracellular matrix. This functional system can be used as an excellent tool for sustained drug release and has a certain prospect in substituting the conventional treatment of IVDD.

Abstract Objective Sarcopenia is a geriatric syndrome that occurs with age and is characterized by a gradual decline in muscle mass, power, and functionality. It serves as a prominent contributor to frailty, disability, and mortality among older individuals. Currently, no standardized global guidelines exist for the diagnosis of sarcopenia. This study aimed to establish the correlation between sarcopenia and the constitutions of traditional Chinese medicine (TCM), considering the connection between physical functioning and sarcopenia. Methods A total of 1441 participants in this study were diagnosed with sarcopenia. The Asian Working Group for Sarcopenia (AWGS) proposed a sarcopenia definition algorithm. To determine the constitution of each participant, classification and determination standards were used in traditional Chinese medicine. This study evaluated the demographics, lifestyles, and self‐reported medical history of individuals diagnosed with sarcopenia through a self‐administered questionnaire. The constitution of the participants was determined using TCM classification and determination standards. Subsequently, we analyzed the results of univariate analysis and multivariate regression and constructed a receiver operating characteristic (ROC) curve. Results Participants who were diagnosed with sarcopenia had substantially lower original Neutral constitution scores (P

Abstract Femoral head necrosis (FHN) is a serious complication after femoral neck fractures (FNF), often linked to sclerosis around screw paths. Our study aimed to uncover the proteomic and metabolomic underpinnings of FHN and sclerosis using integrated proteomics and metabolomics analyses. We identified differentially expressed proteins (DEPs) and metabolites (DEMs) among three groups: patients with FNF (Group A), sclerosis (Group B), and FHN (Group C). Using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses, we examined the roles of these proteins and metabolites. Our findings highlight the significant differences across the groups, with 218 DEPs and 44 DEMs identified between the sclerosis and FNF groups, 247 DEPs and 31 DEMs between the FHN and sclerosis groups, and a stark 682 DEPs and 94 DEMs between the FHN and FNF groups. Activities related to carbonate dehydratase and hydrolase were similar in the FHN and sclerosis groups, whereas extracellular region and lysosome were prevalent in the FHN and FNF groups. Our study also emphasized the involvement of the PI3K-Akt pathway in sclerosis and FHN. Moreover, the key metabolic pathways were implicated in glycerophospholipid metabolism and retrograde endocannabinoid signaling. Using western blotting, we confirmed the pivotal role of specific genes/proteins such as ITGB5, TNXB, CA II, and CA III in sclerosis and acid phosphatase 5 and cathepsin K in FHN. This comprehensive analyses elucidates the molecular mechanisms behind sclerosis and FHN and suggests potential biomarkers and therapeutic targets, paving the way for improved treatment strategies. Further validation of the findings is necessary to strengthen the robustness and reliability of the results.

Abstract Background The trajectory of attention-deficit hyperactivity disorder (ADHD) symptoms in children and adolescents, encompassing descending, stable, and ascending patterns, delineates their ADHD status as remission, persistence or late onset. However, the neural and genetic underpinnings governing the trajectory of ADHD remain inadequately elucidated. Methods In this study, we employed neuroimaging techniques, behavioral assessments, and genetic analyses on a cohort of 487 children aged 6–15 from the Children School Functions and Brain Development project at baseline and two follow-up tests for 1 year each (interval 1: 1.14 ± 0.32 years; interval 2: 1.14 ± 0.30 years). We applied a Latent class mixed model (LCMM) to identify the developmental trajectory of ADHD symptoms in children and adolescents, while investigating the neural correlates through gray matter volume (GMV) analysis and exploring the genetic underpinnings using polygenic risk scores (PRS). Results This study identified three distinct trajectories (ascending-high, stable-low, and descending-medium) of ADHD symptoms from childhood through adolescence. Utilizing the linear mixed-effects (LME) model, we discovered that attention hub regions served as the neural basis for these three developmental trajectories. These regions encompassed the left anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC), responsible for inhibitory control; the right inferior parietal lobule (IPL), which facilitated conscious focus on exogenous stimuli; and the bilateral middle frontal gyrus/precentral gyrus (MFG/PCG), accountable for regulating both dorsal and ventral attention networks while playing a crucial role in flexible modulation of endogenous and extrinsic attention. Furthermore, our findings revealed that individuals in the ascending-high group exhibited the highest PRS for ADHD, followed by those in the descending-medium group, with individuals in the stable-low group displaying the lowest PRS. Notably, both ascending-high and descending-medium groups had significantly higher PRS compared to the stable-low group. Conclusions The developmental trajectory of ADHD symptoms in the general population throughout childhood and adolescence can be reliably classified into ascending-high, stable-low, and descending-medium groups. The bilateral MFG/PCG, left ACC/mPFC, and right IPL may serve as crucial brain regions involved in attention processing, potentially determining these trajectories. Furthermore, the ascending-high pattern of ADHD symptoms exhibited the highest PRS for ADHD.

Abstract The mammalian SWI/SNF-like BAF complexes play critical roles during animal development and pathological conditions. Previous gene deletion studies and characterization of human gene mutations implicate that the complexes both repress and activate a large number of genes. However, the direct function of the complexes in cells remains largely unclear due to the relatively long-term nature of gene deletion or natural mutation. Here we generate a mouse line by knocking in the auxin-inducible degron tag (AID) to the Smarca4 gene, which encodes BRG1, the essential ATPase subunit of the BAF complexes. We show that the tagged BRG1 can be efficiently depleted by osTIR1 expression and auxin treatment for 6 to 10 h in CD4 + T cells, hepatocytes, and fibroblasts isolated from the knock-in mice. The acute depletion of BRG1 leads to decreases in nascent RNAs and RNA polymerase II binding at a large number of genes, which are positively correlated with the loss of BRG1. Further, these changes are correlated with diminished accessibility at DNase I Hypersensitive Sites (DHSs) and p300 binding. The acute BRG1 depletion results in three major patterns of nucleosome shifts leading to narrower nucleosome spacing surrounding transcription factor motifs and at enhancers and transcription start sites (TSSs), which are correlated with loss of BRG1, decreased chromatin accessibility and decreased nascent RNAs. Acute depletion of BRG1 severely compromises the Trichostatin A (TSA) -induced histone acetylation, suggesting a substantial interplay between the chromatin remodeling activity of BRG1 and histone acetylation. Our data suggest BRG1 mainly plays a direct positive role in chromatin accessibility, RNAPII binding, and nascent RNA production by regulating nucleosome positioning and facilitating transcription factor binding to their target sites.

Abstract Background A growing body of research suggests that heat shock proteins (HSPs) may serve as diagnostic biomarkers for hepatocellular carcinoma (HCC), but their results are still controversial. This meta-analysis endeavors to evaluate the diagnostic accuracy of HSPs both independently and in conjunction with alpha-fetoprotein (AFP) as novel biomarkers for HCC detection. Methods Pooled statistical indices, including sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) with 95% confidence intervals (CI), were computed to assess the diagnostic accuracy of HSPs, AFP, and their combinations. Additionally, the area under the summary receiver operating characteristic (SROC) curve (AUC) was determined. Results A total of 2013 HCC patients and 1031 control subjects from nine studies were included in this meta-analysis. The summary estimates for HSPs and AFP are as follows: sensitivity of 0.78 (95% CI: 0.69–0.85) compared to 0.73 (95% CI: 0.65–0.80); specificity of 0.89 (95% CI: 0.81–0.95) compared to 0.86 (95% CI: 0.77–0.91); PLR of 7.4 (95% CI: 3.7–14.9) compared to 5.1 (95% CI: 3.3–8.1); NLR of 0.24 (95% CI: 0.16–0.37) compared to 0.31 (95% CI: 0.24–0.41); DOR of 30.19 (95% CI: 10.68–85.37) compared to 16.34 (95% CI: 9.69–27.56); and AUC of 0.90 (95% CI: 0.87–0.92) compared to 0.85 (95% CI: 0.82–0.88). The pooled sensitivity, specificity, PLR, NLR, DOR and AUC were 0.90 (95% CI: 0.82–0.95), 0.94 (95% CI: 0.82–0.98), 14.5 (95% CI: 4.6–45.4), 0.11 (95% CI: 0.06–0.20), 133.34 (95% CI: 29.65–599.61), and 0.96 (95% CI: 0.94–0.98) for the combination of HSPs and AFP. Conclusion Our analysis suggests that HSPs have potential as a biomarker for clinical use in the diagnosis of HCC, and the concurrent utilization of HSPs and AFP shows notable diagnostic effectiveness for HCC.

The tendril is a climbing organ in cucurbits and functions in physical support and to avoid shading by neighboring vegetation. However, how cucurbits produce tendrils to obtain climbing ability is largely unknown. In this study, tendril phenotypes were investigated during different developmental stages. Our results revealed that tendril growth exhibited an age-dependent pattern in cucurbits. Tendril growth was inhibited, and the tendril was formed as a short tendril [nonfunctional tendril (nonF-tendril), approximately 0.1 cm] during the seedling stage. In contrast, enhanced cell proliferation and cell expansion led to rapid elongation of the tendril during the climbing stage, and the tendril formed as a functional tendril (F-tendril, approximately 30 cm) to obtain climbing ability. RT-qPCR detection showed that age-dependent tendril growth correlated negatively with the abundance of the conserved age regulator CsmiR156. Defoliation induced CsmiR156 to inhibit CsSPLs, and F-tendril formation and climbing ability were delayed in defoliated cucumbers, which confirmed the role of CsmiR156 in regulating tendril growth in vivo. Additionally, exogenous gibberellin (GA) treatment showed that GA positively regulated tendril growth, and RT-qPCR detection showed that the GA bio-synthetic genes and metabolic genes were affected by age pathway, suggesting that the age pathway depended on GA bio-synthetic and metabolic pathway to regulate cell expansion to determine tendril growth. In summary, our work reveals that change in tendril type is an important marker of phase transition in cucumber, and tendril growth is regulated by an intrinsic developmental age signal, ensuring that the cucumber obtains climbing ability at a suitable age.

Invar 36 alloy, renowned for its ultra-low coefficient of thermal expansion (CTE), is a functional Fe–Ni alloy that finds wide applications in aerospace and precision instruments. Additive manufacturing (AM), as a rapid digital manufacturing process, can efficiently and flexibly fabricate Invar 36 alloy parts with complex geometric and exceptional properties. Considering the advantages of AM and the increasing interest and demand for Invar 36 alloy parts fabrication by AM in recent years, it is imperative to provide a comprehensive summary of the current research status and technological advancements pertaining to AM Invar 36 alloy. Firstly, an overview of the AM processes currently employed for fabricating Invar 36 alloy is provided, including laser powder bed fusion, selective laser sintering, directed energy deposition, cold spray additive manufacturing, wire arc additive manufacturing, and binder jetting. Additionally, the microstructure, mechanical properties, and CTE of Invar 36 alloy manufactured by AM are summarized. Even eliminating the post heat treatment, the as-printed Invar 36 alloy can achieve excellent low CTE and mechanical properties, comparable to or exceeding traditional manufacturing processes. Moreover, the advantages and research progress of AM Invar 36 alloy composites are introduced. Enhancing mechanical properties while reducing CTE is a common challenge for both AM Invar 36 alloy and Invar composites. Finally, the technical gaps, research trends, and potential applications of AM Invar 36 alloy are summarized and prospected.

Background: A two-way relationship exists between type 2 diabetes (T2DM) and human nonalcoholic steatohepatitis (NASH). Several diabetic NASH models have the disadvantages of long cycles or inconsistent with the actual incidence of human disease, which would be costly and time-consuming to investigate disease pathogenesis and develop drugs. Therefore, there is an urgent need to establish a diabetic NASH mouse model. Methods: The combination between Fructose-palmitate-cholesterol diet (FPC) and Streptozotocin (STZ) (FPC+STZ) was used to construct diabetic NASH mouse model. The in vivo effects of silencing acid-sensitive Ion Channel 1a (ASIC1a) were examined with an adeno-associated virus 9 (AAV9) carrying ASIC1a short hairpin RNA (shRNA) in FPC+STZ model. Results: The mice fed with FPC for 12 weeks had insulin resistance, hyperinsulinemia, lipid accumulation, and increased hepatic levels of inflammatory factors. However, it still did not develop remarkable liver fibrosis. Most interestingly, noticeable fibrotic scars were observed in the liver of mice from FPC+STZ group. Furthermore, insulin therapy significantly ameliorated FPC+STZ-induced NASH-related liver fibrosis, indicating that hyperglycemia is of great significance in NASH development and progression. Importantly, ASIC1a was found to be involved in the pathogenesis of diabetic NASH as demonstrated that silencing ASIC1a in HSCs significantly ameliorated FPC+STZ-induced NASH fibrosis. Mechanistically, ASIC1a interacted with Poly Adp-adenosine ribose polymerase (PARP1) to promote HSC activation by inducing autophagy. Conclusion: A FPC diet combined with an injection of STZ induces a diabetic NASH mouse model in a shorter period. Targeting ASIC1a may provide a novel therapeutic target for the treatment of diabetic NASH.

Objectives To evaluate changes in health outcomes between years 2 and 3 after discharge following COVID-19 and to identify risk factors for poor health 3-year post-discharge.Design This is a multicentre observational cohort study.Setting This study was conducted in two centres from Wuhan, China.Participants Eligibility screening has been performed in 3988 discharged laboratory-confirmed adult COVID-19 patients. Exclusion criteria were refusal to participate, inability to contact and death before follow-up. The WHO COVID-19 guidelines on defining disease severity were adopted.Results 1594 patients participated in the 1-year, 2-year and 3-year follow-ups, including 796 (49.9%) male patients, and 422 (26.5%) patients were classified in the severe disease group. 3 years after discharge, 182 (11.4%) patients still complained of at least one symptom. The most common symptoms were fatigue, myalgia, chest tightness, cough, anxiety, shortness of breath and expectoration. Fatigue or myalgia, the most common symptom cluster, frequently coexisted with chest symptoms and anxiety. Symptom persistence between years 2 and 3 was reported in 70 patients (4.4%) for which intensive care unit (ICU) admission was a risk factor (p=0.038). Of the 1586 patients who completed the chronic obstructive pulmonary disease assessment test (CAT), 97 (6.1%) scored ≥10, with older age being associated with CAT ≥10 (p=0.007).Conclusions Between years 2 and 3 after SARS-CoV-2 infection, most patients returned to an asymptomatic state, and only a few were still symptomatic. ICU admission was a risk factor for symptom persistence.

BackgroundThe αvβ6-integrin targeting trimeric ligand [68Ga]Ga-Trivehexin has emerged as a promising candidate for clinical application due to its clinical imaging potentials in various malignant cancers. Our objective was to develop a simplified and reproducible module-based automated synthesis protocol to expand its availability in clinical application.MethodsThe pH value and the precursor load of radiolabeling were explored using an iQS-TS fully-automated module. Radiochemical purity was evaluated by radio-HPLC and radio-TLC. The ethanol content, radionuclide purity and identity, bacterial endotoxins, sterility, and stability of the final product [68Ga]Ga-Trivehexin were all tested. Biodistribution of [68Ga]Ga-Trivehexin in healthy volunteers was also conducted.ResultsThe synthesis was explored and established using fully-automated module with outstanding radiochemical purity (>99%). Considering molar activity and economic costs, a pH of 3.6 and precursor dose of 30 μg were determined to be optimal. All relevant quality control parameters were tested and met the requirement of European Pharmacopoeia. In vitro stability test and imaging in healthy volunteer indicated the practical significance in clinical routines.ConclusionsA fully-automated synthesis protocol for [68Ga]Ga-Trivehexin using the iQS-TS synthesis module was achieved and conformed to the clinical quality standards.Clinical trial registrationClinicalTrials.gov, NCT05835570. Registered 28 April 2023, https://www.clinicaltrials.gov/study/NCT05835570.

Abstract To solve the problems of UAV path planning, such as low search efficiency, uneven path, and inability to adapt to unknown environments, this paper proposes A double-layer optimization A* and dynamic window method for UAV path planning. Firstly, the neighboring node clip-off rule is defined to optimize the node expansion mode of the A* algorithm, and the obstacle coverage model is designed to dynamically adjust the heurizing function of the A* algorithm to improve the path search efficiency. Then, the Bresenham algorithm is adopted for collision detection and critical path nodes are extracted to significantly reduce the number of path turning points. Secondly, a new tracking index is proposed to optimize the evaluation function of the dynamic window method to make the local path fit the global path further. By detecting the dangerous distance, the dynamic adaptive method of evaluation function weight is designed to improve the fixed weight of the dynamic window method. Finally, the key turning point of optimizing the A* algorithm is taken as the temporary target point to improve the DWA algorithm, and the local part follows the global part, and the fusion of the two algorithms is realized. Simulation results show that the proposed method can significantly improve the efficiency and smoothness of mobile robot path planning, enhance the real-time obstacle avoidance and adaptive ability of unknown environments, and better meet the requirements of complex planning tasks.

Abstract Background Circulating tumor cell (CTC) clusters play a critical role in carcinoma metastasis. However, the rarity of CTC clusters and the limitations of capture techniques have retarded the research progress. In vitro CTC clusters model can help to further understand the biological properties of CTC clusters and their clinical significance. Therefore, it is necessary to establish reliable in vitro methodological models to form CTC clusters whose biological characteristics are very similar to clinical CTC clusters. Methods The assays of immunofluorescence, transmission electron microscopy, EdU incorporation, cell adhension and microfluidic chips were used. The experimental metastasis model in mice was used. Results We systematically optimized the culture methods to form in vitro CTC clusters model, and more importantly, evaluated it with reference to the biological capabilities of reported clinical CTC clusters. In vitro CTC clusters exhibited a high degree of similarity to the reported pathological characteristics of CTC clusters isolated from patients at different stages of tumor metastasis, including the appearance morphology, size, adhesive and tight junctions-associated proteins, and other indicators of CTC clusters. Furthermore, in vivo experiments also demonstrated that the CTC clusters had an enhanced ability to grow and metastasize compared to single CTC. Conclusions The study provides a reliable model to help to obtain comparatively stable and qualified CTC clusters in vitro, propelling the studies on tumor metastasis.

Abstract The emergence of microhemispherical resonant gyroscopes, which integrate the advantages of exceptional stability and long lifetime with miniaturization, has afforded new possibilities for the development of whole-angle gyroscopes. However, existing methods used for manufacturing microhemispherical resonant gyroscopes based on MEMS technology face the primary drawback of intricate and costly processing. Here, we report the design, fabrication, and characterization of the first 3D-printable microhemispherical shell resonator for a Coriolis vibrating gyroscope. We remarkably achieve fabrication in just two steps bypassing the dozen or so steps required in traditional micromachining. By utilizing the intricate shaping capability and ultrahigh precision offered by projection microstereolithography, we fabricate 3D high-aspect-ratio resonant structures and controllable capacitive air gaps, both of which are extremely difficult to obtain via MEMS technology. In addition, the resonance frequency of the fabricated resonators can be tuned by electrostatic forces, and the fabricated resonators exhibit a higher quality factor in air than do typical MEMS microhemispherical resonators. This work demonstrates the feasibility of rapidly batch-manufacturing microhemispherical shell resonators, paving the way for the development of microhemispherical resonator gyroscopes for portable inertial navigation. Moreover, this particular design concept could be further applied to increase uptake of resonator tools in the MEMS community.

Abstract The substantia nigra (SN), subthalamic nucleus (STN), and red nucleus (RN) have been widely studied as important biomarkers of degenerative diseases. However, how they develop in childhood and adolescence and are affected by emotional behavior has not been studied thus far. This population-based longitudinal cohort study used data from a representative sample followed two to five times. Emotional and behavioral problems were assessed with the Strengths and Difficulties Questionnaire (SDQ). Linear mixed models were used to map developmental trajectories and behavioral regulation. Using an innovative automated image segmentation technique, we quantified the volumes and asymmetries of the SN, STN and RN with 1226 MRI scans of a large longitudinal sample of 667 subjects aged 6–15 years and mapped their developmental trajectories. The results showed that the absolute and relative volumes of the bilateral SN and right STN showed linear increases, while the absolute volume of the right RN and relative volume of the bilateral RN decreased linearly, these effects were not affected by gender. Hyperactivity/inattention weakened the increase in SN volume and reduced the absolute volume of the STN, conduct problems impeded the RN volume from decreasing, and emotional symptoms changed the direction of SN lateralization. This longitudinal cohort study mapped the developmental trajectories of SN, STN, and RN volumes and asymmetries from childhood to adolescence, and found the association of emotional symptoms, conduct problems, and hyperactivity/inattention with these trajectories, providing guidance for preventing and intervening in cognitive and emotional behavioral problems.

Abstract Immune checkpoint inhibitor (ICI) rechallenge in non‐small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD‐1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

Background: Optical coherence tomography (OCT) has gained increasing popularity in coronary artery intervention due to its high resolution and excellent tissue correlation as a novel intravascular imaging modality. However, the current use of OCT requires contrast agent injection for imaging, and excessive use of contrast agents may adversely affect renal function, exacerbate cardiac burden, and even lead to contrast agent-induced nephropathy and heart failure. In recent years, several researchers have proposed the use of low molecular weight dextran (LMWD) as a substitute for contrast agents in OCT imaging because of its low toxicity, low cost, and wide availability. However, the inclusion of lesions in these studies is relatively simple, and the image quality criteria remain to be optimized. Methods: This study included 26 patients with coronary artery disease who were scheduled for OCT imaging in a real-world clinical practice involving various complex lesions. All patients underwent two OCT examinations at the same vascular site, one each using contrast agent and LMWD. Both contrast media and LMWDs were infused by an autoinjector. The primary endpoint of the study was the average image quality score. Secondary endpoints included clear image length, clear image segments, minimum lumen area, average lumen area, and contrast-induced nephropathy, among others. Results: In terms of image clarity, the average image quality score was similar when comparing contrast media with LMWD (3.912 ± 0.175 vs. 3.769 ± 0.392, P = 0.071). The lengths of the clear images and the segments of the clear images were also similar between the two groups (50.97 ± 16.25 mm vs. 49.12 ± 18.15 mm, P = 0.110; 255.5 ± 81.29 vs. 250.5 ± 89.83, P = 0.095). Additionally, strong correlations were noted between the two flushing solutions regarding the minimum lumen area and mean lumen area. During their hospital stay, none of the patient exhibited deterioration in renal function, and no patient experienced any major adverse cardiovascular events. Conclusions: The quality of coronary artery OCT imaging using LMWD may be comparable to that achieved with traditional contrast agents, even in real-world clinical practice involving various complex lesions. For high-risk patients, LMWD may serve as an excellent substitute for contrast agents in OCT examinations.

In this study, we considered the compressible effect on the mutual interaction of two cavitation bubbles by correcting the sound field emitted by one bubble in the radial equations of the other bubble to first order in the Mach number of the flow, and the effect is represented by the incident wave acting on bubbles. The results illustrates that the incident wave can enhance the resonance response at the redistributed resonance frequency, which leads to an increase in radial acceleration and the secondary Bjerknes force, and rapid approach of bubbles. Furthermore, the influence of incident wave on the interaction of bubbles driven at lower frequencies is more significant, due to resonance enhancement caused by the proximity of natural frequencies and frequency multiplications of the external sound field. Our findings reveal that the compressible effect is not only critical to interaction in radial oscillations, but also in translational motion.

The complementary intervention to modulate diabetes mellitus (DM) metabolism has recently brought the global attention, since DM has become among the global burden diseases. Where, several related pathways elevate the production of superoxide in consequences. For example, the flux of glycation-derived end products (AGEs) could lead to the deactivation of insulin signaling pathways. In that context, many vitamins and phytochemicals in natural sources have high antioxidant impacts that reduce oxidative stress and cell damages. These chemicals could be applied as bioactive antidiabetic agents. Their mode of actions could be from regulating the intracellular reactive oxygen species (ROS) which cause several pro-inflammatory pathways related to the oxidative stress (OS) and DM. Besides, they have a great potential to control the epigenetic mutations and hyperglycemia and help in back the blood glucose to the normal level. Therefore, the current review addresses the important role of natural functional antioxidants in DM management and its association with its OS complications.

Efforts to enhance wheat quality without compromising yield are imperative in the context of climate change. However, the quantification of management measures that simultaneously elevate wheat protein concentration, especially its components, while maintaining yield has been scarcely addressed due to its inherent complexity. In this study, we investigated the impact of various combinations of sowing dates, nitrogen fertilizer, and irrigation on improving the protein concentration of strong gluten winter wheat (Jimai 20) using a validated wheat grain protein component simulation model in Tai'an, Shandong. Our results indicate that climate change between 2031 and 2060 is anticipated to cause a significant decrease in wheat yield and an increase in wheat protein concentration compared to the period from 1981 to 2010. Albumin and globulin are projected to decrease, while gliadin and glutenin are expected to increase, respectively. The average glutenin-to-gliadin ratio in the baseline is 1.096, whereas in scenarios SSP2–4.5 and SSP5–8.5, it is 1.093 and 1.102, respectively. Adapted measures can effectively synergize to enhance both wheat protein quality and yield under climate change. Specifically, delaying sowing and reducing nitrogen application to 210–240 kg·ha−1 with 200–240 mm of irrigation contribute to maintaining yields at the current conventional treatment level. Furthermore, these practices result in a 3.89 % and 0.13 % increase in grain protein concentration, and a 1.19 % and 6.02 % enhancement in the glutenin-to-gliadin ratio under scenarios SSP2–4.5 and SSP5–8.5, respectively, compared to conventional treatments. This comprehensive analysis provides valuable insights into practical strategies for synergistically improving wheat yield and protein quality in the face of climate change.

To elucidate the time-dependent swelling behavior of landfill sand-bentonite mixture liners under the effect of organic pollutants, an no loading swelling ratio test was conducted on mixtures with varying sand and diesel content. The evolution characteristics of the swelling time curve morphology were investigated. The micro-mechanisms underlying the swelling time effect evolution were explored. The results indicated that the sand-diesel interaction significantly altered the swelling time curve morphological characteristics of the mixture. As the sand content increased, the swelling coefficient at the stable state decreased. However, during the rapid swell phase, diesel-contaminated mixed soil does not exhibit the increase-then-decrease pattern in swell coefficient seen in unpolluted mixed soil. The duration of both the slow swelling phase and the time to reach a stable state were longer. Mechanistic analysis revealed that cation exchange capacity is insufficient to effectively analyze the evolution characteristics of the swelling time curve. Instead, the initial swelling potential of bentonite is the true indicator of the mixture’s swelling properties. The particle size distribution influences the changes in the swelling coefficient during the rapid swelling phase, but diesel alters the particle size distribution, mitigating its impact. The oil sealing effect within intra-aggregate and inter-aggregate pores not only weakened the swelling characteristics of the mixture at all stages but also increased the permeability resistance, thereby reducing the duration of the rapid swelling phase and extending the slow swelling and stable swelling phases.

ObjectiveSarcopenia is a gradually advancing systemic disorder affecting skeletal muscles, primarily distinguished by diminished muscle mass and functional decline. As of present, a universally accepted diagnostic criterion for sarcopenia has yet to be established. From the perspective of the constitution theory in traditional Chinese medicine (TCM), the Yin-deficiency constitution is believed to have a significant correlation with the development of sarcopenia. The primary objective of this study was to examine the potential association between sarcopenia and Yin-deficiency constitution.MethodsThe present study is a cross-sectional analysis. The Asian Working Group for Sarcopenia (AWGS) recommended a diagnostic criterion for sarcopenia. A total of 141 participants over 50 years of age were diagnosed with sarcopenia. To determine the constitution of each patient, classification and determination standards were used in traditional Chinese medicine. In this study, a combination of logistic regression and propensity score matching (PSM) was employed to analyze a dataset comprising 1,372 eligible observations. The diagnostic efficacy of the test in distinguishing sarcopenia was assessed through receiver operating characteristic (ROC) curve analysis.ResultsThe relationship between Yin-deficiency constitution and sarcopenia was examined using logistic regression analysis. In the crude model, the odds ratio (OR) was found to be 3.20 (95% confidence interval [CI]: 1.70–6.03). After adjusting for various confounding factors, including gender, sex, 6 m walking test/(m/s), SMI, and maximum grip strength/kg, the OR increased to 9.70 (95% CI: 3.20–69.38). The associations between seven other biased traditional Chinese medicine (TCM) constitutions and sarcopenia were not found to be statistically significant in the fully adjusted model. The propensity score matching (PSM) analysis yielded consistent results with the logistic regression analysis. Receiver operating characteristic (ROC) curve analysis showed that the AUC of the Yin-deficiency constitution combined with age and gender reached 0.707.ConclusionAmong the nine TCM constitutions examined, the Yin-deficiency constitution demonstrates an independent association with sarcopenia. Yin-deficiency constitution may serve as a potential risk factor for the development of sarcopenia. To establish a causal relationship, further experimental investigations are warranted. The diagnostic performance of sarcopenia is effectively demonstrated by the Yin-deficiency constitution combined with age and gender.

IntroductionFibroblast activation protein (FAP) overexpression on cancer-associated fibroblasts (CAFs) is associated with poor prognosis and worse clinical outcomes. Selective ablation of pro-tumorgenic FAP+ stromal cells with CAR-T cells may be a new therapeutic strategy. However, the clinical use of FAP-CAR T cells is suggested to proceed with caution for occasional poor efficacy and induction of on-target off-tumor toxicity (OTOT), including lethal osteotoxicity and cachexia. Hence, more investigations and preclinical trials are required to optimize the FAP-CAR T cells and to approve their safety and efficacy.MethodsIn this study, we designed second-generation CAR T cells targeting FAP with 4-1BB as a co-stimulatory molecule, and tested their cytotoxicity against FAP-positive cells (hFAP-HT1080 cells and a variety of primary CAFs) in vitro and in Cell line-derived xenograft (CDX) and a patient-derived xenograft (PDX) model.ResultsResults showed that our FAP-CAR T cells were powerfully potent in killing human and murine FAP-positive tumor cells and CAFs in multiple types of tumors in BALB/c and C57BL/6 mice and in patient-derived xenografts (PDX) model. And they were proved to be biologically safe and exhibit low-level OTOT.DiscussionTaken together, the human/murine cross-reactive FAP-CAR T cells were powerfully potent in killing human and murine FAP positive tumor cells and CAFs. They were biologically safe and exhibit low-level OTOT, warranting further clinical investigation into our FAP-CAR T cells.

This study addresses the challenges of low detection precision and limited generalization across various ripeness levels and varieties for large non-green-ripe citrus fruits in complex scenarios. We present a high-precision and lightweight model, YOLOC-tiny, built upon YOLOv7, which utilizes EfficientNet-B0 as the feature extraction backbone network. To augment sensing capabilities and improve detection accuracy, we embed a spatial and channel composite attention mechanism, the convolutional block attention module (CBAM), into the head’s efficient aggregation network. Additionally, we introduce an adaptive and complete intersection over union regression loss function, designed by integrating the phenotypic features of large non-green-ripe citrus, to mitigate the impact of data noise and efficiently calculate detection loss. Finally, a layer-based adaptive magnitude pruning strategy is employed to further eliminate redundant connections and parameters in the model. Targeting three types of citrus widely planted in Sichuan Province—navel orange, Ehime Jelly orange, and Harumi tangerine—YOLOC-tiny achieves an impressive mean average precision (mAP) of 83.0%, surpassing most other state-of-the-art (SOTA) detectors in the same class. Compared with YOLOv7 and YOLOv8x, its mAP improved by 1.7% and 1.9%, respectively, with a parameter count of only 4.2M. In picking robot deployment applications, YOLOC-tiny attains an accuracy of 92.8% at a rate of 59 frames per second. This study provides a theoretical foundation and technical reference for upgrading and optimizing low-computing-power ground-based robots, such as those used for fruit picking and orchard inspection.

BackgroundWith the remarkable effect of controlling the increase in drug costs by the first batch of National Key Monitoring and Rational Use Drugs (first NKMRUDs), the National Health Commission of the People’s Republic of China releases the second NKMRUDs to further strengthen the reasonable use of drugs. Unfortunately, the second NKMRUDs include some drugs of National Volume-based Procurement and National Essential Medicines, which challenges the management of pharmaceutical affairs on the three kinds of drugs.ObjectiveThe main objective of this study was to investigate the prevalence of the second NKMRUDs and explore their monitoring indicators.MethodsAn adapted WHO methodology for point prevalence surveys was conducted for the second NKMRUDs. For the monitoring indicators, we sought to explore whether the defined daily dose (DDD) and days of therapy (DOT) can be suitable for the second NKMRUDs through comparing differences between DDD and DOT with the prescribed daily dose (PDD).ResultsAmong the 935 included patients, 29.20% of the patients received at least one of the second NKMRUDs. A total of 273 patients were administered with 487 times of the second NKMRUDs. Among them, 162 , 62 , and 49 patients were receiving one, two, and three or more agents, respectively. The most commonly prescribed second NKMRUDs were compound amino acids, budesonide, and ceftazidime. The total DDDs and DOTs of the second NKMRUDs were 3360.68 and 1819.80, respectively, with the PDDs of 1865.26. The deviations (80.17%) of DDDs from PDDs were significantly greater than those (−2.44%) of DOTs.ConclusionThe prevalence of the second NKMRUDs was obtained by using the adapted PPS methodology at a tertiary university hospital. The DOT indicator is found to more accurately reflect actual consumption than the DDD indicator for second NKMRUDs. It is recommended to use the DOT indicator to monitor second NKMRUDs.

Summary: Targeting the stimulator of interferon genes (STING) pathway is a promising strategy to overcome primary resistance to immune checkpoint inhibitors in non-small cell lung cancer with the STK11 mutation. We previously found metformin enhances the STING pathway and thus promotes immune response. However, its low concentration in tumors limits its clinical use. Here, we constructed high-mesoporous Mn-based nanocarrier loading metformin nanoparticles (Mn-MSN@Met-M NPs) that actively target tumors and respond to release higher concentration of Mn2+ ions and metformin. The NPs significantly enhanced the T cells to kill lung cancer cells with the STK11 mutant. The mechanism shows that enhanced STING pathway activation promotes STING, TBKI, and IRF3 phosphorylation through Mn2+ ions and metformin release from NPs, thus boosting type I interferon production. In vivo, NPs in combination with a PD-1 inhibitor effectively decreased tumor growth. Collectively, we developed a Mn-MSN@Met-M nanoactivator to intensify immune activation for potential cancer immunotherapy.

Niclosamide (NIC) is a commonly used insecticide and molluscicide in the prevention and treatment of parasitic diseases in fish. The utilization of NIC has the potential to disrupt the microbial community present on the mucosal tissue of fish, leading to localized inflammatory responses. The objective of this study was to evaluate the impact of NIC on the immune system and bacterial populations within the gill and gut of Mylopharyngodon piceus. Fish were subjected to varying concentrations of NIC, including a control group (0 μg/L), a low NIC group (15% 96 h LC50, LNG, 9.8 μg/L), and a high NIC group (80% 96 h LC50, HNG, 52.5 μg/L). Gill and gut samples were collected 28 days post-exposure for analysis. The findings revealed that the 96-h LC50 for NIC was determined to be 65.7 μg/L, and histopathological examination demonstrated that exposure to NIC resulted in gill filament subepithelial edema, exfoliation, degeneration, and a decrease in gill filament length. Furthermore, the gut exhibited apical enterocyte degeneration and leucocyte infiltration following NIC exposure. Additionally, NIC exposure led to a significant elevation in the levels of immunoglobulin M (IgM), complement component 3 (C3), and complement component 4 (C4) in both gill and gut tissues. Moreover, the activity of lysozyme (LYZ) was enhanced in the gill, while the activities of peroxidase (POD) and immunoglobulin T (IgT) were increased in gut tissue. The exposure to NIC resulted in enhanced mRNA expression of c3, c9, tnfα, il6, il8, and il11 in the gill tissue, while decreasing c3 and il8 expression in the gut tissue. Furthermore, the natural resistance-associated macrophage protein (nramp) mRNA increased, and liver-expressed antimicrobial peptide 2 (leap2) mRNA decreased in gill and gut tissues. And hepcidin (hepc) mRNA levels rose in gill but fell in gut tissue. NIC exposure also led to a decrease in gill bacterial richness and diversity, which significantly differed from the control group, although this separation was not significant in the gut tissue. In conclusion, the administration of NIC resulted in alterations in both the immune response and mucosal microbiota of fish. Furthermore, it was noted that gills displayed a heightened vulnerability to sublethal effects of NIC in comparison to gut tissues.

More and more evidence has showed that low glycaemic index (GI) diet was a benefit to the Type 2 Diabetes Mellitus (T2DM). However, the detailed mechanism was not clear. Here, we detected the effects of low-GI diet on the HFD/STZ-induced T2DM rats model. Our results showed that low-GI diet significantly decreased triglyceride and glucose level in the serum of T2DM rats, and increased the level of insulin and C-peptide in T2DM rats. Besides, low-GI diet also increased Bacteroidota at the phylum level. And at the genus level, low-GI diet promoted the proliferation of the abundance of Turicibacter, Lactobacillus, Desulfovibrio, Prevotellaceae, Lachnospiraceae, Monoglobus, Xylanophilum and Roseburia. Moreover, we also found that low-GI diet significantly improved the contents of valeric acid, acetic acid, propionic acid, isobutyric acid, butyric acid, 2-methylbutyrate, isovaleric acid, 4-methylvaleric acid and hexanoic acid; upregulated the levels of peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and G protein-coupled receptor 41 (GPR41); and increased the numbers of L-cells (P

Background The dynamic interplay between tyrosine kinase inhibitors (TKIs) and the tumor immune microenvironment (TME) plays a crucial role in the therapeutic trajectory of non-small cell lung cancer (NSCLC). Understanding the functional dynamics and resistance mechanisms of TKIs is essential for advancing the treatment of NSCLC.Methods This study assessed the effects of short-term and long-term TKI treatments on the TME in NSCLC, particularly targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations. We analyzed changes in immune cell composition, cytokine profiles, and key proteins involved in immune evasion, such as laminin subunit γ−2 (LAMC2). We also explored the use of aspirin as an adjunct therapy to modulate the TME and counteract TKI resistance.Results Short-term TKI treatment enhanced T cell-mediated tumor clearance, reduced immunosuppressive M2 macrophage infiltration, and downregulated LAMC2 expression. Conversely, long-term TKI treatment fostered an immunosuppressive TME, contributing to drug resistance and promoting immune escape. Differential responses were observed among various oncogenic mutations, with ALK-targeted therapies eliciting a stronger antitumor immune response compared with EGFR-targeted therapies. Notably, we found that aspirin has potential in overcoming TKI resistance by modulating the TME and enhancing T cell-mediated tumor clearance.Conclusions These findings offer new insights into the dynamics of TKI-induced changes in the TME, improving our understanding of NSCLC challenges. The study underscores the critical role of the TME in TKI resistance and suggests that adjunct therapies, like aspirin, may provide new strategies to enhance TKI efficacy and overcome resistance.

ABSTRACT Human immunoglobulin preparations contain a diverse range of polyclonal antibodies that reflect past immune responses against pathogens encountered by the blood donor population. In this study, we examined a panel of intravenous immunoglobulins (IGIVs) manufactured over the past two decades (1998–2020) for their capacity to neutralize or enhance Zika virus (ZIKV) infection in vitro. These IGIVs were selected specifically based on their production dates in relation to the occurrences of two flavivirus outbreaks in the U.S.: the West Nile virus (WNV) outbreak in 1999 and the ZIKV outbreak in 2015. As demonstrated by enzyme-linked immunosorbent assay (ELISA) experiments, IGIVs made before the ZIKV outbreak already harbored antibodies that bind to various peptides across the envelope protein of ZIKV because of the WNV outbreak. Using phage display, the most dominant binding site was mapped precisely to the P2 peptide between residues 211 and 230 within domain II, where BF1176-56, an anti-ZIKV monoclonal antibody, also binds. When tested in permissive Vero E6 cells for ZIKV neutralization, the IGIVs, even after undergoing rigorous enrichment for P2 binding specificity, failed, as did BF1176-56. Meanwhile, BF1176-56 enhanced ZIKV infection in both FcγRII-expressing K562 cells and human peripheral blood mononuclear cells. However, for enhancement by the IGIVs to be detected in these cells, a substantial increase in their P2 binding specificity was required, thus linking the P2 site with ZIKV enhancement in vitro. Our findings warrant further study of the significance of elevated levels of anti-WNV antibodies in IGIVs, considering that various mechanisms operating in vivo may modulate ZIKV infection outcomes.IMPORTANCEWe investigated the capacity of intravenous immunoglobulins manufactured previously over two decades (1998–2020) to neutralize or enhance Zika virus infection in vitro. West Nile virus antibodies in IGIVs could not neutralize Zika virus initially; however, once the IGIVs were concentrated further, they enhanced its infection. These findings lay the groundwork for exploring how preexisting WNV antibodies in IGIVs could impact Zika infection, both in vitro and in vivo. Our observations are historically significant, since we tested a panel of IGIV lots that were carefully selected based on their production dates which covered two major flavivirus outbreaks in the U.S.: the WNV outbreak in 1999 and the ZIKV outbreak in 2015. These findings will facilitate our understanding of the interplay among closely related viral pathogens, particularly from a historical perspective regarding large blood donor populations. They should remain relevant for future outbreaks of emerging flaviviruses that may potentially affect vulnerable populations.

Abstract This study suggests an improved chaos sparrow search algorithm to overcome the problems of slow convergence speed and trapping in local optima in UAV 3D complex environment path planning. First, the quality of the initial solutions is improved by using a piecewise chaotic mapping during the population initialization phase. Secondly, a nonlinear dynamic weighting factor is introduced to optimize the update equation of producers, reducing the algorithm's reliance on producer positions and balancing its global and local exploration capabilities. In the meantime, an enhanced sine cosine algorithm optimizes the update equation of the scroungers to broaden the search space and prevent blind searches. Lastly, a dynamic boundary lens imaging reverse learning strategy is applied to prevent the algorithm from getting trapped in local optima. Experiments of UAV path planning on simple and complex maps are conducted. The results show that the proposed algorithm outperforms CSSA, SSA, and PSO algorithms with a respective time improvement of 22.4%, 28.8%, and 46.8% in complex environments and exhibits high convergence accuracy, which validates the proposed algorithm's usefulness and superiority.

Abstract Background Type 2 diabetes mellitus (T2DM) is an established risk factor for acute ischemic stroke (AIS). Although there are reports on the correlation of diabetes and stroke, data on its pathogenesis is limited. This study aimed to explore the underlying biological mechanisms and promising intervention targets of diabetes-related stroke. Methods Diabetes-related datasets (GSE38642 and GSE44035) and stroke-related datasets (GSE16561 and GSE22255) were obtained from the Gene Expression omnibus (GEO) database. The key modules for stroke and diabetes were identified by weight gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) analyses were employed in the key module. Genes in stroke- and diabetes-related key modules were intersected to obtain common genes for T2DM-related stroke. In order to discover the key genes in T2DM-related stroke, the Cytoscape and protein–protein interaction (PPI) network were constructed. The key genes were functionally annotated in the Reactome database. Results By intersecting the diabetes- and stroke-related crucial modules, 24 common genes for T2DM-related stroke were identified. Metascape showed that neutrophil extracellular trap formation was primarily enriched. The hub gene was granulin precursor (GRN), which had the highest connectivity among the common genes. In addition, functional enrichment analysis indicated that GRN was involved in neutrophil degranulation, thus regulating neutrophil extracellular trap formation. Conclusions This study firstly revealed that neutrophil extracellular trap formation may represent the common biological processes of diabetes and stroke, and GRN may be potential intervention targets for T2DM-related stroke.

MicroRNA156 (miR156), targeting a subset of SQUAMOSA PROMOTOR BINDING PROTEIN-LIKE (SPL) genes, is one of the most evolutionarily conserved microRNAs (miRNAs) in plants. miR156 is a recognized molecular marker of plant age. In addition to being an age indicator, miR156 has demonstrated strong multifunctionality in the regulation of a broad range of biological processes in horticultural plants, including vegetative growth, floral induction, fruit ripening, stress responses, and secondary metabolism. Due to its versatility and high level of conservation among phylogenetically distinct plant species, miR156 may be a powerful tool for biotechnological modification in horticultural plants. Here, we summarize the functional diversity of miR156 in horticultural plants to provide new insights for further research on the biological function and regulatory mechanism of miR156 and on how to employ miR156 to achieve the enhancement of horticultural traits.

Abstract Cortical thinning is an important hallmark of the maturation of brain morphology during childhood and adolescence. However, the connectome-based wiring mechanism that underlies cortical maturation remains unclear. Here, we show cortical thinning patterns primarily located in the lateral frontal and parietal heteromodal nodes during childhood and adolescence, which are structurally constrained by white matter network architecture and are particularly represented using a network-based diffusion model. Furthermore, connectome-based constraints are regionally heterogeneous, with the largest constraints residing in frontoparietal nodes, and are associated with gene expression signatures of microstructural neurodevelopmental events. These results are highly reproducible in another independent dataset. These findings advance our understanding of network-level mechanisms and the associated genetic basis that underlies the maturational process of cortical morphology during childhood and adolescence.

This study presents the biomimetic design of the structure and controller of AutoLEE-II, a self-balancing exoskeleton developed to assist patients in performing multiple rehabilitation movements without crutches or other supporting equipment. Its structural design is founded upon the human body structure, with an eliminated axis deviation and a raised CoM of the exoskeleton. The controller is a physical parameter-independent controller based on the CoM modification. Thus, the exoskeleton can adapt to patients with different physical parameters. Five subjects underwent exoskeleton-assisted rehabilitation training experiments, including squatting, tilting, and walking trainings. The results showed that the exoskeleton can assist patients in completing various rehabilitation exercises and help them maintain their balance during the rehabilitation training. This helpful role of the exoskeleton in rehabilitation training is analyzed through an electromyography (EMG) data analysis. The findings revealed that wearing the exoskeleton can reduce the activity of the lower limb muscles by approximately 20–30% when performing the same rehabilitation exercises.

The problem of decentralized observer-based event-triggered stabilization for an interconnected fractional-order system subject to stochastic cyber-attacks is studied. To address this issue, the decentralized event-triggered mechanism is proposed for the interconnected fractional-order system, where the event-triggered schemes are designed based on the states of fractional-order observers, and the stochastic attacks are considered both on control inputs and observer outputs. By combining decentralized observers and decentralized event-triggered controllers, we aim to achieve decentralized control with reduced amplifying error and use local signals to improve overall system performance. By utilizing the diffusive representation of the fractional-order system, the interconnected fractional-order system is transformed into an equivalent integer-order one to simplify the analysis and control design. Employing the Lyapunov indirect approach, a sufficient condition is obtained to guarantee the stochastic asymptotically stability of the augmented system. Additionally, by the singular value decomposition technique, the approach of simultaneously computing the decentralized observer gains and controller gains is presented. Finally, a simulation example is provided to validate the theoretical findings.

Abstract Immune checkpoint inhibitors (PD‐1/PD‐L1 and CTLA‐4 blockade) have revolutionized the treatment landscape in non‐small cell lung cancer (NSCLC). Secondary resistance to immunotherapy (IO), which poses a substantial challenge in clinical settings, occurs in several initial responders. Currently, new treatment approaches have been extensively evaluated in investigational studies for these patients to tackle this difficult problem; however, the lack of consistency in clinical definition, uniform criteria for enrollment in clinical trials, and interpretation of results remain significant hurdles to progress. Thus, our expert panel comprehensively synthesized data from current studies to propose a practical clinical definition of secondary resistance to immunotherapy in NSCLC in metastatic and neoadjuvant settings. In addition to patients who received IO alone (including IO‐IO combinations), we also generated a definition for patients treated with chemotherapy plus IO. This consensus aimed to provide guidance for clinical trial design and facilitate future discussions with investigators. It should be noted that additional updates in this consensus are required when new data is available.

Abstract From childhood to adolescence, the spatiotemporal development pattern of the human brain white matter connectome and its underlying transcriptomic and cellular mechanisms remain largely unknown. With a longitudinal diffusion MRI cohort of 604 participants, we map the developmental trajectory of the white matter connectome from global to regional levels and identify that most brain network properties followed a linear developmental trajectory. Importantly, connectome-transcriptomic analysis reveals that the spatial development pattern of white matter connectome is potentially regulated by the transcriptomic architecture, with positively correlated genes involve in ion transport- and development-related pathways expressed in excitatory and inhibitory neurons, and negatively correlated genes enriches in synapse- and development-related pathways expressed in astrocytes, inhibitory neurons and microglia. Additionally, the macroscale developmental pattern is also associated with myelin content and thicknesses of specific laminas. These findings offer insights into the underlying genetics and neural mechanisms of macroscale white matter connectome development from childhood to adolescence.