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Abstract Introduction Gestational diabetes mellitus (GDM) is associated with an increased risk of developing type 2 diabetes mellitus (T2DM). The inflammatory potential of diet is crucial in GDM development. This study compares dietary inflammatory indices (DII) in females with and without a history of GDM and constructs a predictive model for prediabetes risk. Methods Cross-sectional data from NHANES cycles (2011–2014) were analyzed using the DII. Independent t tests, chi-square test, and Mann-Whitney U test examined DII scores in relation to GDM history. Multivariate logistic regression assessed DII’s association with prediabetes in females with GDM history. Restricted cubic spline (RCS) and LASSO regression modeled non-linear relationships and predicted prediabetes risk. Results 971 female participants were included. Those with GDM history had lower DII scores (1.62 (0.58, 2.93) vs. 2.05 (0.91, 2.93)). Higher DII scores in females with GDM were linked to prediabetes, remaining significant after adjusting for confounders. RCS analysis found no non-linear correlation (non-linear p = 0.617). The prediabetes model for GDM history had strong predictive performance (AUC = 88.6%, 95% CI: 79.9-97.4%). Conclusion Females with GDM history show lower DII levels, potentially reflecting improved diet and health awareness. Higher DII scores correlate with increased prediabetes risk in this group, emphasizing diet’s role in diabetes risk. Further studies are needed to confirm these findings.

The increasing demand for glass products has led to a rise in waste glass (WG), which is commonly disposed of in landfills, causing environmental degradation. Moreover, the direct adoption of a high volume of WG as aggregates in concrete can lead to unfavorable ASR expansion due to its high level of reactive silica. This study explores a one-part alkali activation method to produce WG-based aggregates, aiming to reduce the reactive silica content, mitigate ASR expansion and increase the recycling rate of WG. Waste glass powder (WGP) with a replacement ratio of 100% was combined with two different alkalis (sodium metasilicate pentahydrate (Na2SiO3.5H2O) and sodium aluminate (NaAlO2)) through the cold-bonded one-part alkali activation method to produce WG-based alkali-activated aggregates (WG-AAAs). The influence of various activator contents (0%, 6%, 9%, 12% and 15%) on the physical and mechanical properties of the WG-AAAs was investigated. The WG-AAAs had a bulk density ranging from 920 to 1010 kg/m3, which can be classified as lightweight aggregates. The WG-AAAs with 12% NaAlO2 showed the best performance, with a water absorption of 8.46% and single particle crushing strength of 3.19 MPa. SEM-EDS and XRD results indicated that WG-AAAs with the supply of alumina from NaAlO2 exhibited a lower Si/Al ratio, leading to the formation of C-(N)-A-S-H gel, which improved the strength and creating a denser microstructure. Furthermore, the WG-AAAs showed no ASR expansion concerns, conforming to the expansion limit specified in ASTM C1260.

Abstract The electrocatalytic valorization of polyethylene terephthalate-derived ethylene glycol to valuable glycolic acid offers considerable economic and environmental benefits. However, conventional methods face scalability issues due to rapid activity decay of noble metal electrocatalysts. We demonstrate that a dynamic potential cycling approach, which alternates the electrode potential between oxidizing and reducing values, significantly mitigates surface deactivation of noble metals during electrochemical oxidation of ethylene glycol. This method enhances catalyst activity by 20 times compared to a constant-potential approach, maintaining this performance for up to 60 h with minimal deactivation. In situ Raman and X-ray absorption spectroscopy show that this effectiveness results from efficient removal of surface oxide during the reaction. The strategy is applicable to polyethylene terephthalate hydrolysates and various noble metals, such as palladium, gold, and platinum, with palladium showing a high conversion rate in recent studies. Our approach offers an efficient and durable method for electrochemical upcycling of biomass-derived compounds.

Immunotherapies hold immense potential for achieving durable potency and long-term survival opportunities in cancer therapy. As vital biological mediators, peptides with high tissue penetration and superior selectivity offer significant promise for enhancing cancer immunotherapies (CITs). However, physicochemical peptide features such as conformation and stability pose challenges to their on-target efficacy. This review provides a comprehensive overview of recent advancements in therapeutic peptides targeting key steps of the cancer-immunity cycle (CIC), including tumor antigen presentation, immune cell regulation, and immune checkpoint signaling. Particular attention is given to the opportunities and challenges associated with these peptides in boosting CIC within the context of clinical progress. Furthermore, possible future developments in this field are also discussed to provide insights into emerging CITs with robust efficacy and safety profiles.

BackgroundIndividuals with obesity often experience elevated blood lipid levels, leading to a chronic low-grade inflammatory state, exacerbating liver oxidative stress, and increasing the risk of various metabolic diseases. Recent evidence suggests that intestinal microbiota and short-chain fatty acids (SCFAs) play crucial roles in the development and progression of obesity. While the mechanisms by which Lingguizhugan decoction (LGZGD) intervenes in obesity by improving lipid metabolism, enhancing insulin sensitivity, and reducing inflammatory responses are well-documented, its potential in intestinal microbiota and SCFAs remains unclear. This study aims to explore the impact of LGZGD on high-fat diet (HFD) induced obesity in rats and its regulatory effects on intestinal microbiota and SCFAs, providing new insights for obesity prevention and treatment.MethodsFifty-one male SD rats were randomly divided into groups, with six in the normal control group (NC) receiving a ddH2O treatment and a standard diet. The remaining 45 rats were fed a high-fat diet (HFD) using D12451 feed. After 10 weeks, the rats on the HFD gained 20% more weight than the NC group, confirming the successful modeling of obesity. These rats were then randomly divided into the following groups: ddH2O high-fat diet model group (MC), 20 mg/kg/day Orlistat positive control group (Orlistat), 1.62 g/kg/day low-dose LGZGD group (LGZGL), and 3.24 g/kg/day high-dose LGZGD group (LGZGH) for 8 weeks. We evaluated changes in body weight, serum total cholesterol (TC), total triacylglycerol (TG), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) levels. Fat and liver tissues were collected for pathological analysis. Intestinal contents were aseptically collected for 16S rRNA gene sequencing and gas chromatography–mass spectrometry (GC–MS) to assess gut microbiota and SCFA levels.ResultsLGZGD reduces body weight, TC, TG, LDL, and HDL levels, significantly reducing hepatic steatosis. Besides, it restored the richness and diversity of gut microbiota, which was reduced by HFD, altering the overall structure. Specifically, LGZGD significantly promoted the growth of Muribaculaceae and Dubosiella while inhibiting the growth of Christensenellaceae_R_7_group and UCG_005. It also restricts the production of caproic acid. Correlation analysis indicated positive correlations: Muribaculaceae with Butyric acid and Isovaleric acid; UCG_005 with TC, LDL, and HDL; and Christensenellaceae_R_7_group with TC and LDL.ConclusionLGZGD increased the abundance of beneficial gut microbiota in HFD-induced obese rats, improved gut microbiota dysbiosis, and inhibited the increase in caproic acid content. These results suggest that LGZGD can mitigate HFD-induced obesity, and its active components warrant further investigation.

IntroductionPrime quality kamaboko (cooked surimi) is produced from Alaska pollock. The main challenge of using cheaper fish fillets, including Barramundi, is achieving similar textures.MethodsCombined with fish gelatin, modified starch by vortex fluidic device was used to enhance the quality of kamaboko made from Barramundi.ResultsModification by a continuous flow vortex fluidic device (VFD) significantly reduces the size of particles of starch relative to conventional homogenization. Blending this VFD-modified starch with fish gelatin resulted in a well-organized cross-linked matrix compared to products manufactured from homogenization modified starch. This led to higher gel strength of the former (1,708.32 g/cm2) relative to the latter (832.56 g/cm2). Mixing different proportions of fish gelatin and VFD-processed starch to make Barramundi kamaboko (5, 10, and 15%), yielded a product with greater chewiness relative to Alaska pollock kamaboko. Sensory evaluation indicated that the 5% product was optimal and the 15% product with the highest chewiness (56.10 N) was the least favorable.DiscussionThese results clearly indicate the potential of VFD processed starch, blended with fish gelatin to enhances the quality of kamaboko.

Background: Higher greenness was associated with a lower risk of adult mortality. However, the effects of greenness on the mortality of infant and child under-5 have not been fully examined. Objectives: The association of greenness on the infant mortality rate (IMR) and child under-5 mortality rate (U5MR) in 147 Chinese cities from 2009 to 2020 was evaluated. Methods: Average and maximum annual population-weighted greenness, IMR (per 1000 live births), and U5MR (per 1000 live births) in 147 cities from 2009 to 2020 were collected, and a longitudinal panel study was conducted. Greenness exposure was evaluated using satellite-derived data at a spatial resolution of 250 m ×250 m in urban regions, and linear mixed-effect models were applied to assess the associations between greenness and IMR or U5MR in China. Results: This national study showed that long-term exposure to greenness was associated with lower IMR and U5MR, respectively. Specifically, a 0.1 increase of Normalized Difference Vegetation Index (NDVI) in greenness was statistically significant with a decrease in IMR (-1.05 ‰, 95 % CI: −1.48, −0.63 ‰) and U5MR (-1.82 ‰, 95 % CI: −2.39, −1.25 ‰) in fully-adjusted model, respectively. In the stratified analyses, greenness effects on U5MR in the western (-2.33 ‰, 95 % CI: −3.43, −1.23 ‰) and central regions (-2.06 ‰, 95 % CI: −3.01, −1.10 ‰) were stronger than that in the eastern region (-0.86 ‰, 95 % CI: −1.66, −0.07 ‰). Conclusions: This nationwide study indicated that exposure to higher greenness was associated with lower mortality rates in infant and child under-5 in China.

BackgroundVacuum bell (VB) is a technique to treat pectus excavatum in children. Its effectiveness and influencing factors, however, remain under investigated. The aim of this study was to examine the therapeutic effect and its influencing factors of VB in children with pectus excavatum.MethodsA cross-sectional observational study was conducted. Parents of children with pectus excavatum who underwent treatment with a VB between January 2018 and December 2019 were recruited. A survey was designed based on previously related studies and delivered to the parents in September–October 2021. The therapeutic effect was analyzed using subjective experiences by parents. Factors related to effectiveness were analyzed through univariate analysis and multivariate logistic regression.ResultsOf the 77 surveys distributed, 65 (84%) were returned. The mean duration of VB was 23.20 (SD 9.86) months. Caregivers rated the effect of VB treatment as moderate (41.5%), good (46.2%), excellent (12.3%). There were 39 children (60%) who had at least one pause of using VB for more than two weeks. Univariate analysis showed no significant difference between age, height, weight, duration of VB (months) and the effectiveness of VB therapy as defined by caregivers (p > 0.05) and significant difference were observed of the variables “complication of petechiae” (p = 0.034) and “device returned to manufacturer for repair” (p = 0.011). The multivariate logistic regression showed that the occurrence of complication petechiae (p = 0.046) was an influential factor for the effectiveness of VB.ConclusionsThe evaluations reported by the parents suggested that the VB treatment was effective, although with varying degrees. The complication of petechiae seems an influencing factor to successful VB treatment in children with pectus excavatum. Further studies are needed to assess the long-term outcome and effect of VB and to improve the device and to reduce complications in order to enhance compliance and improve effectiveness.

Background: The sleep quality of medical staff was severely affected during COVID-19, but the factors influencing the sleep quality of frontline staff involved in medical assistance remained unclear, and screening tools for their sleep quality were lacking. Methods: From June 25 to July 14, 2022, we conducted an Internet-based cross-sectional survey. The Pittsburgh Sleep Quality Index (PSQI), a self-designed general information questionnaire, and a questionnaire regarding the factors influencing sleep quality were combined to understand the sleep quality of frontline medical staff in Fujian Province supporting Shanghai in the past month. A chi-square test was used to compare participant characteristics, and multivariate unconditional logistic regression analysis was used to determine the predictors of sleep quality. Stratified sampling was used to divide the data into a training test set ( n = 1061, 80%) and an independent validation set ( n = 265, 20%). Six models were developed and validated using logistic regression, artificial neural network, gradient augmented tree, random forest, naive Bayes, and model decision tree. Results: A total of 1326 frontline medical staff were included in this survey, with a mean PSQI score of 11.354 ± 4.051. The prevalence of poor sleep quality was 80.8% ( n = 1072, PSQI >7). Six variables related to sleep quality were used as parameters in the prediction model, including type of work, professional job title, work shift, weight change, tea consumption during assistance, and basic diseases. The artificial neural network (ANN) model produced the best overall performance with area under the curve, accuracy, sensitivity, specificity, precision, F1 score, and kappa of 71.6%, 68.7%, 66.7%, 69.2%, 34.0%, 45.0%, and 26.2% respectively. Conclusions: In this study, the ANN model, which demonstrated excellent predictive efficiency, showed potential for application in monitoring the sleep quality of medical staff and provide some scientific guidance suggestions for early intervention.

Abstract Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that reduces the developmental period, restores fat levels, enhances body mass, and fully rescues survivorship without compromise to adult lifespan. To demonstrate an application of this formula, we explored pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder affecting the metabolism of branched-chain amino acids. We reveal rapid, specific, and predictable nutrient effects on the disease state consistent with observations from mouse and patient studies. Together, our diet provides a powerful means with which to examine the interplay between diet and metabolism across all life stages in an animal model.

Abstract Ischemic stroke produces the highest adult disability. Despite successful recanalization, no-reflow, or the futile restoration of the cerebral perfusion after ischemia, is a major cause of brain lesion expansion. However, the vascular mechanism underlying this hypoperfusion is largely unknown, and no approach is available to actively promote optimal reperfusion to treat no-reflow. Here, by combining two-photon laser scanning microscopy (2PLSM) and a mouse middle cerebral arteriolar occlusion (MCAO) model, we find myogenic vasomotion deficits correlated with post-ischemic cerebral circulation interruptions and no-reflow. Transient occlusion-induced transient loss of mitochondrial membrane potential (ΔΨm) permanently impairs mitochondria-endoplasmic reticulum (ER) contacts and abolish Ca2+ oscillation in smooth muscle cells (SMCs), the driving force of myogenic spontaneous vasomotion. Furthermore, tethering mitochondria and ER by specific overexpression of ME-Linker in SMCs restores cytosolic Ca2+ homeostasis, remotivates myogenic spontaneous vasomotion, achieves optimal reperfusion, and ameliorates neurological injury. Collectively, the maintaining of arteriolar myogenic vasomotion and mitochondria-ER contacts in SMCs, are of critical importance in preventing post-ischemic no-reflow.

We study the problem of mass screening of heterogeneous populations under limited testing budget. Mass screening is an essential tool that arises in various settings, e.g., the COVID-19 pandemic. The objective of mass screening is to classify the entire population as positive or negative for a disease as efficiently and accurately as possible. Under limited budget, testing facilities need to allocate a portion of the budget to target sub-populations (i.e., proactive screening) while reserving the remaining budget to screen for symptomatic cases (i.e., reactive screening). This paper addresses this decision problem by taking advantage of accessible population-level risk information to identify the optimal set of sub-populations for proactive/reactive screening. The framework also incorporates two widely used testing schemes: Individual and Dorfman group testing. By leveraging the special structure of the resulting bilinear optimization problem, we identify key structural properties, which in turn enable us to develop efficient solution schemes. Furthermore, we extend the model to accommodate customized testing schemes across different sub-populations and introduce a highly efficient heuristic solution algorithm for the generalized model. We conduct a comprehensive case study on COVID-19 in the US, utilizing geographically-based data. Numerical results demonstrate a significant improvement of up to 52% in total misclassifications compared to conventional screening strategies. In addition, our case study offers valuable managerial insights regarding the allocation of proactive/reactive measures and budget across diverse geographic regions.

Immune-related adverse events, particularly colitis (irAE-colitis), are significant impediments to the advancement of immune checkpoint therapy. To address this, blocking TNF-α and modulating gut microbiota are effective strategies. However, their precise roles in irAE-colitis pathogenesis and potential reciprocal relationship remain unclear. An irAE-colitis model was established to evaluate the toxicity of DICB and the efficacy of Infliximab, validated through a tumor irAE-colitis mice model. Co-administration of Infliximab with DICB mitigates colitis and enhances efficacy. Analysis of fecal samples from mice reveals altered gut microbiota composition and function induced by irAE-colitis, restored by Infliximab. Notably, Bacteriodes abundance is significantly higher in irAE-colitis. Disruption of arachidonic acid and tyrosine metabolism, and steroid hormone biosynthesis is evident. Mechanistically, a regenerative feedback loop involving DICB, TNF-α and gut microbiota underlies irAE-colitis pathogenesis. In conclusion, Infliximab shows therapeutic effects against DICB toxicity, highlighting the unforeseen roles of gut microbiota and TNF-α in irAE-colitis.

Abstract The binding of peroxisome proliferator‐activated receptor γ (PPARγ) to the orphan nuclear receptor Nur77 facilitates the ubiquitination and degradation of Nur77, and leads to aberrant fatty acid uptake for breast cancer progression. Because of its crucial role in clinical prognosis, the interaction between Nur77 and PPARγ is an attractive target for anti‐breast‐cancer therapy. However, developing an inhibitor of the Nur77‐PPARγ interaction poses a technical challenge due to the absence of the crystal structure of PPARγ and its corresponding interactive model with Nur77. Here, ST‐CY14, a stapled peptide, is identified as a potent modulator of Nur77 with a KD value of 3.247 × 10−8 M by in silico analysis, rational design, and structural modification. ST‐CY14 effectively increases Nur77 protein levels by blocking the Nur77‐PPARγ interaction, thereby inhibiting lipid metabolism in breast tumor cells. Notably, ST‐CY14 significantly suppresses breast cancer growth and bone metastasis in mice. The findings demonstrate the feasibility of exploiting directly Nur77‐PPARγ interaction in breast cancer, and generate what to the best knowledge is the first direct inhibitor of the Nur77‐PPARγ interaction available for impeding fatty acid uptake and therapeutic development.

This study explores the feasibility of using sorted municipal solid waste, namely waste-derived paper ash (PA) and food waste ash (FWA) as partial cement substitute (0–15 %) in both paste and mortar. Although the introduction of PA and FWA into the mortar mix leads to a slight expansion of the blended cement paste, it is still compliant with the requirement of EN 197-1. Notably, PA has a significant impact on both the initial and final setting times of the cement paste, attributed to its high CaO content. On the other hand, FWA demonstrates better promise in term of strength consideration, with a lower extent of 7.2 % reduction compared to the control group at a 5 % cement substitution level. Besides that, the chloride content of the blended cement paste, with up to 15 % PA and FWA substitution, still adheres to the 0.1 % limit outlined in EN 196-2. In terms of environmental considerations, the raw materials of PA and FWA exceed the hazardous waste thresholds for certain elements (As, Zn, Pb, Cr, Cu and Sb) as per UNE EN 12457-4 standards. However, when blended into cement mortar at a 15 % substitution level, these heavy metals exhibit significantly reduced concentrations, meeting the criteria for non-hazardous and even inert waste. In overall, this study suggests that utilizing sorted PA and FWA as cement substitute can offer a sustainable option. Despite observed reductions in compressive strength, these materials hold potential advantages in terms of environmental impact mitigation and waste management.

BackgroundThe concept of the gut-retinal axis proposed by previous scholars primarily focused on the relationship between intestinal microbiota and retinal diseases, and few further expanded the relationship between intestinal diseases and retinal diseases. To further substantiate the concept of the gut-retinal axis, we analyzed inflammatory bowel disease (IBD) and diabetic retinopathy (DR) using Mendelian randomization (MR), and use mediation analysis to further explore the potential substances that influence this causal relationship.MethodsThe genome-wide association study’s (GWAS) summary statistics for genetic variations were utilized in a Mendelian randomization (MR) investigation. GWAS data on IBD (including ulcerative colitis (UC), Crohn’s disease (CD), and IBD) for non-Finnish Europeans (NFE) were sourced from published articles. In contrast, data on DR (including DR and diabetic maculopathy (DMP)) were obtained from FinnGen R9. The causal relationship has been investigated using inverse variance weighted (IVW), MR-Egger, and weighted median and sensitivity analysis was applied to verify the stability of the results. In addition, we applied mediation analysis to investigate whether circulating inflammatory proteins and plasma lipids played a mediating role, and calculated its effect ratio.ResultsThe causal relationship between IBD and DR was discovered by employing the inverse variance weighted (IVW) method and weighted median method. In forward MR, UC was significantly associated with lower risk of DR (IVW: OR=0.874; 95%CI= 0.835–0.916; P value= 1.28E-08) (Weighted median: OR=0.893; 95%CI= 0.837–0.954; P value= 7.40E-04). In reverse MR, it was shown that DR (IVW: OR=0.870; 95%CI= 0.828–0.914; P value= 2.79E-08)(Weighted median: OR=0.857; 95%CI= 0.801–0.916; P value= 6.40E-06) and DMP (IVW: OR=0.900; 95%CI= 0.865–0.937; P value= 3.34E-07)(Weighted median: OR=0.882; 95%CI= 0.841–0.924; P value= 1.82E-07) could reduce the risk of CD. What’s more, DR is associated with a lower risk of IBD according to genetic prediction (IVW: OR=0.922; 95%CI= 0.873–0.972; P value= 0.002) (Weighted median: OR=0.924; 95%CI= 0.861–0.992; P value= 0.029). Fibroblast growth factor 21 (FGF21), phosphatidylcholine (PC), and triacylglycerol (TG) serve as mediators in these relationships.ConclusionsOur research offers novel insights and sources for investigating the gut-retina axis in the genetic relationship between IBD and DR. We discover four mediators and more about the association between the intestine and retinal disorders and provide more evidence for the gut-retinal axis theory.

Abstract Hepatic insulin resistance is central to the metabolic syndrome. Here we investigate the role of BTB and CNC homology 1 (BACH1) in hepatic insulin signaling. BACH1 is elevated in the hepatocytes of individuals with obesity and patients with non-alcoholic fatty liver disease (NAFLD). Hepatocyte-specific Bach1 deletion in male mice on a high-fat diet (HFD) ameliorates hyperglycemia and insulin resistance, improves glucose homeostasis, and protects against steatosis, whereas hepatic overexpression of Bach1 in male mice leads to the opposite phenotype. BACH1 directly interacts with the protein-tyrosine phosphatase 1B (PTP1B) and the insulin receptor β (IR-β), and loss of BACH1 reduces the interaction between PTP1B and IR-β upon insulin stimulation and enhances insulin signaling in hepatocytes. Inhibition of PTP1B significantly attenuates BACH1-mediated suppression of insulin signaling in HFD-fed male mice. Hepatic BACH1 knockdown ameliorates hyperglycemia and improves insulin sensitivity in diabetic male mice. These results demonstrate a critical function for hepatic BACH1 in the regulation of insulin signaling and glucose homeostasis.

Abstract Background Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in‐depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies. Methods We integrated single‐cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three‐dimensional bioprinting technique, canonical ex vivo co‐culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME. Results This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7+/THBS1+ myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte‐mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A+ macrophages that exhibit M2‐phenotype were enriched in the tumoral niche and high expression of MS4A4A+ was associated with poor prognosis in the cohort data. The ligand‐receptor‐based intercellular communication analysis revealed the tight interaction of MUC1+ malignant cells and ZEB1+ endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications. Conclusions Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA. Key points Tumour microenvironment profiling of MCA is developed. MUC1+ tumour cells interplay with FGF7+/THBS1+ myofibroblasts to promote MCA development. MS4A4A+ macrophages exhibit M2 phenotype in MCA. ZEB1+ endotheliocytes engage in EndMT process in MCA.

Here we report a rare morphology of a cardiac fibroma in a child. A 2-year and 8-month-old toddler came for “chronic constipation” and was found to have a heart murmur on cardiac auscultation. Further transthoracic echocardiography suggested “a strong echogenic mass in the left ventricular wall, with some part of “a string of beads” in shape extending into left ventricle outflow tract”, which was atypical for either a tumor, thrombus or vegetation. The child underwent resection of the mass and mitral valvuloplasty. Pathological examination confirmed the mass as a cardiac fibroma.

Summary: Inherited metabolic disorders are a group of genetic conditions that can cause severe neurological impairment and child mortality. Uniquely, these disorders respond to dietary treatment; however, this option remains largely unexplored because of low disorder prevalence and the lack of a suitable paradigm for testing diets. Here, we screened 35 Drosophila amino acid disorder models for disease-diet interactions and found 26 with diet-altered development and/or survival. Using a targeted multi-nutrient array, we examine the interaction in a model of isolated sulfite oxidase deficiency, an infant-lethal disorder. We show that dietary cysteine depletion normalizes their metabolic profile and rescues development, neurophysiology, behavior, and lifelong fly survival, thus providing a basis for further study into the pathogenic mechanisms involved in this disorder. Our work highlights the diet-sensitive nature of metabolic disorders and establishes Drosophila as a valuable tool for nutrigenomic studies for informing potential dietary therapies.

Biomineralization occurs in natural organisms, such as bones, teeth, shells and tendons. The formation mechanism and mechanical properties have been extensively studied for mineralized hard tissues, especially for bone and teeth. However, the research on the evolution of mechanical properties for mineralized soft tissues remains challenging due to the long period of mineralization. Here we use polymer-induced liquid-precursor (PILP) method to achieve accelerated in vitro mineralization of bovine pericardium with SrCO3. The modulus, tensile strength, toughness, and suture retention force of mineralized tissues have been characterized. After 30 days of mineralization, both the tensile strength and toughness decrease by two orders of magnitude. We carry out cyclic suture retention test to characterize the fatigue properties of mineralized tissues, and find that the cycle to failure of mineralized tissues is 10-100 times lower than that of unmineralized tissues. The degradation of mechanical properties results from the microstructure change of mineralized tissues, where collagen fibers change from curled to straight configuration. After mineralization, the interfibrous slippage is limited, and the fracture mode changes from fiber pullout to fiber break. Finite element analysis has been carried out to simulate the fracture and suture retention properties, and the simulation can well reproduce experimental results. The study may provide insights for tissue replacement and repairing.

World cultural heritage (WHS) is of great significance to promoting the sustainable development of cities, and history culture is very important to achieve the goal of sustainable development. The purpose of this paper is to construct a cultural heritage evaluation system and to explore and optimize tourist routes. We take cultural heritage sites as the research object, and comprehensively use Analytic Hierarchy Process (AHP), Delphi method and fuzzy mathematics to establish a cultural heritage tourism resource evaluation system. According to the evaluation results and questionnaires, a decision-making system for cultural tourism route planning is established, and additional sites of Qin culture are found, and a complete Qin culture route is established to provide data and theoretical basis for Xi'an's perfect cultural tourism route. The traveling salesman problem is the most basic path problem. In this study, the ant colony algorithm is used to improve the model combined with the actual problem of Xi'an tourist routes, and the optimal solution of the cultural parade route is obtained. Xi'an authorities and managers can strategically use these findings to promote Xi'an as a green destination WHS.

Summary: The role of BACH1 in the process of vascular smooth muscle cell (VSMC) differentiation from human embryonic stem cells (hESCs) remains unknown. Here, we find that the loss of BACH1 in hESCs attenuates the expression of VSMC marker genes, whereas overexpression of BACH1 after mesoderm induction increases the expression of VSMC markers during in vitro hESC-VSMC differentiation. Mechanistically, BACH1 binds directly to coactivator-associated arginine methyltransferase 1 (CARM1) during in vitro hESC-VSMC differentiation, and this interaction is mediated by the BACH1 bZIP domain. BACH1 recruits CARM1 to VSMC marker gene promoters and promotes VSMC marker expression by increasing H3R17me2 modification, thus facilitating in vitro VSMC differentiation from hESCs after the mesoderm induction. The increased expression of VSMC marker genes by BACH1 overexpression is partially abolished by inhibition of CARM1 or the H3R17me2 inhibitor TBBD in hESC-derived cells. These findings highlight the critical role of BACH1 in hESC differentiation into VSMCs by CARM1-mediated methylation of H3R17.

Abstract Cancer cell membrane (CCM) derived nanotechnology functionalizes nanoparticles (NPs) to recognize homologous cells, exhibiting translational potential in accurate tumor therapy. However, these nanoplatforms are majorly generated from fixed cell lines and are typically evaluated in cell line-derived subcutaneous-xenografts (CDX), ignoring the tumor heterogeneity and differentiation from inter- and intra- individuals and microenvironments between heterotopic- and orthotopic-tumors, limiting the therapeutic efficiency of such nanoplatforms. Herein, various biomimetic nanoplatforms (CCM-modified gold@Carbon, i.e., Au@C-CCM) were fabricated by coating CCMs of head and neck squamous cell carcinoma (HNSCC) cell lines and patient-derived cells on the surface of Au@C NP. The generated Au@C-CCMs were evaluated on corresponding CDX, tongue orthotopic xenograft (TOX), immune-competent primary and distant tumor models, and patient-derived xenograft (PDX) models. The Au@C-CCM generates a photothermal conversion efficiency up to 44.2% for primary HNSCC therapy and induced immunotherapy to inhibit metastasis via photothermal therapy-induced immunogenic cell death. The homologous CCM endowed the nanoplatforms with optimal targeting properties for the highest therapeutic efficiency, far above those with mismatched CCMs, resulting in distinct tumor ablation and tumor growth inhibition in all four models. This work reinforces the feasibility of biomimetic NPs combining modular designed CMs and functional cores for customized treatment of HNSCC, can be further extended to other malignant tumors therapy.

Several TMED protein family members are overexpressed in malignant tumors and associated with tumor progression. TMED1 belongs to the TMED protein family and is involved in protein vesicular trafficking. However, the expression level and biological role of TMED1 in colorectal cancer (CRC) have yet to be fully elucidated. In this study, the integration of patient survival and multi-omics data (immunohistochemical staining, transcriptomics, and proteomics) revealed that the highly expressed TMED1 was related to the poor prognosis in CRC. Crystal violet staining indicated the cell growth was reduced after knocking down TMED1. Moreover, the flow cytometry results showed that TMED1 knockdown could increase cell apoptosis. The expression of TMED1 was positively correlated with other TMED family members (TMED2, TMED4, TMED9, and TMED10) in CRC, and the protein–protein interaction network suggested its potential impact on immune regulation. Furthermore, TMED1 expression was positively associated with the infiltration levels of regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and endothelial cells and negatively correlated with the infiltration levels of CD4+ T cells, CD8+ T cells, and B cells. At last, the CTRP and GDSC datasets on the GSCA platform were used to analyze the relationship between TMED1 expression and drug sensitivity (IC50). The result found that the elevation of TMED1 was positively correlated with IC50 and implied it could increase the drug resistance of cancer cells. This research revealed that TMED1 is a novel prognostic biomarker in CRC and provided a valuable strategy for analyzing potential therapeutic targets of malignant tumors.

In order to understand the effect of covalent graft modification of protein on its emulsifying stability, WPI-EGCG graft was prepared by free radical grafting using whey protein isolate (WPI) and epigallocatechingallate (EGCG) as raw materials. Scanning electron microscopy (SEM) was used to observe the microstructure, and the effect of covalent grafting on the interface stability was investigated by measuring the adsorption capacity of interfacial protein and the rheological properties of the interface. Lycopene nano-emulsion was constructed by WPI-EGCG graft as emulsifier, and its physicochemical stability and storage stability were studied. The results showed that the free radical grafting of EGCG changed the structure of WPI and made it higher viscosity and interfacial stability, so that the lycopene nano-emulsion system using the graft as emulsifier had higher physical and chemical stability. The size and ζ-potential of the WPI-EGCGE graft-stabilized lycopene nano-emulsion increased 268.3 nm and 17.6 mV, respectively, after 30 days of storage at 37 ℃. The retention rate of lycopene in the emulsion was 66.23%, showing a better lycopene protection effect. This study would provide a reference for the construction of nano-emulsion transport system of functional active substances.

Electrochemical reduction of CO2 (CO2RR) coupled with renewable electrical energy is an attractive way of upgrading CO2 to value-added chemicals and closing the carbon cycle. However, CO2RR electrocatalysts still suffer from high overpotential, and the complex reaction pathways of CO2RR often lead to mixed products. Early research focuses on tuning the binding of reaction intermediates on electrocatalysts, and recent efforts have revealed that the design of electrolysis reactors is equally important for efficient and selective CO2RR. In this review, we present an overview of recent advances and challenges toward achieving high activity and high selectivity in CO2RR at ambient conditions, with a particular focus on the progress of CO2RR electrocatalyst engineering and reactor design. Our discussion begins with three types of electrocatalysts for CO2RR (noble metal-based, none-noble metal-based, and metal-free electrocatalysts), and then we examine systems-level strategies toward engineering specific components of the electrolyzer, including gas diffusion electrodes, electrolytes, and polymer electrolyte membranes. We close with future perspectives on catalyst development, in-situ/operando characterization, and electrolyzer performance evaluation in CO2RR studies.

Abstract In China, dauciform roots were hardly studied and only reported in alpine meadows, where sedges showed a different tendency from other functional groups such as grasses and forbs with degradation. In addition, Carex species were proved to have shifting scaling relationships among LES (leaf economics spectrum) traits under disturbance. So, are these unique performances of sedges related to the presence of dauciform roots, and if so, how? An alpine meadow dominated by Carex filispica in Baima Snow Mountain was selected, and quantitative trampling was performed (0, 50, 200, and 500 passes). The cover and dauciform root properties of Carex filispica were measured, as well as the morphological, chemical traits and biomass of leaves and roots, their correlations and the differences between individuals with and without dauciform roots were analyzed. After the trampling, individuals with dauciform roots showed multiple resource‐acquisitive traits: Larger, thicker leaves, more aboveground biomass, higher efficiency of nutrient utilization, and slenderer roots. Additionally, they had a tighter correlation among belowground biomass, morphological and chemical traits, as well as dauciform root properties and morphology of leaves, suggesting that their traits were more related than those without dauciform roots. The presence of dauciform roots in Carex filispica was related to advantages in multiple traits after trampling, which is consistent with and might be responsible for the unique performances of sedges.

Abstract Background Climate change caused by environmental pollution is the most important one of many environmental health hazards currently faced by human beings. In particular, the extreme temperature is an important risk factor for death from respiratory and circulatory diseases. This study aims to explore the meteorological-health effect and find out the vulnerable individuals of extreme temperature events in a less developed city in western China. Method We collected the meteorological data and data of death caused by respiratory and circulatory diseases in Mianyang City from 2013 to 2019. The nonlinear distributed lag model and the generalized additive models were combined to study the influence of daily average temperature (DAT) on mortality from respiratory and circulatory diseases in different genders, ages. Results The exposure-response curves between DAT and mortality from respiratory and circulatory diseases presented a nonlinear characteristic of the “V” type. Cumulative Relative Risk of 30 days (CRR 30 ) of deaths from respiratory diseases with 4.48 (2.98, 6.73) was higher than that from circulatory diseases with 2.77 (1.96, 3.92) at extremely low temperature, while there was no obvious difference at extremely high temperature. The health effects of low temperatures on the respiratory system of people of all ages and genders were persistent, while that of high temperatures were acute and short-term. The circulatory systems of people aged

Urban parks, as an important component of urban green spaces, play a crucial role in improving the urban environment and enhancing residents’ quality of life. This review summarizes the main content and research progress of urban park microclimate studies through analysis and synthesis of relevant literature from academic databases such as Web of Science and Google Scholar. Using Citespace or VOSviewer for bibliometric analysis, we found that the number of academic papers on the urban park microclimate has been growing year by year. The research content primarily covers the monitoring and analysis of temperature, humidity, wind speed, and other indicators in urban parks, as well as the impact of park design and planning on the microclimate. Keyword analysis revealed that researchers have mainly focused on the cooling effects of the urban park microclimate, mitigation of the urban heat island effect, and improvement of air quality. In terms of research methods, a combination of field observations and simulation models is commonly employed, with data being analyzed and validated using mathematical and statistical methods. The research results indicate that well-designed and planned parks can significantly improve the microclimate environment, reduce temperatures, and provide comfortable climatic conditions in urban areas. Additionally, vegetation arrangements and water features in urban parks also contribute to microclimate regulation. Moreover, windbreak measures and cooling strategies in parks can help alleviate the urban heat island effect, enhance air quality, and promote the health of ecosystems. However, this review also identified some issues in urban park microclimate research, including limitations in research scope, methods, and practical applicability. Future studies could deepen the comprehensive understanding of the urban park microclimate and explore more effective strategies for park design and planning to optimize and enhance the microclimate environment. It is also important for researchers to continuously innovate in terms of research methods and verify the feasibility of practical applications to better address the challenges of urban development.

In this study, typical open spaces were selected in the urban area of Lanzhou, China, with varying distances from the Yellow River and different plant configuration spaces. Then, the thermal perception of respondents was investigated through meteorological measurements, thermal comfort questionnaires, and parametric modeling. The findings indicate the following: (1) Wind speed decreases significantly as the distance from the Yellow River increases in the three open green spaces. (2) The cold lake effect of the Yellow River dominates the wind environment. (3) The closest site to the Yellow River exhibits the strongest correlation between wind speed and the respondents’ thermal sensation. (4) There is a strong positive correlation between the model output and different spatial measurement values. (5) There is a certain discrepancy between the UTCI values and the actual measurements, but the fit is high and consistent with an R-squared value of 0.936. This study quantitatively evaluated the thermal comfort and perception in typical spaces and validated the reliability of parameterized modeling for such spaces, providing a reference basis for thermal environment planning in these spaces.

As concrete is one of the most commonly used construction materials, there is a massive production of cement, which causes cement manufacturing to be an energy-intensive industry. A significant amount of the cost of cement production, ranging from 20% to 25%, is attributed to thermal energy. In addition, the action of mining and burning fossil fuels results in the unfavorable emission of hazardous compounds into the environment. Therefore, the switch from conventional fossil fuels to alternative fuels (AFs) in the cement manufacturing business has attracted attention due to environmental and financial concerns. In this paper, four commonly used AFs are discussed, which are waste tires, municipal solid waste, meat and bone meal, and sewage sludge. It is found that each AF has a unique calorific value and properties, attributed to its source, treatment, and technology. Furthermore, the availability of AF is important as the amount varies depending on the location. In addition, their effects on gaseous emissions from the cement plant and the quality of clinker are found to be inconsistent. Thus, there will not be a single best type of AF option to be used in the cement industry. A good AF should be able to provide sufficient thermal energy while reducing the environmental impacts and costs. A careful analysis and multicriteria decision-making approach are always vital when employing AFs in order to prevent environmental problems, cost increases, as well as clinker quality degradation.

Abstract Epitranscriptomic remodeling such as N6‐methyladenosine (m6A) modification plays a critical role in tumor development. However, little is known about the underlying mechanisms connecting m6A modification and nasopharyngeal carcinoma (NPC) progression. Here, CBX1 is identified, a histone methylation regulator, to be significantly upregulated with m6A hypomethylation in metastatic NPC tissues. The m6A‐modified CBX1 mRNA transcript is recognized and destabilized by the m6A reader YTHDF3. Furthermore, it is revealed that CBX1 promotes NPC cell migration, invasion, and proliferation through transcriptional repression of MAP7 via H3K9me3‐mediated heterochromatin formation. In addition to its oncogenic effect, CBX1 can facilitate immune evasion through IFN‐γ‐STAT1 signaling‐mediated PD‐L1 upregulation. Clinically, CBX1 serves as an independent predictor for unfavorable prognosis in NPC patients. The results reveal a crosstalk between epitranscriptomic and epigenetic regulation in NPC progression, and shed light on the functions of CBX1 in tumorigenesis and immunomodulation, which may provide an appealing therapeutic target in NPC.

The aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology–based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule–based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC — especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer.

Background: Emotion recognition deficits are linked with social dysfunction in psychosis, as is inaccurate self-assessment of emotion recognition abilities. However, little is known about the link between ER and real-time social appraisals and behavior. Methods: In 136 people with psychotic disorders or affective disorder with psychosis we administered a novel ecological momentary cognitive test of emotion recognition which both assesses emotion recognition ability and self-assessed performance in conjunction with ecological momentary assessment of social appraisals, motivation, and time spent alone. Hybrid mixed effects models evaluated emotion recognition's associations with social experiences. Results: Better recognition ability was associated with greater pleasure and more positive appraisals of others during interactions, whereas accuracy of self-assessment of emotion recognition ability was associated with more positive appraisals of interactions and social motivation. Overestimation of emotion recognition was linked with concurrent higher social motivation yet greater desire to avoid others. Time alone was unrelated to emotion recognition ability or self-assessment of ability. Discussion: Mobile emotion recognition performance was associated with appraisals of recent interactions but not behavior. Self-assessment of social cognitive performance was associated with more positive appraisals and social motivation, and may be a novel target for interventions aimed at social dysfunction.

The radial gate corbel beam is a kind of gate support structure more often used in large and medium-sized reservoirs, but the current corresponding structural design code does not give a review calculation method for it. Because there are obvious differences between a corbel and a corbel beam in structural form and force, if the corbel beam is just simplified in the calculation as a corbel structure, it can easily lead to misjudgment of insufficient bearing capacity. This misjudgment has a significant impact on later safety assessment, danger removal, and reinforcement. Currently, there are limited studies available on the internal stress distribution of the corbel beam. In this study, taking the danger removal and reinforcement of the radial gate beam of a medium reservoir in Beijing as an example, the concrete quality of the dam was tested by the core drilling method, and two safety review methods of the corbel beam for different types of reservoirs were proposed in combination with the Code for Design of Hydraulic Concrete Structures (SL191-2008). Then, three different types of calculation model were established by the method of theoretical mechanics calculation and finite element simulation. Combined with the safety test data, the stress state of the combined stress structure of the corbel beam and gate pier under the real state was analyzed and the safety evaluation was carried out. The calculation results of these two corbel beam safety review methods were respectively reduced by 32% and 47% compared with the current calculation method. Engineering practice has proved the rationality of the two safety evaluation methods proposed in this paper, which can provide a certain reference for similar engineering reinforcement.

Abstract Background Nucleus pulposus cell (NPC) degeneration is widely accepted as one of the major causes of intervertebral disc (IVD) degeneration (IVDD). The pathogenesis of IVDD is complex and consists of inflammation, oxidative stress, and the loss of extracellular matrix (ECM). Cannabinoid type 2 receptor (CB2) has been shown to be involved in the pathological mechanism of a variety of diseases due to its anti-inflammatory effects and antioxidative stress capacity. Method In Vitro, H2O2 was used to induce degeneration of nucleus pulposus cells, mRNA and protein expression level was determined by RT-PCR and Western Blot, and Immunocytochemical staining were used to detect expression of collagen II, aggrecan, MMP3/13, superoxide dismutase 2 (SOD2) and inducible nitric oxide synthase (iNOS). In vivo, the potential therapeutic effect of CB2 was detected in the rat acupuncture model. Result In vitro, we found that the CB2 agonist (JWH133) treatment reduced the oxidative stress level in NPCs induced by hydrogen peroxide (H2O2) treatment. Furthermore, the expression of inflammatory cytokines was also decreased by JWH133 treatment. We found that collagen II and aggrecan expression was preserved, whereas matrix metalloproteinase levels were reduced. In vivo, we established a rat model by needle puncture. Imaging assessment revealed that the disc height index (DHI) and morphology of IVD were significantly improved, and the disc degeneration process was delayed by treatment of JWH133. Furthermore, immunohistochemical (IHC) staining revealed that JWH133 could inhibit the degradation of collagen II and decrease the expression of MMP3. Conclusions The experiment indicates the oxidative stress and inflammatory response of rat NPCs induced by H2O2 could be inhibited by activating CB2. This study reveals that CB2 activation can effectively delay the development of IVDD, providing an effective therapeutic target for IVDD.

Selective labeling of distinct bacteria and biofilm is poised for the fundamental understanding of bacterial activities, interactions, and coupled phenomena occurring at the microscale. However, a simple and effective way to achieve selective bacterial labeling is still lacking. Herein, we report a fluorescence probe with core-shell nanostructure that has polydopamine (PDA) coating on the surface of fluorescent silicon quantum dots (SiQDs@PDA). The surface of the SiQDs@PDA can be functionalized by various molecules (2-mercaptoethylamine hydrochloride, PEG, d-alanine, glucose amide) through different strategies (Michael addition, π-π interaction, and ion–ion interaction). Importantly, the d-alanine (D-Ala)- and gluconamide (Glc)-functionalized SiQDs@PDA fluorescence probes are capable of selectively labeling gram-positive and gram-negative bacteria, as well as their biofilms. The excellent performance in universal functionalization and selective labeling and imaging of bacteria and their biofilms demonstrate that SiQDs@PDA are a promising fluorescence tool in microbe research.

Among the Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-on temporal gravity products, the north–south stripe noise in the spherical harmonic coefficient (SHC) products contaminates the inversion of the Earth’s mass field. In this study, GRACE SHC products are adopted to estimate the mass changes in Nicaragua. To improve this estimation, we propose an empirical low-pass filter to suppress stripe noise. After only using our filter, the Nicaragua regional uncertainty diminishes from 123.26 mm to 69.11 mm, and the mean signal-to-noise ratio of all available months (2002–2021) improves from 1.67 to 1.8. Subsequently, our filter is employed to estimate the basin terrestrial water storage (TWS) change in Nicaragua. In the end, TWS change estimations are compared with various observations such as mascon products, hydrological models, and in situ groundwater observation. The main conclusions are as follows: (1) After using the wavelet coherent analysis, there is a negative resonance between TWS and the climate factor (El Nino–Southern Oscillation) with a period of 2~4 years; (2) The significant ~3.8-year periodic signal in groundwater storage change estimation is contributed by GRACE aliasing error. Our work can provide new knowledge and references for mass change in small areas.

Pine wilt disease (PWD), caused by pine wood nematode (PWN, Bursaphelenchus xylophilus), poses a serious threat to the coniferous forests in China. This study used unmanned aerial vehicle (UAV)-based hyperspectral imaging conducted at different altitudes to investigate the impact of spatio-temporal scales on PWD detection in an monoculture Masson pine plantation. The influence of spatio-temporal scales on hyperspectral responses of pine trees infected with PWD and detection accuracies were evaluated by Jeffries–Matusita (J-M) distances and the random forest (RF) algorithm. The optimal vegetation indices (VIs) and spatial resolutions were identified by comparing feature importance and model accuracy. The main results showed that the VIs and J-M distances were greatly affected by spatio-temporal scales. In the early, mid-, and late infection stages, the RF-based PWD detection model had accuracies ranging between 72.05 and 79.48%, 83.71 and 89.59%, and 96.81 and 99.28%, peaking at the 10 cm, 8 cm, and 4 cm spatial resolutions, respectively. The green normalized difference vegetation index (GNDVI) and red edge position (REP) were the optimal VIs in early and mid-infection stages, respectively. This study can be important to improve the efficiency of PWD detection and reducing the loss of forests resources.

Surgery is the final choice for most patients with intervertebral disc degeneration (IDD). Operation-caused trauma will cause inflammation in the intervertebral disc. Serious inflammation will cause tissue defects and induce tissue degeneration, IDD recurrence and the occurrence of other diseases. Therefore, we proposed a scheme to treat recurrence after discectomy by inhibiting inflammation with an aspirin (ASP)-loaded hydrogel to restore the mechanical stability of the spine and relieve local inflammation. ASP-liposomes (ASP-Lips) were incorporated into a photocrosslinkable gelatin-methacryloyl (GelMA) via mixing. This material can effectively alleviate inflammation by inhibiting the release of high mobility group box 1 (HMGB1) from the nucleus to the cytoplasm. We further assessed the expression of inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), and degeneration-related factors, such as type II collagen (COL-2), Aggrecan, matrix metallopeptidases-3 (MMP-3), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 in rat nucleus pulpous cells. The level of IDD was analyzed through H&E, safranin-O staining and immunohistochemistry in rabbit samples. In vitro, we found that ASP-Lip@GelMA treatment significantly decreased inflammatory cytokines, MMP-3 and -13, and ADAMTS-4 and -5 and up-regulated COL-2 and Aggrecan via the inhibited release of HMGB-1 from the nucleus. In vivo, ASP-Lip@GelMA can effectively inhibit inflammation of local tissue after disc surgery and fill local tissue defects. This composite hydrogel system is a promising way to treat the recurrence of IDD after surgery without persistent complications.

Abstract Background SPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown. Methods We retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center. Results SPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort. Conclusions We concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

ObjectiveThe aim of this study is to verify whether melatonin (Mel) could mitigate intervertebral disk degeneration (IVDD) in rats and to investigate the potential mechanism of it.MethodA rat acupuncture model of IVDD was established with intraperitoneal injection of Mel. The effect of Mel on IVDD was analyzed via radiologic and histological evaluations. The specific Mel receptors were investigated in both the nucleus pulposus (NP) and cartilaginous endplates (EPs). In vitro, EP cartilaginous cells (EPCs) were treated by different concentrations of Mel under lipopolysaccharide (LPS) and Luzindole conditions. In addition, LPS-induced inflammatory response and matrix degradation following nuclear factor kappa-B (NF-κB) pathway activation were investigated to confirm the potential mechanism of Mel on EPCs.ResultsThe percent disk height index (%DHI) and MRI signal decreased after initial puncture in the degeneration group compared with the control group, while Mel treatment protected disk height from decline and prevented the loss of water during the degeneration process. In the meantime, the histological staining of the Mel groups showed more integrity and well-ordered construction of the NP and EPs in both low and high concentration than that of the degeneration group. In addition, more deep-brown staining of type II collagen (Coll-II) was shown in the Mel groups compared with the degeneration group. Furthermore, in rat samples, immunohistochemical staining showed more positive cells of Mel receptors 1a and 1b in the EPs, instead of in the NP. Moreover, evident osteochondral lacuna formation was observed in rat EPs in the degeneration group; after Mel treatment, the osteochondral destruction alleviated accompanying fewer receptor activator for nuclear factor-κB ligand (RANKL) and tartrate-resistant acid phosphatase (TRAP)-stained positive cells expressed in the EPs. In vitro, Mel could promote the proliferation of EPCs, which protected EPCs from degeneration under LPS treatment. What is more, Mel downregulated the inflammatory response and matrix degradation of EPCs activated by NF-κB pathway through binding to its specific receptors.ConclusionThese results indicate that Mel protects the integrity of the EPs and attenuates IVDD by binding to the Mel receptors in the EPs. It may alleviate the inflammatory response and matrix degradation of EPCs activated by NF-κB pathway.

Abstract Background Female patients are more likely to have tendon injuries than males, especially those who has a higher concentration of relaxin. Previous studies have demonstrated that relaxin attenuates extracellular matrix (ECM) formation. However, the mechanism of relaxin on tendon repair remains unclear. We hypothesize that relaxin inhibits tendon healing by disrupting collagen synthesis. Methods A patellar tendon window defect model was established using Sprague-Dawley rats. The center of the patellar tendon was removed from the patella distal apex and inserted to the tibia tuberosity in width of 1 mm. Then, the rats were injected with saline (0.2 μg/kg/day) or relaxin (0.2 μg/kg/day) for two and four weeks, which was followed by biomechanical analysis and histological and histochemical examination. Results Mechanical results indicated that relaxin induces a significant decrease in tear resistance, stiffness, and Young’s modulus compared to those rats without relaxin treatment. In addition, it was shown that relaxin activates relaxin family peptide receptor 1(RXFP1), disturbs the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs), and reduces the deposition of collagen in injury areas. Conclusions Relaxin impairs tendon healing in rats. Also, relaxin might lead to tendon injury more commonly for females than males.

Whether or not the process of somitogenesis and myogenesis is affected by excessive caffeine intake still remains ambiguous. In this study, we first showed that caffeine treatment results in chest wall deformities and simultaneously reduced mRNA expressions of genes involved in myogenesis in the developing chicken embryos. We then used embryo cultures to assess in further detail how caffeine exposure affects the earliest steps of myogenesis, and we demonstrated that the caffeine treatment suppressed somitogenesis of chicken embryos by interfering with the expressions of crucial genes modulating apoptosis, proliferation, and differentiation of myogenic progenitors in differentiating somites. These phenotypes were abrogated by a retinoic acid (RA) antagonist in embryo cultures, even at low caffeine doses in C2C12 cells, implying that excess RA levels are responsible for these phenotypes in cells and possibly in vivo. These findings highlight that excessive caffeine exposure is negatively involved in regulating the development of myogenic progenitors through interfering with RA signaling. The RA somitogenesis/myogenesis pathway might be directly impacted by caffeine signaling rather than reflecting an indirect effect of the toxicity of excess caffeine dosage.

Stem cell–based tissue engineering therapy is the most promising method for treating volumetric muscle loss. Human amniotic mesenchymal cells possess characteristics similar to those of embryonic stem cells. In this study, we verified the stem cell characteristics of human amniotic mesenchymal cells by the flow cytometry analysis, and osteogenic and adipogenic differentiation. Through induction with the DNA demethylating agent 5-azacytidine, human amniotic mesenchymal cells can undergo myogenic differentiation and express skeletal muscle cell–specific markers such as desmin and MyoD. The Wnt/β-catenin signaling pathway also plays an important role. After 5-azacytidine-induced human amniotic mesenchymal cells were implanted into rat tibialis anterior muscle with volumetric muscle loss, we observed increased angiogenesis and improved local tissue repair. We believe that human amniotic mesenchymal cells can serve as a potential source of cells for skeletal muscle tissue engineering.

Eucalyptus is harvested for wood and fiber production in many tropical and sub-tropical habitats globally. Plantation has been controversial because of its influence on the surrounding environment, however, the influence of massive Eucalyptus planting on soil microbial communities is unclear. Here we applied high-throughput sequencing of the 16S rRNA gene to assess the microbial community composition and diversity of planting chronosequences, involving two, five and ten years of Eucalyptus plantation, comparing to that of secondary-forest in South China. We found that significant changes in the composition of soil bacteria occurred when the forests were converted from secondary-forest to Eucalyptus. The bacterial community structure was clearly distinct from control and five year samples after Eucalyptus was grown for 2 and 10 years, highlighting the influence of this plantation on local soil microbial communities. These groupings indicated a cycle of impact (2 and 10 year plantations) and low impact (5-year plantations) in this chronosequence of Eucalyptus plantation. Community patterns were underpinned by shifts in soil properties such as pH and phosphorus concentration. Concurrently, key soil taxonomic groups such as Actinobacteria showed abundance shifts, increasing in impacted plantations and decreasing in low impacted samples. Shifts in taxonomy were reflected in a shift in metabolic potential, including pathways for nutrient cycles such as carbon fixation, which changed in abundance over time following Eucalyptus plantation. Combined these results confirm that Eucalyptus plantation can change the community structure and diversity of soil microorganisms with strong implications for land-management and maintaining the health of these ecosystems.

Recently, automated software vulnerability detection and exploitation in Internet of Things (IoT) has attracted more and more attention, due to IoT’s fast adoption and high social impact. However, the task is challenging and the solutions are non-trivial: the existing methods have limited effectiveness at discovering vulnerabilities capable of compromising IoT systems. To address this, we propose an Automated Vulnerability Discovery and Exploitation framework with a Scheduling strategy, AutoDES that aims to improve the efficiency and effectiveness of vulnerability discovery and exploitation. In the vulnerability discovery stage, we use our Anti-Driller technique to mitigate the “path explosion” problem. This approach first generates a specific input proceeding from symbolic execution based on a Control Flow Graph (CFG). It then leverages a mutation-based fuzzer to find vulnerabilities while avoiding invalid mutations. In the vulnerability exploitation stage, we analyze the characteristics of vulnerabilities and then propose to generate exploits, via the use of several proposed attack techniques that can produce a shell based on the detected vulnerabilities. We also propose a genetic algorithm (GA)-based scheduling strategy (AutoS) that helps with assigning the computing resources dynamically and efficiently. The extensive experimental results on the RHG 2018 challenge dataset and the BCTF-RHG 2019 challenge dataset clearly demonstrate the effectiveness and efficiency of the proposed framework.

Chemistry education has been affected in various aspects, especially teaching models, teaching technology, curriculum design, and teaching assessment, in Chinese Mainland since COVID-19 struck. To explore the change in teaching performance and differences in those teaching performances between middle school teachers and university teachers, this study analyzes 46 chemical education journal articles in three academic levels, including Junior High School (JHS), Senior High School (SHS), and university through content analysis method. The result shows that all levels of chemistry teachers (CTs) prefer to adopt two teaching models (live teaching or a combination of live and recorded teaching) and use Tencent Meeting as a teaching platform, but, university chemistry professors can integrate some software (MOOC and WeiXin as well as QQ) into their class to improve the effectiveness of teaching. As for curriculum design and teaching assessment, university teachers can employ the news in the context of the COVID-19 pandemic to carry out teaching more deeply than middle school teachers because university students learn more professional chemistry knowledge, but, all of them tend to evaluate students promptly (like oral assessment) through classroom interaction. Thus, it suggests the government and the school develop educational applications/software and teaching resources and a diverse curriculum to enhance online teaching work both domestically and foreign. And, it is also suggested that teachers should actively participate in the training of educational technology and strengthen cooperation with teachers in other disciplines to build interdisciplinary classrooms.