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In order to obtain the observed scale height at high altitude a calculation method has been derived for determining density scale height from the difference between two satellite's heights. Two balloon satellites, Chinese DQ-1A and DQ-1B, were launched together into a nearly circular orbit at a height near 900 km and they were together in orbit for 190 days. According to the difference of the orbital heights of these two balloon satellites from 19 September 1990 to 9 March 1991, 67 values of density scale height at heights of about 544–877 km were determined. In comparison with CIRA model the results show that: (1) the trend of the variation of the scale height with height is in agreement with CIRA; (2) the determined scale height values present an oscillatory variation with time and height; and (3) the mean of the observed scale height is 3.7% lower than the mean of corresponding values from CIRA-72 and 0.8% lower than CIRA-86.

Abstract Due to the complex maritime navigation environment, Unmanned Surface Vessels (USVs) are influenced by unknown nonlinear dynamics arising from external disturbances and internal uncertainties. Achieving effective formation control while maintaining obstacle avoidance performance presents significant challenges. This article proposes a Neural Networks (NNs) adaptive formation Artificial Potential Field (APF) obstacle avoidance control method for multiple USVs. By employing online updates of Radial Basis Function (RBF) NNs technology, the unknown nonlinear dynamics are approximated, thus addressing complex nonlinear dynamics problems. In scenarios involving multiple USVs navigating under high wind and wave conditions, collisions with obstacles frequently occur. To tackle this issue, a leader-follower control strategy is designed that effectively addresses risk assessment and obstacle avoidance under such challenging conditions. Additionally, to account for saturation constraints or potential faults in the controller inputs commonly encountered in engineering applications, it implements an asymmetric auxiliary control system. Furthermore, the Lyapunov stability theorem is utilized to ensure the stability of both the formation control and obstacle avoidance algorithms for multiple USVs. Finally, the effectiveness of the proposed algorithm is validated through simulations.

Abstract Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.

Abstract The exploration potential within deep-water petroliferous basins holds great promise for oil and gas resources. However, the dearth of geochemical and isotopic data poses a formidable challenge in comprehending the intricate hydrocarbon charging processes, thereby impeding the comprehensive understanding of hydrocarbon accumulation mechanisms and models. Consequently, the establishment of robust source–reservoir relationships in deep-water petroliferous basins represents a pivotal challenge that significantly influences the exploration strategies and the comprehension of hydrocarbon enrichment dynamics within such basins. In this study, we introduce a novel approach, termed the “source–reservoir dynamic evaluation method,” tailored to investigate reservoir accumulation models in deep-water petroliferous basins. This method uses basin simulation technology to recover the thermal evolution history and hydrocarbon generation and expulsion history of source rocks, and on this basis delimits the hydrocarbon kitchen range. At the same time, the maturity of source rocks corresponding to crude oil and natural gas in typical reservoirs is calculated. Then, when the thermal evolution degree of source rocks adjacent to the reservoir reaches this maturity, the corresponding geological period is the main charging period of hydrocarbon. As a typical deep-water petroliferous basin, the Santos Basin in Brazil has abundant oil and gas reservoirs under the thick salt rock, but there are still some fundamental problems such as unclear oil–gas accumulation process and model. Therefore, in this paper, the main charging periods of typical hydrocarbon reservoirs are determined based on the internal relationship between the thermal evolution history of the main source rocks and the maturity of crude oil and natural gas, and then the hydrocarbon accumulation process is analyzed and the dynamic accumulation model is established. Finally, the favorable prospecting direction is pointed out. The results show that the oil and gas in the Barra Velha Formation in the Santos basin are mainly derived from the Itapema Formation lacustrine shale source rock, and the source rock is mainly developed in the Eastern Sag of the Central Depression, and its main hydrocarbon generation period is from the deposition period of Florianopolis Formation to the deposition period of Santos Formation. The main hydrocarbon expulsion period was from the deposition period of the Santos Formation to the Early deposition of the Iguape Formation. The oil and gas in the Barra Velha Formation were mainly charged from the Late deposition period of the Santos Formation to the Early deposition period of the Iguape Formation. During this period, the hydrocarbon migrated vertically along the normal fault formed in the rift period to the trap of the adjacent inheritance structural highs and accumulated in the reservoir, which was dominated by the accumulation model of the “lower generation-upper reservoir-salt cap”. Since the Barra Velha Formation has the characteristics of near-source accumulation, based on the hydrocarbon expulsion center and hydrocarbon expulsion intensity of the source rock of the Itapema Formation, the distribution ranges of 85% and 50% Pre-salt accumulation probability in the Santos basin were calculated by using the quantitative analysis model of the hydrocarbon distribution threshold. It is suggested that the next oil and gas exploration should be carried out in the paleo-structural highs and slope of Class I favorable area (the hydrocarbon accumulation probability is more than 85%) and Class II favorable area (the hydrocarbon accumulation probability is 85–50%).

Abstract Gut bacteria might play an important role in male reproductive disorders, such as male infertility and sperm abnormalities; however, their causal role is unclear. Herein, Mendelian randomization (MR)-Egger, weighted median, inverse variance weighting, Simple mode, and Weighted mode were used to test the causal relationship between gut microbes and male reproductive diseases. The MR results were validated using various metrics. The MR results were also consolidated using reverse causality speculation, conducted using two-way MR analysis and Steiger filtering. Biological function was analysed using enrichment analyses. The results suggested that eight intestinal microflorae were causally associated with male infertility. The Eubacterium oxidoreducens group was associated with an increased risk of male infertility, while the family Bacteroidaceae was negatively associated with male reproductive diseases. Eight intestinal microflorae were causally associated with abnormal spermatozoa. The family Streptococcaceae was associated with a high risk of abnormal spermatozoa, whereas the family Porphyromonadaceae was associated with a low risk of abnormal spermatozoa. No pleiotropy was observed, this study identified a high correlation between the gut flora and the likelihood of male reproductive diseases. Future research will attempt to advance microbial-focused treatments for such diseases.

Abstract The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves’ disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.

Abstract Alcohol consumption is a heritable behavior seriously endangers human health. However, genetic studies on alcohol consumption primarily focuses on common variants, while insights from rare coding variants are lacking. Here we leverage whole exome sequencing data across 304,119 white British individuals from UK Biobank to identify protein-coding variants associated with alcohol consumption. Twenty-five variants are associated with alcohol consumption through single variant analysis and thirteen genes through gene-based analysis, ten of which have not been reported previously. Notably, the two unreported alcohol consumption-related genes GIGYF1 and ANKRD12 show enrichment in brain function-related pathways including glial cell differentiation and are strongly expressed in the cerebellum. Phenome-wide association analyses reveal that alcohol consumption-related genes are associated with brain white matter integrity and risk of digestive and neuropsychiatric diseases. In summary, this study enhances the comprehension of the genetic architecture of alcohol consumption and implies biological mechanisms underlying alcohol-related adverse outcomes.

Abstract Iron plays a fundamental role in multiple brain disorders. However, the genetic underpinnings of brain iron and its implications for these disorders are still lacking. Here, we conduct an exome-wide association analysis of brain iron, measured by quantitative susceptibility mapping technique, across 26 brain regions among 26,789 UK Biobank participants. We find 36 genes linked to brain iron, with 29 not being previously reported, and 16 of them can be replicated in an independent dataset with 3,039 subjects. Many of these genes are involved in iron transport and homeostasis, such as FTH1 and MLX. Several genes, while not previously connected to brain iron, are associated with iron-related brain disorders like Parkinson’s (STAB1, KCNA10), Alzheimer’s (SHANK1), and depression (GFAP). Mendelian randomization analysis reveals six causal relationships from regional brain iron to brain disorders, such as from the hippocampus to depression and from the substantia nigra to Parkinson’s. These insights advance our understanding of the genetic architecture of brain iron and offer potential therapeutic targets for brain disorders.

Abstract Our research endeavors are directed towards unraveling the stem cell characteristics of lower-grade glioma patients, with the ultimate goal of formulating personalized treatment strategies. We computed enrichment stemness scores and performed consensus clustering to categorize phenotypes. Subsequently, we constructed a prognostic risk model using weighted gene correlation network analysis (WGCNA), random survival forest regression analysis as well as full subset regression analysis. To validate the expression differences of key genes, we employed experimental methods such as quantitative Polymerase Chain Reaction (qPCR) and assessed cell line proliferation, migration, and invasion. Three subtypes were assigned to patients diagnosed with LGG. Notably, Cluster 2 (C2), exhibiting the poorest survival outcomes, manifested characteristics indicative of the subtype characterized by immunosuppression. This was marked by elevated levels of M1 macrophages, activated mast cells, along with higher immune and stromal scores. Four hub genes—CDCA8, ORC1, DLGAP5, and SMC4—were identified and validated through cell experiments and qPCR. Subsequently, these validated genes were utilized to construct a stemness risk signature. Which revealed that Lower-Grade Glioma (LGG) patients with lower scores were more inclined to demonstrate favorable responses to immune therapy. Our study illuminates the stemness characteristics of gliomas, which lays the foundation for developing therapeutic approaches targeting CSCs and enhancing the efficacy of current immunotherapies. By identifying the stemness subtype and its correlation with prognosis and TME patterns in glioma patients, we aim to advance the development of personalized treatments, enhancing the ability to predict and improve overall patient prognosis.

Abstract To investigate the screening and predicting functions of obesity- and lipid-related indices for type 2 diabetes (T2D) in middle-aged and elderly Chinese, as well as the ideal predicted cut-off value. This study's data comes from the 2011 China Health and Retirement Longitudinal Study (CHARLS). A cross-sectional study design was used to investigate the relationship of T2D and 13 obesity- and lipid-related indices, including body mass index (BMI), waist circumference (WC), waist–height ratio (WHtR), visceral adiposity index (VAI), a body shape index (ABSI), body roundness index (BRI), lipid accumulation product (LAP), conicity index (CI), Chinese visceral adiposity index (CVAI), triglyceride- glucose index (TyG index) and its correlation index (TyG-BMI, TyG-WC, TyG-WHtR). The unadjusted and adjusted correlations between 13 indices and T2D were assessed using binary logistic regression analysis. The receiver operating characteristic curve (ROC) was used to determine the usefulness of anthropometric indices for screening for T2D and determining their cut‑off value, sensitivity, specificity, and area under the curve (AUC). The study comprised 9488 people aged 45 years or above in total, of whom 4354 (45.89%) were males and 5134 (54.11%) were females. Among them were 716 male cases of T2D (16.44%) and 870 female cases of T2D (16.95%). A total of 13 obesity- and lipid-related indices were independently associated with T2D risk after adjusted for confounding factors (P

Abstract The purpose of the study was to determine whether changes in body mass index (BMI) and waist circumference (WC) in middle-aged and elderly Chinese are associated with metabolic syndrome. In this cohort investigation, 3697 middle-aged and elderly people aged 45 or over were recruited from the China Health and Retirement Longitudinal Study (CHARLS). The National Cholesterol Education Program Adult Treatment Panel III (2005) defined metabolic syndrome (MetS). With Cox regression analysis, we calculated hazard ratio (HR) and 95% confidence intervals (CIs) for MetS based on BMI-WC change categories. To assess the prevalence of MetS, the changes in BMI and WC levels were classified into four quartiles based on their relative and absolute changes. In subjects whose BMI and WC decreased (HR = 0.338; 95% CIs 0.264, 0.433) as well as those whose BMI increased and their WC decreased (HR = 0.375; 95% CIs 0.228, 0.499), metabolic syndrome risk was significantly lower compared with those with increases in both BMI and WC. Regarding the absolute changes in BMI, the lowest percentile of BMI was significantly lower in both males (HR = 0.302; 95% CIs 0.204, 0.448) and females (HR = 0.486; 95% CIs 0.354, 0.667) for the risk of metabolic syndrome. Similar results were observed in the absolute changes in WC, with the lowest quantile of WC having a significant impact on MetS risk in males (HR = 0.170; 95% CIs 0.107, 0.270) and females (HR = 0.303; 95% CIs 0.217, 0.424). The risk of metabolic syndrome was significantly associated with changes in BMI and WC in middle-aged and elderly Chinese. A reduced BMI and WC are associated with lower metabolic syndrome risks in middle-aged and elderly people.

Abstract Lack of liver regenerative capacity is the primary cause of hepatic failure and even mortality in patients undergoing hepatectomy, with no effective intervention strategies currently available. Therefore, identifying efficacious interventions to enhance liver regeneration is pivotal for optimizing clinical outcomes. Recent studies have demonstrated that vagotomy exerts an inhibitory effect on liver regeneration following partial hepatectomy, thereby substantiating the pivotal role played by the vagus nerve in the process of liver regeneration. In recent years, electroacupuncture (EA) has emerged as a non‐invasive technique for stimulating the vagus nerve. However, EA on hepatic regeneration remains uncertain. In this study, a 70% partial hepatectomy (PH) mouse model is utilized to investigate the effects of EA on acute liver regeneration and elucidate its underlying molecular mechanisms. It is observed that EA at ST36 acutely activated cholinergic neurons in the dorsal motor nucleus of the vagus nerve (DMV), resulting in increased release of acetylcholine from hepatic vagal nerve endings and subsequent activation of IL‐6 signaling in liver macrophages. Ultimately, these events promoted hepatocyte proliferation and facilitated liver regeneration. These findings provide insights into the fundamental brain‐liver axis mechanism through which EA promotes liver regeneration, offering a novel therapeutic approach for post‐hepatectomy liver regeneration disorders.

Abstract Therapeutic benefits and underlying biomechanism(s) of antibody drug conjugates (ADC) in combination with other targeted therapeutics are largely unknown. Here, the synergy between ADC and epigenetic drug decitabine (DAC), a clinically approved DNA methylation inhibitor, in multiple preclinical models of melanoma specifically investigated. Mechanistically, the underlying biomechanisms of how DAC cooperatively worked with ICAM1 antibody conjugated DNA topoisomerase I inhibitor DXd (I1‐DXd) is elucidated. DAC treatment significantly enhanced anti‐tumor efficacy of I1‐DXd by upregulating antigen expression, enhancing antibody internalization and potentiating tumor sensitivity by epigenetically reprogramming of melanoma. Meanwhile, I1‐DXd/DAC combination also exerted regulatory effects on tumor microenvironment (TME) by enhancing tumor infiltration of innate and adaptive immune cells and improving penetration of ADCs with a boosted antitumor immunity. This study provides a rational ADC combination strategy for solid tumor treatment.

Abstract We aimed to analyze the risk factors and construct a new nomogram to predict non-sentinel lymph node (NSLN) metastasis for cT1-2 breast cancer patients with positivity after sentinel lymph node biopsy (SLNB). A total of 830 breast cancer patients who underwent surgery between 2016 and 2021 at multi-center were included in the retrospective analysis. Patients were divided into training (n = 410), internal validation (n = 298), and external validation cohorts (n = 122) based on periods and centers. A nomogram-based prediction model for the risk of NSLN metastasis was constructed by incorporating independent predictors of NSLN metastasis identified through univariate and multivariate logistic regression analyses in the training cohort and then validated by validation cohorts. The multivariate logistic regression analysis revealed that the number of positive sentinel lymph nodes (SLNs) (P

Abstract The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met. Further studies show that MAPK inhibitor U0126 could mimic thyroid dysgenesis in zebrafish, and the phenotypes are rescued by overexpression of constitutively active MEK or Snail, downstream molecules of the HGF/Met pathway, in thyrocytes. Moreover, HGF promotes thyrocyte migration, which is probably mediated by downregulation of E-cadherin expression. The delayed bifurcation of the thyroid primordium is also observed in thyroid-specific Met knockout mice. Together, our findings reveal that HGF/Met is indispensable for the bifurcation of the thyroid primordium during thyroid development mediated by downregulation of E-cadherin in thyrocytes via MAPK-snail pathway.

Abstract Previous genetic studies of venous thromboembolism (VTE) have been largely limited to common variants, leaving the genetic determinants relatively incomplete. We performed an exome-wide association study of VTE among 14,723 cases and 334,315 controls. Fourteen known and four novel genes (SRSF6, PHPT1, CGN, and MAP3K2) were identified through protein-coding variants, with broad replication in the FinnGen cohort. Most genes we discovered exhibited the potential to predict future VTE events in longitudinal analysis. Notably, we provide evidence for the additive contribution of rare coding variants to known genome-wide polygenic risk in shaping VTE risk. The identified genes were enriched in pathways affecting coagulation and platelet activation, along with liver-specific expression. The pleiotropic effects of these genes indicated the potential involvement of coagulation factors, blood cell traits, liver function, and immunometabolic processes in VTE pathogenesis. In conclusion, our study unveils the valuable contribution of protein-coding variants in VTE etiology and sheds new light on its risk stratification.

Abstract Hypertrophic scar (HS) considerably affects the appearance and causes tissue dysfunction in patients. The low bioavailability of 5-fluorouracil poses a challenge for HS treatment. Here we show a separating microneedle (MN) consisting of photo-crosslinked GelMA and 5-FuA-Pep-MA prodrug in response to high reactive oxygen species (ROS) levels and overexpression of matrix metalloproteinases (MMPs) in the HS pathological microenvironment. In vivo experiments in female mice demonstrate that the retention of MN tips in the tissue provides a slowly sustained drug release manner. Importantly, drug-loaded MNs could remodel the pathological microenvironment of female rabbit ear HS tissues by ROS scavenging and MMPs consumption. Bulk and single cell RNA sequencing analyses confirm that drug-loaded MNs could reverse skin fibrosis through down-regulation of BCL-2-associated death promoter (BAD), insulin-like growth factor 1 receptor (IGF1R) pathways, simultaneously regulate inflammatory response and keratinocyte differentiation via up-regulation of toll-like receptors (TOLL), interleukin-1 receptor (IL1R) and keratinocyte pathways, and promote the interactions between fibroblasts and keratinocytes via ligand-receptor pair of proteoglycans 2 (HSPG2)-dystroglycan 1(DAG1). This study reveals the potential therapeutic mechanism of drug-loaded MNs in HS treatment and presents a broad prospect for clinical application.

Abstract DNA methylation is an important part of the genomic biology, which recently allowed the identification of key biomarkers for a variety of cancers, including cutaneous melanoma. Despite the current knowledge in cutaneous melanoma, there is a clear need for new efficient biomarkers in clinical application of detection. We use The Cancer Genome Atlas data as a training set and a multi-stage screening strategy to identify prognostic characteristics of melanoma based on DNA methylation. Three DNA methylation CpG sites were identified to be related to the overall survival in the skin cutaneous melanoma cohort. This signature was validated in two independent datasets from Gene Expression Omnibus. The stratified analysis by clinical stage, age, gender, and grade retained the statistical significance. The methylation signature was significantly correlated with immune cells and anti-tumor immune response. Moreover, gene expression corresponding to the candidate CpG locus was also significantly correlated with the survival rate of the patient. About 49% of the prognostic effects of methylation are mediated by affecting the expression of the corresponding genes. The prognostic characteristics of DNA methylation combined with clinical information provide a better prediction value tool for melanoma patients than the clinical information alone. However, more experiments are required to validate these findings. Overall, this signature presents a prospect of novel and wide-ranging applications for appropriate clinical adjuvant trails.

Abstract There are no models for assessing the factors that determine moderate to poor performance status in patients with cancer after chemotherapy. This study investigated the influencing factors and identified the best model for predicting moderate–poor performance status. A convenience sampling method was used. Demographic and clinical data and evaluation results for fatigue, pain, quality of life and Eastern Cooperative Oncology Group status were collected three days after the end of chemotherapy. Decision tree, random forest and logistic regression models were constructed. Ninety-four subjects in the case group had moderate to poor performance status, and 365 subjects in the control group had no or mild activity disorders. The random forest model was the most accurate model. Physical function, total protein, general quality of life within one week before chemotherapy, hemoglobin, pain symptoms and globulin were the main factors. Total protein and hemoglobin levels reflect nutritional status, and globulin levels are an index of liver function. Therefore, physical function, nutritional status, general quality of life and pain symptoms within one week before chemotherapy and liver function can be used to predict moderate–poor performance status. Nurses should pay more attention to patients with poor physical function, poor nutritional status, lower quality of life and pain symptoms after chemotherapy.

Abstract Accurate identification and localization of multiple abnormalities are crucial steps in the interpretation of chest X-rays (CXRs); however, the lack of a large CXR dataset with bounding boxes severely constrains accurate localization research based on deep learning. We created a large CXR dataset named CXR-AL14, containing 165,988 CXRs and 253,844 bounding boxes. On the basis of this dataset, a deep-learning-based framework was developed to identify and localize 14 common abnormalities and calculate the cardiothoracic ratio (CTR) simultaneously. The mean average precision values obtained by the model for 14 abnormalities reached 0.572-0.631 with an intersection-over-union threshold of 0.5, and the intraclass correlation coefficient of the CTR algorithm exceeded 0.95 on the held-out, multicentre and prospective test datasets. This framework shows an excellent performance, good generalization ability and strong clinical applicability, which is superior to senior radiologists and suitable for routine clinical settings.

Abstract Neural mechanisms underlying semantic processing have been extensively studied by using functional magnetic resonance imaging, nevertheless, the individual differences of it are yet to be unveiled. To further our understanding of functional and anatomical brain organization underlying semantic processing to the level of individual humans, we used out-of-scanner language behavioral data, T1, resting-state, and story comprehension task-evoked functional image data in the Human Connectome Project, to investigate individual variability in the task-evoked semantic processing network, and attempted to predict individuals’ language skills based on task and intrinsic functional connectivity of highly variable regions, by employing a machine-learning framework. Our findings first confirmed that individual variability in both functional and anatomical markers were heterogeneously distributed throughout the semantic processing network, and that the variability increased towards higher levels in the processing hierarchy. Furthermore, intrinsic functional connectivities among these highly variable regions were found to contribute to predict individual reading decoding abilities. The contributing nodes in the overall network were distributed in the left superior, inferior frontal, and temporo-parietal cortices. Our results suggested that the individual differences of neurobiological markers were heterogeneously distributed in the semantic processing network, and that neurobiological markers of highly variable areas are not only linked to individual variability in language skills, but can predict language skills at the individual level.

Abstract Breast cancer metastasis and invasion are both promoted by the oncoprotein Metadherin (MTDH). However, the the role of Metadherin in breast cancer progression and its role in the immune microenvironment. Are not clear. A bioinformatic analysis was performed to demonstrate the prognostic value of Metadherin in BC. In the present study, we found that Metadherin is overexpressed in BC and is significantly correlated with individual cancer stage, age, subclasses, menopause and nodal metastasis status. Metadherin overexpression was associated with a significant decrease in OS and DSS. Cox multivariate analysis indicated that Metadherin was an independent negative prognostic indicator for OS and DSS. Moreover, Metadherin hypomethylation status was associated with poor prognosis. A negative correlation was also noted between Metadherin overexpression and the number of plasmacytoid dendritic cells, cluster of differentiation 8+ T cells, and natural killer cells. Association patterns varied with different subtypes. Various associations between Metadherin levels and immune cell surface markers were revealed. A total of 40 groups of BC and adjacent normal breast tissue samples were collected. Metadherin mRNA was detected by PCR, and its expression levels in BC tissues were significantly increased compared with those noted in normal tissues. The expression levels of Metadherin were also measured in normal and BC cell lines, respectively, and similar conclusions were obtained. The Metadherin mRNA levels were knocked down in SK-BR3 and MDA-MB-231 cell lines and the cell proliferative and migratory activities were determined using Cell Counting Kit-8 and scratch assays, respectively. The results indicated that the cell proliferative and migratory abilities were reduced following knockdown of Metadherin expression. Therefore, Metadherin may be considered as a novel prognostic biomarker in BC.

Abstract The pathogenesis of thyroid dysgenesis (TD) is not well understood. Here, using a combination of single-cell RNA and spatial transcriptome sequencing, we identify a subgroup of NF-κB-activated thyrocytes located at the center of thyroid tissues in postnatal mice, which maintained a partially mesenchymal phenotype. These cells actively protruded out of the thyroid primordium and generated new follicles in zebrafish embryos through continuous tracing. Suppressing NF-κB signaling affected thyrocyte migration and follicle formation, leading to a TD-like phenotype in both mice and zebrafish. Interestingly, during thyroid folliculogenesis, myeloid cells played a crucial role in promoting thyrocyte migration by maintaining close contact and secreting TNF-α. We found that cebpa mutant zebrafish, in which all myeloid cells were depleted, exhibited thyrocyte migration defects. Taken together, our results suggest that myeloid-derived TNF-α-induced NF-κB activation plays a critical role in promoting the migration of vertebrate thyrocytes for follicle generation.

Abstract Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.

Abstract Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light and feeding). The presence of tissue niche-dependent physiological time cues has been proposed, allowing tissues the ability of circadian phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns of mechanical loading and associated osmotic challenge within physiological ranges reset circadian clock phase and amplitude in cartilage and intervertebral disc tissues in vivo and in tissue explant cultures. Hyperosmolarity (but not hypo-osmolarity) resets clocks in young and ageing skeletal tissues and induce genome-wide expression of rhythmic genes in cells. Mechanistically, RNAseq and biochemical analysis revealed the PLD2-mTORC2-AKT-GSK3β axis as a convergent pathway for both in vivo loading and hyperosmolarity-induced clock changes. These results reveal diurnal patterns of mechanical loading and consequent daily oscillations in osmolarity as a bona fide tissue niche-specific time cue to maintain skeletal circadian rhythms in sync.

Regarding the terrestrial water storage anomaly (TWSA) gap between the Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-on (-FO) gravity satellite missions, a BEAST (Bayesian estimator of abrupt change, seasonal change and trend)+GMDH (group method of data handling) gap-filling scheme driven by hydrological and meteorological data is proposed. Considering these driving data usually cannot fully capture the trend changes of the TWSA time series, we propose first to use the BEAST algorithm to perform piecewise linear detrending for the TWSA series and then fill the gap of the detrended series using the GMDH algorithm. The complete gap-filling TWSAs can be readily obtained after adding back the previously removed piecewise trend. By comparing the simulated gap filled by BEAST + GMDH using Multiple Linear Regression and Singular Spectrum Analysis with reference values, the results show that the BEAST + GMDH scheme is superior to the latter two in terms of the correlation coefficient, Nash-efficiency coefficient, and root-mean-square error. The real GRACE/GFO gap filled by BEAST + GMDH is consistent with those from hydrological models, Swarm TWSAs, and other literature regarding spatial distribution patterns. The correlation coefficients there between are, respectively, above 0.90, 0.80, and 0.90 in most of the global river basins.

The bright band (BB) is an important symbol of the ice–water transition zone in stratiform precipitation, and the presence or absence of BB will lead to different microphysical processes. In this paper, the characteristics of BB and precipitation characteristics with and without BB in summer at Tibetan Plateau (TP) as well as Central-eastern China (CEC) are analyzed by using Global Precipitation Measurement (GPM) and the fifth generation ECMWF atmospheric reanalysis of the global climates (ERA5) datasets. The results show the freezing level height and BB height in TP are 0.5 km higher than those in CEC. With the increase in rain rate, the BB height decreases in TP but increases in CEC. The BB width becomes wider with the increase in maximum radar reflectivity. Secondly, the maximum reflectivity factor and particle diameter of stratiform precipitation with BB appear at 5 km, while the maximum reflectivity factor of stratiform precipitation without BB and convective precipitation appear near the ground. The particle diameter first decreases and then increases from the cloud top to the ground. Thirdly, the land surface temperature of convective precipitation is about 2.5 °C higher than stratiform precipitation with BB, indicating higher land surface temperatures are more likely to trigger convection. Lastly, BB can lead to a decrease in brightness temperature and an increase in polarized difference at 89 GHZ and 166 GHZ in CEC, likely due to the increasing ice particles in stratiform precipitation with BB.

Summary: The pandemic of the coronavirus disease 2019 resulted in an increased prevalence of social isolation and loneliness. Cox proportional hazards regression was used to test the association between social isolation/loneliness, multiple cardiometabolic diseases (CMDs) and cardiometabolic multimorbidity (CMM). In the multivariable adjusted models, compared with the least isolated, the most isolated had independently associated with CMD (HR 1.07, 95% CI 1.03 to 1.11) and CMM (HR 1.24, 95% CI 1.12 to 1.36) in stage I, and CMM in stage II (HR 1.14, 95% CI 1.05 to 1.23). Compared with those with the least loneliness, those who with most loneliness had about 20% increased risk of CMD and 29% increased risk of CMM in stage I. Those with the most loneliness were also significantly associated with increased CMM risk (HR 1.30, 95% CI 1.19 to 1.42) in stage II. This study revealed the associations of social isolation/loneliness with CMD and CMM.

Summary: The background climatic conditions and urban morphology greatly influence urban heat island effects (UHIs), but one-size-fits-all solutions are frequently employed to mitigate UHIs. Here, attribution models for surface UHIs (SUHIs) and canopy UHIs (CUHIs) were developed to describe UHI formation. The contribution of factors to SUHIs and CUHIs shows similar dependencies on background climate and urban morphology. Furthermore, the factors that mainly contributed to CUHIs were more complex, and anthropogenic heat was the more critical factor. Influence from urban morphology also highlights that there is no one-size-fit-all solution for heat mitigation at the neighborhood. In particular, maintaining a low building density should be prioritized, especially mitigating CUHIs. Moreover, it is more effective to prioritize urban irrigation maintenance over increasing green cover in arid regions but the opposite in humid regions. The work can provide scientific evidence to support developing general and regional guidelines for urban heat mitigation.

Optimal scheduling of renewable energy sources and building energy systems serves as a pivotal strategy for achieving zero carbon emission. However, the coordination of zero carbon building energy systems (ZCBS) is still challenging due to the complicated interactions among multi-energy hybrid storage and the complex coordination between seasonal and daily scheduling. Therefore, this study develops a coordination scheduling approach for ZCBS. An operation model and a seasonal-daily scheduling approach are developed to optimize the operation of hydrogen, geothermal, and water storage devices. The performance of the developed method is demonstrated using numerical case studies. The results show that the ZCBS can be achieved by using renewable energy sources with the system flexibility provided by hydrogen, geothermal, and water storage devices. It is also found that the developed scheduling approach reduces operation costs by more than 43.4% under the same device capacity, compared with existing scheduling approaches.

Abstract Heating and cooling in buildings accounts for over 20% of total energy consumption in China. Therefore, it is essential to understand the thermal requirements of building occupants when establishing building energy codes that would save energy while maintaining occupants’ thermal comfort. This paper introduces the Chinese thermal comfort dataset, established by seven participating institutions under the leadership of Xi’an University of Architecture and Technology. The dataset comprises 41,977 sets of data collected from 49 cities across five climate zones in China over the past two decades. The raw data underwent careful quality control procedure, including systematic organization, to ensure its reliability. Each dataset contains environmental parameters, occupants’ subjective responses, building information, and personal information. The dataset has been instrumental in the development of indoor thermal environment evaluation standards and energy codes in China. It can also have broader applications, such as contributing to the international thermal comfort dataset, modeling thermal comfort and adaptive behaviors, investigating regional differences in indoor thermal conditions, and examining occupants’ thermal comfort responses.

Abstract The Santos Basin, located in the southeastern waters of Brazil, is a passive continental margin basin with the most abundant deepwater petroleum resources in the world discovered to date. However, few studies have been conducted on the present geothermal fields of the Santos Basin, which severely restricts the oil and gas resource evaluation of the basin. This study first utilizes 35 temperature data from 16 post-salt drilling wells and 370 temperature data from 31 pre-salt drilling wells to calculate the post-salt and pre-salt geothermal gradients and terrestrial heat flows in the Santos Basin. Then, the basin simulation software BasinMod 1D is used to quantitatively evaluate the impacts of salt rock sedimentation on the present geothermal fields and the maturity of pre-salt hydrocarbon source rocks. The results demonstrate that the present post-salt geothermal gradient in the Santos Basin is 2.20–3.97 °C/100 m, with an average value of 2.99 °C /100 m, and the post-salt terrestrial heat flow is 54.00–97.32 mW/m2, with an average value of 73.36 mW/m2, while the present pre-salt geothermal gradient is 2.21–2.95 °C/100 m, with an average value of 2.53 °C/100 m, and the pre-salt terrestrial heat flow is 61.85–82.59 mW/m2, with an average value of 70.69 mW/m2. These values are characteristic of a low-temperature geothermal field in a zone with a stable structure. The sedimentation of the salt rock causes a decrease in the temperature of the pre-salt strata, which inhibits pre-salt hydrocarbon source rock maturity, with an inhibition rate of up to 1.32%. The inhibition degree decreases with increasing salt rock thickness. At the same time, the salt rock thickness is positively correlated with the present surface heat flow. The unique distribution of the salt rock and related salt structures lead to present terrestrial heat flow differences among different structural units in the basin. This study is of great significance for evaluating and exploring the pre-salt oil and gas resources in the Santos Basin.

Abstract Constructing 2D/3D perovskite heterojunctions is effective for the surface passivation of perovskite solar cells (PSCs). However, previous reports that studying perovskite post-treatment only physically deposits 2D perovskite on the 3D perovskite, and the bulk 3D perovskite remains defective. Herein, we propose Cl2-dissolved chloroform as a multifunctional solvent for concurrently constructing 2D/3D perovskite heterojunction and inducing the secondary growth of the bulk grains. The mechanism of how Cl2 affects the performance of PSCs is clarified. Specifically, the dissolved Cl2 reacts with the 3D perovskite, leading to Cl/I ionic exchange and Ostwald ripening of the bulk grains. The generated Cl− further diffuses to passivate the bulk crystal and buried interface of PSCs. Hexylammonium bromide dissolved in the solvent reacts with the residual PbI2 to form 2D/3D heterojunctions on the surface. As a result, we achieved high-performance PSCs with a champion efficiency of 24.21% and substantially improved thermal, ambient, and operational stability.

Abstract Physical reservoirs holding intrinsic nonlinearity, high dimensionality, and memory effects have attracted considerable interest regarding solving complex tasks efficiently. Particularly, spintronic and strain-mediated electronic physical reservoirs are appealing due to their high speed, multi-parameter fusion and low power consumption. Here, we experimentally realize a skyrmion-enhanced strain-mediated physical reservoir in a multiferroic heterostructure of Pt/Co/Gd multilayers on (001)-oriented 0.7PbMg1/3Nb2/3O3−0.3PbTiO3 (PMN-PT). The enhancement is coming from the fusion of magnetic skyrmions and electro resistivity tuned by strain simultaneously. The functionality of the strain-mediated RC system is successfully achieved via a sequential waveform classification task with the recognition rate of 99.3% for the last waveform, and a Mackey-Glass time series prediction task with normalized root mean square error (NRMSE) of 0.2 for a 20-step prediction. Our work lays the foundations for low-power neuromorphic computing systems with magneto-electro-ferroelastic tunability, representing a further step towards developing future strain-mediated spintronic applications.

Abstract It is important to explore the effective approaches to prevent dry age-related macular degeneration (AMD). In this study, significantly decreased full-field electroretinograms wave amplitudes and disordered retina structures were detected in rat retinas of sodium iodate induced dry AMD model. Six a- and b-wave amplitudes and the antioxidant activities were significantly increased, and the outer nuclear layer thickness was significantly improved in the rat retinas treated with the combination of Lactobacillus fermentum NS9 (LF) and aronia anthocyanidin extract (AAE) compared with the model. The effects were much better than the treatment with AAE alone. The proteomics analysis showed the expressions of α-, β- and γ-crystallins were increased by 3–8 folds in AAE treated alone and by 6–11 folds in AAE + LF treatment compared with the model, which was further confirmed by immuno-blotting analysis. Analysis of gut microbial composition indicated that higher abundance of the genus Parasutterella and species P. excrementihominis was found in the AAE + LF treatment compared with the other groups. The results indicated that the combined treatment of AAE + LF is a potential way to prevent the retina degeneration which is significantly better than the AAE treated alone.

The physical arch and the arch effect are related to many geotechnical problems, such as the stability of mine openings, a tunnel’s shape, and disaster prevention. However, observing the arch in geo-material is challenging due to Earth’s invisible force network distribution. The arch shape is a critical parameter related to the arching effect, which is still an open question. Specifically, the force network evolution after local excavation in granular material is revealed using the photo-elastic technique, and the system pressure variation is calculated qualitatively in particle scale according to the G2 algorithm. Besides, the force chain arch is formed by strong force chains, which are important in redistributing the stress field. The principal direction of the spatial correlation colormap represents the direction of the strong force chains in the network. Based on this preferred angle between the strong force chain and the horizontal direction, a simplified force chain arch trajectory is iteratively rebuilt. Then, the total force chain distribution is studied considering both G2 and the total length of strong force chains, with the corresponding results demonstrating a relationship between the changes in these characteristics and the force chain arch formation.

The spatial characteristics of element flow and its spillover are important topics in economics, sociology, and geography, and significant to the promotion of the coordinated development of urban agglomerations. To study element flow in the Lanxi urban agglomeration and its effect to economic development, the spatial network characteristics and economic spillover effect were studied using the methods of spatial network analysis, the spatial Durbin model, and spatial effect decomposition. The results showed that (1) the scale of element flow in the Lanxi urban agglomeration is in an unbalanced distribution state, the scale of element flow in Lanzhou and Xining is higher than that in surrounding cities, and the connection between surrounding cities is also higher than that between other cities; (2) the network structure of element flow in the Lanxi urban agglomeration is relatively intensive, with Lanzhou and Xining as the center of element concentration, which indicates an obvious 'center periphery' structure, and gradually spreads from the core area to the surrounding areas; and (3) the element concentration level of the Lanxi urban agglomeration has a significant positive spillover effect, which plays a significant role in driving the development of surrounding cities. Other factors, such as the social consumption level, have significant direct effects, whereas the industrial structure and residents' income have significant direct and spillover effects, and are the main factors that affect the coordinated development of the regional economy.

BackgroundCirculating aminotransferases (ALT and AST) have been used as biomarkers for liver injury. The causal relationships between aminotransferases and metabolic syndrome remain ambiguous.MethodsWe conducted bidirectional and multivariable Mendelian randomization (MR) analyses between aminotransferases and traits related to metabolic syndrome using genetic variants obtained from genome-wide association studies (GWASs). MR-PRESSO tests were adopted to remove outliers and eliminate pleiotropy. MR steiger tests were conducted to ensure the correct direction of the causal effects.ResultsBoth aminotransferases were risk factors for essential hypertension. ALT is a risk factor for type 2 diabetes. The bidirectional causal relationship between ALT and hyperglycemia, serum lipids, and obesity was demonstrated. The effect of fasting glucose on AST was demonstrated, while type 2 diabetes did not affect AST. The effect of HDL-C on ALT and the effect of triglycerides on AST were found in multivariable MR analyses.ConclusionsOur bidirectional MR analyses suggest that ALT and AST are causally associated with several metabolic syndrome-related traits, especially hypertension and type 2 diabetes. These findings highlight the potential role of aminotransferases as biomarkers and therapeutic targets for metabolic syndrome.

Egypt is among the world's largest producers of sugarcane. This crop is of great economic importance in the country, as it serves as a primary source of sugar, a vital strategic material. The pre-cutting planting mode is the most used technique for cultivating sugarcane in Egypt. However, this method is plagued by several issues that adversely affect the quality of the crop. A proposed solution to these problems is the implementation of a sugarcane-seed-cutting device, which incorporates automatic identification technology for optimal efficiency. The aim is to enhance the cutting quality and efficiency of the pre-cutting planting mode of sugarcane. The developed machine consists of a feeding system, a node scanning and detection system, a node cutting system, a sugarcane seed counting and monitoring system, and a control system. The current research aims to study the pulse widths (PW) of three-color channels (R, G, and B) of the RGB color sensors under laboratory conditions. The output PW of red, green, and blue channel values were recorded at three color types for hand-colored nodes [black, red, and blue], three speeds of the feeding system [7.5 m/min, 5 m/min, and 4.3 m/min], three installing heights of the RGB color sensors [2.0 cm, 3.0 cm, and 4.0 cm], and three widths of the colored line [10.0 mm, 7.0 mm, and 3.0 mm]. The laboratory test results s to identify hand-colored sugarcane nodes showed that the recognition rate ranged from 95% to 100% and the average scanning time ranged from 1.0 s to 1.75 s. The capacity of the developed machine ranged up to 1200 seeds per hour. The highest performance of the developed machine was 100% when using hand-colored sugarcane stalks with a 10 mm blue color line and installing the RGB color sensor at 2.0 cm in height, as well as increasing the speed of the feeding system to 7.5 m/min. The use of IoT and RGB color sensors has made it possible to get analytical indicators like those achieved with other automatic systems for cutting sugar cane seeds without requiring the use of computers or expensive, fast industrial cameras for image processing.

Cervical cancer poses a significant health challenge in developing countries, emphasizing the need for appropriate screening strategies to accelerate the elimination of this disease. This study summarized the results of a large-scale community-based cervical cancer screening program conducted in Chengdu, China, to understand the prevalence of HPV infection and cervical lesions in the population, and to compare the real-world effectiveness of two different screening methods implemented in the program. From January 2021 to December 2022, a total of 363,376 women aged 35-64 years in Chengdu received free screenings. Among these participants, 70.1% received cytology screening and 29.9% received HPV testing combined with 16/18 genotyping and cytology triage. Ultimately, 824 cases of high-grade lesions and cervical cancer were detected, with a total detection rate of cervical cancer and precancerous lesions of 226.8 per 100,000. The follow-up rate of patients with high-grade lesions and above was 98.9%, and the treatment rate was 86.6%. The overall high-risk HPV infection rate was 11.7%, with the HPV 16/18 infection rate of 1.4%. The rate of abnormal cytology results was 2.8%. The attendance rates for colposcopy and histopathology were 71.6% and 86.1%, respectively. By calculating the age-standardized rates to eliminate the different age composition between the two group, the HPV-based screening strategy had a higher rate of primary screening abnormalities (3.4% vs. 2.8%, P

Due to warm and humid air currents of the Indian Ocean and the southwest monsoon, the Palong Zangbo catchment in southeastern Tibet has developed oceanic glaciers in the valley, and the activity of glacial debris flows has been gradually intensified under neotectonic activity, frequent earthquakes, climate change, and extreme rainfall. In this paper, the topographic and morphological data of the debris flow basin, the dynamic evolution characteristics of glaciers and glacial lakes were analyzed by using multisource long-term series of remote sensing images. Simultaneously, the distribution of moraines and landslide sources were extracted based on satellite image. In addition, climate change in the study area was analysed using temperature and rainfall data from the last 40 years, revealing that the average temperature in the study area from May to October presented a fluctuating tendency as a whole, especially after 2013, when the temperature gradually increased. As these temperature changes led to continuous melting of the glaciers in the study area, the glacier area decreased from 8,300 km2 in 1988–4,584 km2 in 2019, which decreased nearly 45%. However, the number and area of glacial lakes in the study area gradually increased under a power-law trend, which further led to a significant increase on the possibility of glacial lake rupture in the study area. Due to the joint effects of earthquakes, glacier melting and glacial lake collapse, the debris flows in the study area were well developed, and a total of 122 debris flows were found with varying channel lengths, areas and material sources. Importantly, the characteristics of the glaciers, glacial lakes and climate change in the study area have indicated that the glaciers have retreated, the number of glacial lakes has increased, and the risk of debris flow in this basin will increase in the future. Therefore, it is necessary to strengthen monitoring and early warnings on floods due to glacial lake collapses and debris flows in the study area to improve the risk management of debris flows and floods and the prevention and mitigation of disasters.

Weighted mean temperature (Tm) is an important parameter in the water vapor inversion of global navigation satellite systems (GNSS). High-precision Tm values can effectively improve the accuracy of GNSS precipitable water vapor. In this study, a new regional grid Tm empirical model called the RGTm model over China and the surrounding areas was proposed by combining ERA5 reanalysis data, radiosonde data, and TanDEM-X 90m products. In the process of model establishment, we considered the setting of the reference height in the height correction formula and the bias correction for the Tm lapse rate. Tm values derived from ERA5 and radiosonde data in 2019 were used as references to validate the performance of the RGTm model. At the same time, the GPT3, GGNTm, and uncorrected seasonal model were used for comparison. Results show that compared with the other three models, the accuracy of the RGTm model’s Tm was improved by approximately 12.21% (15.32%), 1.17% (3.09%), and 2.31% (5.05%), respectively, when ERA5 (radiosonde) Tm data were used as references. In addition, the introduction of radiosonde data prevented the accuracy of the Tm empirical model from being entirely dependent on the accuracy of the reanalysis data.

Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.

Abstract Tooth roots embedded in the alveolar bone do not typically undergo resorption while the bone continues remodeling in its physiological state. In this study, we analyzed genetically modified mice with the functional inactivation of nucleotide pyrophosphatase 1 (Npp1), encoded by ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1). This mutation leads to the formation of ectopic cervical cementum vulnerable to external tooth root resorption. Cementoblasts with the inactivation of Enpp1 extensively expressed non-collagenous matrix proteins enriched with bone sialoprotein (Bsp), dentin matrix protein 1 (Dmp1), and osteopontin (Opn), which have roles in mineralization through nucleation and in cell adhesion through the Arg-Gly-Asp (RGD) motif. In cementoblasts with the inactivation of Enpp1, β-catenin was significantly activated and induced the expression of these non-collagenous matrix proteins. In addition, adenosine triphosphate (ATP), which is the most preferred substrate of Npp1, accumulated extracellularly and autocrinally induced the expression of the receptor activator of nuclear factor κB ligand (Rankl) in cementoblasts with inactivated Npp1. Consequently, these results strongly suggest that functional Npp1 preserves cervical cementum integrity and supports the anti-resorptive properties of tooth roots through ATP homeostasis in the physiological state of cervical cementum.

Osteosarcoma survival rates have been largely unchanged for several decades, and treatment response is variable. Here, the authors analyzed genomic, transcriptomic and epigenomic data from 121 osteosarcoma patients and identify subtypes related to treatment outcome.

Abstract Unrestricted reproduction and spread of pest had caused great damage to the quality and yield of crops in recent years. Besides the use of traditional chemical pesticides, natural products also make a huge contribution against pests. Chasmanthinine, a diterpenoid alkaloid isolated from Aconitum franchetii var. villosulum, shown extremely antifeedant activity against Spodoptera exigua. Therefore, a series of novel Chasmanthinine derivatives were synthesized and their biological activity was studied in this work. Compound 33 showed the strongest antifeedant activity (EC50 = 0.10 mg/cm2) among all the test compounds. The mechanism research of 33 revealed that its antifeedant effect was related to the inhibition of carboxylesterase (CES), and proved the thiophene acyl group could form a strong binding effect with CES by molecular docking. Moreover, compound 10 exhibited the strongest cytotoxicity (IC50 = 12.87 μM) against Sf9 cell line and moderate contact toxicity. The mechanism research indicated that compound 10 could induce Sf9 cells apoptosis. In summary, the results lay a foundation for the application of diterpene alkaloids in plant protection.

Abstract Crocodiles are cultured in large numbers in Asia and other places in order to protect wild resources and meet the needs of human life. In this study, crocodile (Crocodylus siamensis) meat proteins were extracted and hydrolyzed into peptides, their antioxidant peptides were isolated and purified by silica gel chromatography and identified by LC/MS. Crocodile meat proteins were optimally extracted with water and hydrolyzed by papain based on the degree of hydrolysis and antioxidant activity. The hydrolysates were fractionated by ultrafiltration into 3 kDa, 3–30 kDa, and ≥ 30 kDa fractions. The 3 kDa fraction showed most antioxidant activity of the hydrolysates. Its active peptides were separated by silica gel column chromatography and purified by silica gel TLC, based on TLC bio-autographic assays of the activity. Four highly active peptides were identified by LC/MS as SSLTIQFVEGQFVDSYDPTIENTFTK, VPPHIY, VAPEEHPVLLTEAPLNPK, and RNGLPGPIGPAG. The identified peptides were synthesized and showed 50% free radical scavenging activities at 1.0 mg/mL, equal or higher to ascorbic acid at 0.5 mg/mL, in both DPPH and ABTS assays. The results indicated that the 3 kDa hydrolyzed peptides of crocodile meat had high antioxidant activity and the active peptides can be effectively separated and purified by silica gel column chromatography and TLC.

Perovskite structure is disturbed by environmental moisture, limiting the device performance. Here, Wei et al. monitor the effect of moisture during the growth by N2-protected characterization techniques, and obtain an operationally stable perovskite solar cell with efficiency approaching 24%.

Abstract The water-soluble β-cyclodextrin–curcumin (CDC) is used in pharmaceutical applications and as a natural food colorant. The previous study revealed that curcumin potentially impacted the reproductive system. The present study investigated the possible roles of the CDC in testosterone secretion in Leydig cells and mice. Primary Leydig cells were treated with the CDC to determine their effect on cell proliferation, testosterone levels, the protein and mRNA expression of the transcription factor, and steroidogenic enzymes. Our data showed that CDC stimulated testosterone production via upregulating transcription factor steroidogenic factor-1 (NR5A1), cAMP-response element-binding protein (CREB), and steroidogenic enzymes steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (CYP11A1), 17-alpha-hydroxylase/17,20-lyase (CYP17A1), 3β-/17β-hydroxysteroid dehydrogenase type 1 (3β/17β-HSD, HSD3b1/HSD17b1). CDC could significantly stimulate H89-suppressed StAR and CREB expression but not reverse melatonin-suppressed StAR expression. We further detected the hormonal activity with transgenic yeast, and CDC showed potential androgenic antagonistic activity. Meanwhile, we investigated its aphrodisiac effect on hydrocortisone-induced mice. Exposure to hydrocortisone decreased the mating ability, reproductive organs, and testosterone level and disrupted testicular histology. However, all of these effects were significantly improved by CDC treatment. In conclusion, these results indicated that mechanisms of CDC in stimulating testosterone production involve upregulating the cAMP-PKA pathway.

Abstract Traffic accidents and derailed train-related incidents have occurred more often than ever in recent years, resulting in some economic damage and casualties. Reinforced concrete (RC) constructions often involve derailed train and vehicle accidents. Rarely are such side collisions studied in previous studies. To do this, high-fidelity simulation-based finite-element (FE) models are created in this paper to accurately simulate the collision of circular RC members with a derailed train. The reinforced concrete member structure is common in high-speed railway stations. The impact energy of the impact body is significant, causing structural member failure. It analyses the dynamic behavior of reinforced concrete members under unequal span impact loads. Numerical implementations of impact issues are discussed from the perspective of geometric, contact, and material properties. The reliability and precision of the ABAQUS code to solve impact issues are verified by comparing failure modes, impact, and deflection time history experimental outputs. By analysing the impact response characteristics, used the control variables to study the failure process and mode (including the characteristics of impact and reaction forces, deflection time history curve, impact force–deflection curve, and bearing reaction force–deflection curve). The reinforcement ratio, impact velocity, concrete strength, and slenderness ratio significantly affect shear crack pattern and development. Changes in impact velocity and slenderness ratio also affect member failure modes.