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Abstract Background Glucose fluctuations may be involved in the pathophysiological process of cardiomyocyte apoptosis, but the exact mechanism remains elusive. This study focused on exploring the mechanisms related to glucose fluctuation-induced cardiomyocyte apoptosis. Methods Diabetic rats established via an injection of streptozotocin were randomized to five groups: the controlled diabetic (CD) group, the uncontrolled diabetic (UD) group, the glucose fluctuated diabetic (GFD) group, the GFD group rats with the injection of 0.9% sodium chloride (NaCl) (GFD + NaCl) and the GFD group rats with the injection of N-acetyl-L-cysteine (NAC) (GFD + NAC). Twelve weeks later, cardiac function and apoptosis related protein expressions were tested. Proteomic analysis was performed to further analyze the differential protein expression pattern of CD and GFD. Results The left ventricular ejection fraction levels and fractional shortening levels were decreased in the GFD group, compared with those in the CD and UD groups. Positive cells tested by DAB-TUNEL were increased in the GFD group, compared with those in the CD group. The expression of Bcl-2 was decreased, but the expressions of Bax, cleaved caspase-3 and cleaved caspase-9 were increased in response to glucose fluctuations. Compared with CD, there were 527 upregulated and 152 downregulated proteins in GFD group. Txnip was one of the differentially expressed proteins related to oxidative stress response. The Txnip expression was increased in the GFD group, while the Akt phosphorylation level was decreased. The interaction between Txnip and Akt was enhanced when blood glucose fluctuated. Moreover, the application of NAC partially reversed glucose fluctuations-induced cardiomyocyte apoptosis. Conclusions Glucose fluctuations lead to cardiomyocyte apoptosis by up-regulating Txnip expression and enhancing Txnip-Akt interaction.

Background Diabetes-induced cardiac fibrosis is one of the main mechanisms of diabetic cardiomyopathy. As a common histone methyltransferase, enhancer of zeste homolog 2 (EZH2) has been implicated in fibrosis progression in multiple organs. However, the mechanism of EZH2 in diabetic myocardial fibrosis has not been clarified. Methods In the current study, rat and mouse diabetic model were established, the left ventricular function of rat and mouse were evaluated by echocardiography and the fibrosis of rat ventricle was evaluated by Masson staining. Primary rat ventricular fibroblasts were cultured and stimulated with high glucose (HG) in vitro. The expression of histone H3 lysine 27 (H3K27) trimethylation, EZH2, and myocardial fibrosis proteins were assayed. Results In STZ-induced diabetic ventricular tissues and HG-induced primary ventricular fibroblasts in vitro, H3K27 trimethylation was increased and the phosphorylation of EZH2 was reduced. Inhibition of EZH2 with GSK126 suppressed the activation, differentiation, and migration of cardiac fibroblasts as well as the overexpression of the fibrotic proteins induced by HG. Mechanical study demonstrated that HG reduced phosphorylation of EZH2 on Thr311 by inactivating AMP-activated protein kinase (AMPK), which transcriptionally inhibited peroxisome proliferator-activated receptor γ (PPAR-γ) expression to promote the fibroblasts activation and differentiation. Conclusion Our data revealed an AMPK/EZH2/PPAR-γ signal pathway is involved in HG-induced cardiac fibrosis.

Abstract Myeloid cells are vital components of the immune system and have pivotal functions in orchestrating immune responses. Understanding their functions within the tumor microenvironment and their interactions with tumor-infiltrating lymphocytes presents formidable challenges across diverse cancer types, particularly with regards to cancer immunotherapies. Here, we explore tumor-infiltrating myeloid cells (TIMs) by conducting a pan-cancer analysis using single-cell transcriptomics across eight distinct cancer types, encompassing a total of 192 tumor samples from 129 patients. By examining gene expression patterns and transcriptional activities of TIMs in different cancer types, we discern notable alterations in abundance of TIMs and kinetic behaviors prior to and following immunotherapy. We also identify specific cell-cell interaction targets in immunotherapy; unique and shared regulatory profiles critical for treatment response; and TIMs associated with survival outcomes. Overall, our study illuminates the heterogeneity of TIMs and improves our understanding of tissue-specific and cancer-specific myeloid subsets within the context of tumor immunotherapies.

Abstract Single-cell sequencing datasets are key in biology and medicine for unraveling insights into heterogeneous cell populations with unprecedented resolution. Here, we construct a single-cell multi-omics map of human tissues through in-depth characterizations of datasets from five single-cell omics, spatial transcriptomics, and two bulk omics across 125 healthy adult and fetal tissues. We construct its complement web-based platform, the Single Cell Atlas (SCA, www.singlecellatlas.org ), to enable vast interactive data exploration of deep multi-omics signatures across human fetal and adult tissues. The atlas resources and database queries aspire to serve as a one-stop, comprehensive, and time-effective resource for various omics studies.

Abstract Background and purpose Research to date has lacked definitive evidence to determine whether mirror therapy promotes the recovery of upper extremity function after stroke. Considering that previous studies did not stratify patients based on structural retention, this may be one of the reasons for the negative results obtained in many trials. The goal evaluates the efficacy of TBMT (utilizing an innovatively designed mirror) versus standard occupational therapy for stroke patient’s upper limb functionality. Methods and analysis This single-center randomized controlled trial will involve 50 patients with stroke. All patients will be randomly assigned to either the task-based mirror therapy or the control group. The interventions will be performed 5 days per week for 4 weeks. The primary outcomes will be the mean change in scores on both the FMA-UE and modified Barthel Index (MBI) from baseline to 4 weeks intervention and at 12 weeks follow-up between the two groups and within groups. The other outcomes will include the Action Research Arm Test (ARAT), the Nine Hole Peg Test (9HPT), the Functional Independence Measure, and MRI. Discussion This trial will not only to establish that task-based mirror therapy (TBMT) could improve the recovery of hand function after stroke but also to explore the underlying mechanisms. We expect that this finding will clarify the brain activation and brain network mechanisms underlying the improvement of hand function with task-oriented mirror therapy and lead to new ideas for stroke hand function rehabilitation. Trial registration URL: https://www.chictr.org.cn ; Unique identifier: ChiCTR2300068855. Registered on March 1, 2023

With the development of comprehensive treatment, locoregional transarterial chemotherapy has become an alternative conversion therapy, palliative therapy, and neoadjuvant therapy for many solid malignant tumors. Locoregional transarterial chemotherapy, which is most frequently used for treating liver cancer, has the characteristics of high regional efficacy and few systemic adverse reactions. In recent years, the number of relevant reports of locoregional chemotherapy for treating initially inoperable colorectal cancer (CRC), including non-metastatic and metastatic CRC, has gradually increased. However, the specific treatment options for such locoregional therapy are not the same, and its indications, medication regimens and combined treatments have not reached any consensus. In this review, the application status of locoregional transarterial chemotherapy in primary and metastatic CRC patients has been reviewed and summarized to provide a reference for future clinical work and scientific research.

Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant medications and remain the cornerstone of systemic lupus erythematosus (SLE) therapy. However, ongoing exposure to GCs has the potential to elicit multiple adverse effects. Considering the irreplaceability of GCs in SLE therapy, it is important to explore the optimal regimen of GCs. Here, we compared the long-term efficacy and safety of pulsed and oral GC therapy in a lupus-prone mouse model. Mice were grouped using a randomized block design. We monitored survival rates, proteinuria, serum autoantibodies, and complement 3 (C3) levels up to 28 weeks of age, and assessed renal damage, bone quality, lipid deposition in the liver and marrow, glucose metabolic parameters, and levels of hormones of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, we explored the mechanisms underlying the superior efficacy of the pulse regimen over oral prednisone regimen. We found that both GC regimens alleviated the poor survival rate, proteinuria, and glomerulonephritis, while also reducing serum autoantibodies and increasing the level of C3. The pulsed GC regimen showed less resistance to insulin, less suppression of the HPA axis, less bone loss, and less bone marrow fat deposition than the oral GC regimen. Additionally, GC-induced leucine zipper (GILZ) was significantly overexpressed in the GC pulse group. These results suggest that the GC pulse regimen ameliorated symptoms in lupus-prone mice, with fewer side effects, which may be related to GILZ overexpression. Our findings offer a potentially promising GC treatment option for SLE.

Background: The western region of China has a dense population, relatively underdeveloped economy, and a significant number of left-behind children. Currently, the prevalence of adolescent psychological abuse, neglect, and the factors associated with these issues in the region remain unclear. This study aims to evaluate the current status of adolescent psychological abuse and neglect and its associated factors in this region.Methods: Data were collected from 50 schools in western China through cluster sampling to target adolescents aged 12 to 18. A comprehensive survey form was used to collect socio-demographic characteristics of adolescents. The Child Psychological Abuse and Neglect Scale was employed to assess the current psychological abuse and neglect of adolescents. Independent samples t-tests were used for inter-group comparisons. A Directed Acyclic Graph was constructed for controlling confounding variables. Subsequently, binary logistic regression analysis was performed, and a nomogram risk factors model was developed using R Studio.Results: This study included 12,743 teenagers, with an average age of 15.53(±1.39) years. Among them, 4,965 individuals, accounting for 39.0%, reported experiences of psychological abuse, while 4,167 individuals, accounting for 32.7%, reported experiences of neglect. The rates of psychological abuse and neglect in adolescents are influenced by gender, grade, left-behind experience, parental marital status, and living on campus (P

AbstractFirst published in 1970, The 70s Bi-weekly (hereafter, The 70s) stands out from many other independent magazines in Hong Kong around the same time by its unique ‘action-oriented-ness’. More than a printed magazine whose contents blend radical political theories, social activism, and avant-garde art, the ‘action-oriented’ feature of The 70s is seen in both of its political and cultural actions. This article places The 70s in the context of the production and screening of experimental films in Hong Kong at the time, and discusses two (experimental) films made by the magazine’s editorial board in the 1970s. They are a documentary (1971) that records the ‘Defend Diaoyu Islands’ protests on April 10th of the same year in Hong Kong and an experimental film To the Arty Youths of Hong Kong (1978), imbued with political metaphors and critical sarcasm. Extending Charles Tilly’s (2008) discussion on the repertoire of contentious politics to the cultural dimension, I argue that these films constitute one of their diverse repertoires of social activism. The transformation of the cinematic style from realism to postmodern collage also illustrates a vital shift of the media performativity in their repertoire of dissent.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

Abstract Background Individuals with X chromosomal translocations, variable phenotypes, and a high risk of live birth defects are of interest for scientific study. These characteristics are related to differential breakpoints and various types of chromosomal abnormalities. To investigate the effects of X chromosome translocation on clinical phenotype, a retrospective analysis of clinical data for patients with X chromosome translocation was conducted. Karyotype analysis plus endocrine evaluation was utilized for all the patients. Additional semen analysis and Y chromosome microdeletions were assessed in male patients. Results X chromosome translocations were detected in ten cases, including seven females and three males. Infantile uterus and no ovaries were detected in case 1 (FSH: 114 IU/L, LH: 30.90 mIU/mL, E2:

IntroductionSuicidal ideation is a critical early stage in the progression towards suicidal be havior. Prior research has established links between sleep quality, impulsivity, and suicidal tendencies, yet the interaction among these factors has been less explored. This study aims to explore the mediating role of impulsivity in the relationship between sleep quality and suicidal ideation in adolescents.MethodsEmploying a cross-sectional study design, 6,974 questionnaires were distributed,including the Socio-demographic Characteristics Questionnaire, Barratt Impulsiveness Scale, the Positive and Negative Suicide Ideation Inventory,and the Pittsburgh Sleep Quality Index Scale. The participants were high school and middle school students from 33 schools in northeastern Sichuan, China, selected through random cluster sampling.ResultsOf these 6,786 questionnaires were analyzed. The participant distribution included 47.2% male and 52.8% female students, with 68.3% from junior schools and 31.7% from senior schools. The prevalence of suicidal ideation was found to be 13.6%. The analysis, which involved correlation analysis and the construction of a structural equation model, revealed that sleep quality had a significant positive effect on impulsivity (β:0.289,p < 0.05), and impulsivity, in turn, had a positive impact on suicidal ideation (β:0.355,p < 0.05).Moreover, sleep quality was directly linked to suicidal ideation (β:0.208,p < 0.05). Thus, sleep quality affects suicidal ideation both directly and indirectly through impulsivity.DiscussionThe results of this study suggest that both sleep quality and impulsivity are significant direct influencers of suicidal ideation among adolescents in the region studied, with impulsivity also playing an indirect role in the relationship between sleep quality and suicidal ideation.

Objective: The purpose of this study was to explore the protective effects of Polygonatum sibiricum extract (PSE) on the important organs of D-galactose (D-gal)-induced aging mice and its potential molecular mechanisms. Methods: The mice were randomly divided into five groups (n=10): control group, D-gal (500 mg/kg) group, low-PSE dose (0.5 g/kg) group, medium-PSE dose (1 g/kg) group, and high-PSE dose (2 g/kg) group. The organ indices (thymus, spleen, liver, and kidney) were detected. The levels of creatine kinase (CK), creatine kinase isoenzyme (CK-MB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), uric acid (UA), urea (UREA), creatinine (CREA), urea–creatinine ratio (BUN/Scr), and glomerular filtration rate (eGFR) in serum were measured. Pathological changes in the skin, liver, kidney, heart, brain, and lung of mice in different groups were analyzed by HE and Masson staining. The expressions of p53, p16, p21, RB, HO-1, Nrf2, and Keap1 mRNA in the liver, kidney, heart, and brain of each group of mice were detected by real-time PCR. Results: The thymus, spleen, liver, and kidney indices were increased in each PSE treatment group compared with those in the D-gal group (P

Abstract Stroke is a major healthcare problem worldwide, particularly in the elderly population. Despite limited research on the development of prediction models for mortality in elderly individuals with ischemic stroke, our study aimed to address this knowledge gap. By leveraging data from the Medical Information Mart for Intensive Care IV database, we collected comprehensive raw data pertaining to elderly patients diagnosed with ischemic stroke. Through meticulous screening of clinical variables associated with 28-day mortality, we successfully established a robust nomogram. To assess the performance and clinical utility of our nomogram, various statistical analyses were conducted, including the concordance index, integrated discrimination improvement (IDI), net reclassification index (NRI), calibration curves and decision curve analysis (DCA). Our study comprised a total of 1259 individuals, who were further divided into training (n = 894) and validation (n = 365) cohorts. By identifying several common clinical features, we developed a nomogram that exhibited a concordance index of 0.809 in the training dataset. Notably, our findings demonstrated positive improvements in predictive performance through the IDI and NRI analyses in both cohorts. Furthermore, calibration curves indicated favorable agreement between the predicted and actual incidence of mortality (P > 0.05). DCA curves highlighted the substantial net clinical benefit of our nomogram compared to existing scoring systems used in routine clinical practice. In conclusion, our study successfully constructed and validated a prognostic nomogram, which enables accurate short-term mortality prediction in elderly individuals with ischemic stroke.

Abstract N 6-methyladenosine (m6A) is a form of posttranscriptional modification that plays important roles in cancer including oral squamous cell carcinoma (OSCC). Most studies to date have focused on a limited number of regulators and oncogenic pathways, thus failing to provide comprehensive insight into the dynamic effects of m6A modification. In addition, the role of m6A modification in shaping immune cell infiltration in OSCC has yet to be clarified. This study was designed to assess m6A modification dynamics in OSCC and to understand how such modifications influence clinical immunotherapeutic treatment outcomes. m6A modification patterns linked with 23 m6A regulators were analyzed in 437 OSCC patients from TCGA and GEO cohorts. These patterns were then quantified through m6A score based on algorithms derived from a principal component analysis (PCA) approach. The m6A modification patterns of OSCC samples were grouped into two clusters based on the m6A regulators expression, and immune cell infiltration was linked with the 5-year survival outcomes of patients in these clusters. 1575 genes associated with OSCC patient prognosis were identified and used to re-cluster these samples into two groups. Patients in clusters exhibiting higher levels of m6A regulator expression exhibited poorer overall survival (OS), whereas patients with high m6A scores survived for longer (p

BackgroundA proper evaluation on the intention of using nutrition label in patients with coronary heart disease (CHD) is crucial to design and formulate of behavior-based interventions. A valid and reliable instrument based on theoretical basis is needed to measure individual intention toward nutrition label use and identify underlying socio-cognitive factors.ObjectTo develop and test validity and reliability of the theoretically based nutrition label use (NLU) scale and to promote the use of nutrition labels in CHD patients.MethodsA questionnaire was developed based on the theory of planned behavior (TPB), empirical literatures, expert review and pilot tested. A total of 460 CHD patients in a hospital in Changsha were investigated using this questionnaire from April 2021 to August 2021. The items and dimensions in the scale were explored and confirmed using item-analysis, content validity, exploratory factor analytical (EFA), confirmatory factor analytical (CFA), internal consistency and split-half reliability tests.ResultsA total of 33 items with 4 structural factors were identified, including 10 items of attitude, 6 items of subjective norm, 12 items of perceived behavior control, and 5 items of intention. The total variance explained by the EFA model was 68.563%. The model was further tested with CFA. The measurement model fitted the data well (Ratio of chi-square minimum and degree of freedom (CMIN/DF) =1.743, goodness of fit index (GFI) =0.814, incremental fit index (IFI) =0.946, Tuker-Lewis index (TLI) =0.940, the comparative fit index (CFI) =0.945, the root mean square error of approximation (RMSEA) =0.057). The content validation index (CVI) of the scale was 0.82, and the CVI of the items ranged from 0.8 to 1.00. The reliability of the scale was 0.976 (p

For connecting plate of shock absorber bracket in automobile suspension, lightweight requirement is a mainstream design tendency. Based on the principle of maximum stiffness, this work conducts a case study on structural optimization design of shock absorber brackets in automobile suspension. Firstly, both TI-6AL-4V alloy material and the motion simulation function of Inspire software are employed for use in the investigation. It is expected to simulate the motion state of automobile shock absorber extract the load effectively. Hence, the load is applied to the finite element model of the shock absorber connecting plate as the boundary condition. Then, the software is used to explore the shape control method for the connecting plate under different optimization objectives. Also, the topology optimization is carried out on the premise of 2-factor 4-level orthogonal test, and the extrusion is used as the shape control method. Finally, using 8 mm thickness as constraint condition, the optimized structure with safety factor of 2.3 and weight loss rate of 72.6% can be obtained.

Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease that results in significant damage and often needs more aggressive treatment. Compared to adult-onset SLE, cSLE has a stronger genetic background and more prevalent elevated type I Interferon expression. The management of cSLE is more challenging because the disease itself and treatment can affect physical, psychological and emotional growth and development. High dose oral glucocorticoid (GC) has become the rule for treating moderate to severe cSLE activity. However, GC-related side effects and potential toxicities are problems that cannot be ignored. Recent studies have suggested that GC pulse therapy can achieve disease remission rapidly and reduce GC-related side effects with a reduction in oral prednisone doses. This article reviews characteristics, including pathogenesis and manifestations of cSLE, and summarized the existing evidence on GC therapy, especially on GC pulse therapy in cSLE, followed by our proposal for GC therapy according to the clinical effects and pathogenesis.

Amyotrophic lateral sclerosis (ALS) is a primary neurodegenerative disease, which is characterized by increased immune cell infiltration of the central nervous system. Here authors show that the phenotypic profile of T cells in the blood and cerebrospinal fluid of newly diagnosed ALS patients can predict disease progression, thus providing evidence that T cells contribute to disease pathology.

Abstract Background Metastatic breast carcinoma is commonly considered during differential diagnosis when metastatic disease is detected in females. In addition to the tumor morphology and documented clinical history, sensitive and specific immunohistochemical (IHC) markers such as GCDFP-15, mammaglobin, and GATA3 are helpful for determining breast origin. However, these markers are reported to show lower sensitivity in certain subtypes, such as triple-negative breast cancer (TNBC). Materials and methods Using bioinformatics analyses, we identified a potential diagnostic panel to determine breast origin: matrix Gla protein (MGP), transcriptional repressor GATA binding 1 (TRPS1), and GATA-binding protein 3 (GATA3). We compared MGP, TRPS1, and GATA3 expression in different subtypes of breast carcinoma of (n = 1201) using IHC. As a newly identified marker, MGP expression was also evaluated in solid tumors (n = 2384) and normal tissues (n = 1351) from different organs. Results MGP and TRPS1 had comparable positive expression in HER2-positive (91.2% vs. 92.0%, p = 0.79) and TNBC subtypes (87.3% vs. 91.2%, p = 0.18). GATA3 expression was lower than MGP (p

ObjectiveTraumatic brain injury (TBI) leads to death and disability. This study developed an effective prognostic nomogram for assessing the risk factors for TBI mortality.MethodData were extracted from an online database called “Multiparameter Intelligent Monitoring in Intensive Care IV” (MIMIC IV). The ICD code obtained data from 2,551 TBI persons (first ICU stay, >18 years old) from this database. R divided samples into 7:3 training and testing cohorts. The univariate analysis determined whether the two cohorts differed statistically in baseline data. This research used forward stepwise logistic regression after independent prognostic factors for these TBI patients. The optimal variables were selected for the model by the optimal subset method. The optimal feature subsets in pattern recognition improved the model prediction, and the minimum BIC forest of the high-dimensional mixed graph model achieved a better prediction effect. A nomogram-labeled TBI-IHM model containing these risk factors was made by nomology in State software. Least Squares OLS was used to build linear models, and then the Receiver Operating Characteristic (ROC) curve was plotted. The TBI-IHM nomogram model's validity was determined by receiver operating characteristic curves (AUCs), correction curve, Hosmer-Lemeshow test, integrated discrimination improvement (IDI), net reclassification improvement (NRI), and decision-curve analysis (DCA).ResultThe eight features with a minimal BIC model were mannitol use, mechanical ventilation, vasopressor use, international normalized ratio, urea nitrogen, respiratory rate, and cerebrovascular disease. The proposed nomogram (TBI-IHM model) was the best mortality prediction model, with better discrimination and superior model fitting for severely ill TBI patients staying in ICU. The model's receiver operating characteristic curve (ROC) was the best compared to the seven other models. It might be clinically helpful for doctors to make clinical decisions.ConclusionThe proposed nomogram (TBI-IHM model) has significant potential as a clinical utility in predicting mortality in TBI patients.

Abstract Knowledge of Martian crust and uppermost mantle aid us studying the planet's evolution. NASA's InSight mission provides seismic data being used to reveal the interior structure. Most studies have focused on the crustal structure beneath InSight lander, but the seismic structure of other regions has remained poorly known. We use surface‐wave data to investigate the crustal structure of a large region along the Medusa Fossae Formation and the dichotomy. We adopt the largest‐magnitude marsquake (S1222a) that has been recorded, which provides both Rayleigh‐ and Love‐wave signals. We measure and jointly invert these surface‐wave fundamental‐mode group velocities from ∼15 to 40 s to estimate the average 1D isotropic velocity models. These models includes a high‐velocity layer at ∼7‐km depth, which could be due to a regional basaltic activity or regional stress. Our models also indicate that a common intra‐crustal structure (∼12–40 km depth) may exist in this region along the dichotomy.

A prerequisite for prebiotic chemistry is the accumulation of critical building blocks of life. Some studies argue that more frequent impact events on the primitive Earth could have induced a more reducing steam atmosphere and thus favor widespread and more efficient synthesis of life building blocks. However, elevated temperature is also proposed to threaten the stability of organics and whether life building blocks could accumulate to appreciable levels in the reducing yet hot surface seawater beneath the steam atmosphere is still poorly examined. Here, we used a thermodynamic tool to examine the synthesis affinity of various life building blocks using inorganic gasses as reactants at elevated temperatures and corresponding steam pressures relevant with the steam-seawater interface. Our calculations show that although the synthesis affinity of all life building blocks decreases when temperature increases, many organics, including methane, methanol, and carboxylic acids, have positive synthesis affinity over a wide range of temperatures, implying that these species were favorable to form (>10–6 molal) in the surface seawater. However, cyanide and formaldehyde have overall negative affinities, suggesting that these critical compounds would tend to undergo hydrolysis in the surface seawaters. Most of the 18 investigated amino acids have positive affinities at temperature

This paper investigates the sparse β model with 𝓁1 penalty in the field of network data models, which is a hot topic in both statistical and social network research. We present a refined algorithm designed for parameter estimation in the proposed model. Its effectiveness is highlighted through its alignment with the proximal gradient descent method, stemming from the convexity of the loss function. We study the estimation consistency and establish an optimal bound for the proposed estimator. Empirical validations facilitated through meticulously designed simulation studies corroborate the efficacy of our methodology. These assessments highlight the prospective contributions of our methodology to the advanced field of network data analysis.

In this paper,a high strength Al-4.82Mg-0.75Sc-0.49Mn-0.28Zr (Al–Mg-Sc-Mn) alloy was prepared by selective laser melting (SLM). The effects of laser power on microstructures, relative density, and mechanical properties of SLM-fabricated Al–Mg-Sc-Mn alloy were studied. The results shown that the bimodal structure with an ultra-equiaxed grain and columnar crystal is formed in Slammed-fabricated Al–Mg-Sc-Mn alloy. The columnar crystal is surrounded by ultra-fine equiaxed crystal, and the columnar crystal shows (001) preferred orientation, the ultra-fine equiaxed structure shows no anisotropy in SLM-fabricated alloy. With increase of laser power, the molten pool size increases during SLM process, and the samples relative density and hardness decrease as laser power increase. The relative density of SLM-fabricated Al–Mg-Sc-Mn alloy is 99.74% under the process parameters of laser power 310W and scanning speed 1200 mm/s, and the hardness of alloy is as high as 107.73 ± 1.27 HV. The tensile strength of SLM-fabricated Al–Mg-Sc-Mn alloy samples are all higher than 400 MPa, and elongations are more than 19%. The fracture morphology of SLM-fabricated Al–Mg-Sc-Mn alloy is a typical ductile fracture feature, which shows a high comprehensive mechanical property. Supersaturated solid solution is formed in Al–Mg-Sc-Mn alloy because of rapid cooling during SLM process, resulting in grain refinement and improvement of mechanical properties. Fine-grain strengthening and second phase strengthening are the main reasons for the improvement of mechanical properties of SLM-fabricated Al–Mg-Sc-Mn alloy.

Abstract H2 in a CO2 atmosphere may serve as a potential solution to the early Mars climate paradox, but its unknown sources cast doubts on the proposed mechanism. Impact cratering is an energetic process that may modify the surface redox budget. Here, we investigate the potential influence of impact‐related melt oxidation and serpentinization on global climate conditions. We show that impact melt and the projectile's significant oxidizing potential during basin‐forming impacts (Basin size ≥1,250 km) result in sufficient H2 to raise the global mean temperature to above 273K, which lasts for up to 105 − 106 yr considering rate‐limited regime. Impact‐induced serpentinization has limited consequences on the global climate in comparison. Episodic warming after large impacts may have enabled the presence of liquid water for up to several million years in the Noachian, resulting in the chemical evolution of the planet's surface co‐evolving with the planetary atmosphere in an episodic manner.

Prenatal exposure to nicotine that are mainly produced from tobacco smoke has been reported to affect infants. Therefore, nicotine exposure is one of important health concerns for newborn screening. Detecting nicotine and its metabolites such as cotinine in meconium were widely used to evaluate the tobacco exposure of pregnancy. In this study, disposable wooden tips were applied for touch sampling of meconium from newborn infants, and then were directly mounted on mass spectrometer (MS) to perform rapid screening of nicotine and cotinine. Choice of extraction/spray solvents was optimized. The limits of detection, reproducibility, linear response for direct analysis of meconium were also investigated. It is found the limits of detection (S/N = 3) to be as low as 0.36 ng/mg and 1.18 ng/mg for nicotine and cotinine, respectively, while the limits of quantitation (S/N = 10) to be 1.19 ng/mg and 3.94 ng/mg for nicotine and cotinine, respectively. The relative standard deviations (RSD) were found to be at 8.4%–19.8% (n = 6) for nicotine and cotinine, a good linear range from 5–500 ng/mL (R2 > 0.99). These analytical performances are well-accepted levels for ambient mass spectrometer analysis. In this study, evaluation of nicotine and cotinine in 22 puerpera volunteers were conducted by the established wooden-tip spray mass spectrometry (WTS-MS). These results showed that wooden-tip spray mass spectrometry would be useful for newborn screening of nicotine and cotinine in meconium with high reproducibility, speed, sensitivity, and specificity. Owing to the use of disposable wooden tips that involves no sample preparation and no chromatographic separation, our results show that wooden-tip spray mass spectrometry is a powerful tool for determination of nicotine in newborn meconium.

Background: Evidence regarding the cardiopulmonary effects of indoor coarse particulate matter (PM2.5-10) and its chemical constituents and sources remains limited. Methods: Five consecutive daily visits (200 person-visits in total) were completed among 40 male patients with chronic obstructive pulmonary disease (COPD) in this panel study from November 2015 to May 2016 in Beijing, China. Daily indoor PM2.5-10 was collected and twenty-one elements were measured using inductively coupled plasma mass spectrometry. Lung function and blood pressure were measured at daily visit. Principal component analysis (PCA) was used for source appointment. Bayesian kernel machine regression (BKMR) and linear mixed-effect models were used to establish the exposure-response relationships. Results: An interquartile range (IQR, 23.12μg/m3) increase in 1-day average concentration of indoor PM2.5-10 was associated with changes of 0.88 (95CI: -0.25, 2.01) mmHg in systolic blood pressure (SBP), 1.15 (95CI: 0.25, 2.06) mmHg in diastolic blood pressure (DBP), -2.29% (95CI: -4.07%, -0.51%) in forced expiratory volume in the first second (FEV1) and -1.68% (95CI: -3.41%, 0.06%) in peak expiratory flow (PEF). According to the results of PCA, soil/dust, coal combustion, and natural Ni/Cr sources were identified as three main sources of indoor PM2.5-10 inorganic elements. BKMR analysis revealed a significant association of all measured constituents with elevated SBP and a negative trend of FEV1. Coal combustion-related constituents posed a stronger joint effect on blood pressure than the other two sources. Stronger associations of indoor PM2.5-10 constituents with elevated blood pressure and decreased PEF were observed during the heating period than during the non-heating period. And the adverse effects of coal combustion-related constituents on blood pressure and lung function were also stronger in the heating season. Conclusions: Indoor PM2.5-10 constituents were associated with impaired cardiopulmonary health of COPD patients, and those from coal combustion source may play a dominant role, especially during the heating period.

Abstract Radiation‐induced intestinal injury is a serious concern during abdominal and pelvic cancers radiotherapy. Ubiquitin (Ub) is a highly conserved protein found in all eukaryotic cells. This study aims to explore the role and mechanism of free Ub against radiogenic intestinal injury. We found that free Ub levels of irradiated animals and human patients receiving radiotherapy were upregulated. Radiation‐induced Ub expression was associated with the activation of interferon regulatory factor 1 (IRF1). Intraperitoneal injection of free Ub significantly reduced the mortality of mice following 5–9 Gy total body irradiation (TBI) through the Akt pathway. Free Ub facilitates small intestinal regeneration induced by TBI or abdominal irradiation. At the cellular level, free Ub or its mutants significantly alleviated cell death and enhanced the survival of irradiated intestinal epithelial cells. The radioprotective role of free Ub depends on its receptor CXCR4. Mechanistically, free Ub increased fibroblast growth factor‐2 (FGF2) secretion and consequently activated FGFR1 signaling following radiation in vivo and in vivo. Thus, free Ub confers protection against radiation‐induced intestinal injury through CXCR4/Akt/FGF2 axis, which provides a novel therapeutic option.

In utero hematopoietic cell transplantation (IUHCT) is considered a potentially efficient therapeutic approach with relatively few side effects, compared to adult hematopoietic cell transplantation, for various hematological genetic disorders. The principle of IUHCT has been extensively studied in rodent models and in some large animals with close evolutionary similarities to human beings. However, IUHCT has only been used to rebuild human T cell immunity in certain patients with inherent immunodeficiencies. This review will first summarize the animal models utilized for IUHCT investigations and describe the associated outcomes. Recent advances and potential barriers for successful IUHCT are discussed, followed by possible strategies to overcome these barriers experimentally. Lastly, we will outline the progress made towards utilizing IUHCT to treat inherent disorders for patients, list out associated limitations and propose feasible means to promote the efficacy of IUHCT clinically.

In this paper, high-silicon Al–42Si alloy was prepared by selective laser melting (SLM) with different process parameters. Microstructures evolution and defects formation were studied and process parameters were optimized. The results shown that the density of SLM-fabricated Al–42Si alloy increases as input energy density increases. The highest and lowest density of SLM-fabricated Al–42Si alloy are obtained, when input energy density is 42.9J/mm3 and 33.8J/mm3 respectively. The microstructures of Al–42Si alloy fabricated by selective laser melting is mainly composed of primary silicon phase and eutectic silicon phase, which is distinct from casting alloy because of diffient grains size and shapes of the primary silicon. With higher energy density, larger size of the primary silicon observed during process due to higher heat released by powder. The size of primary silicon phase particles is in the range of 2.9–9.4μm, and the size of molten pool during SLM process is in the range of 125 ± 10μm–140 ± 10μm in this study. Also the hardness of SLM-fabricated Al–42Si alloy increases as input energy density increases between 40.0J/mm3 and 42.9J/mm3. After heat treatment, the residual stress is eliminated, microstructure stability and homogeneous of SLM-fabricated Al–42Si alloy are improved. The silicon distribution is more uniform and sizes increases about 1∼2μm, and the hardness decreases after heat treatment. The optimal SLM parameters for Al–42Si alloy are laser power of 320W, scanning speed of 1355 mm/s, layer thickness of 50μm and scanning space of 110μm.

Abstract Background There is a growing body of evidences indicating iNOS has involved in the pathogenesis of SLE. However, the role of iNOS in SLE is inconsistency. This systematic review was designed to evaluate the association between iNOS and SLE. Results Six studies were included, reporting on a total of 277 patients with SLE. The meta-analysis showed that SLE patients had higher expression of iNOS at mRNA level than control subjects (SMD = 2.671, 95%CI = 0.446–4.897, z = 2.35, p = 0.019), and a similar trend was noted at the protein level (SMD = 3.602, 95%CI = 1.144–6.059, z = 2.87, p = 0.004) and positive rate of iNOS (OR = 9.515, 95%CI = 1.915–47.281, z = 2.76, p = 0.006) were significantly higher in SLE group compared with control group. No significant difference was observed on serum nitrite level between SLE patients and control subjects (SMD = 2.203, 95%CI = -0.386–4.793, z = 1.64, p = 0.095). The results did not modify from different sensitivity analysis, representing the robustness of this study. No significant publication bias was detected from Egger’s test. Conclusions There was a positive correlation between increasing iNOS and SLE. However, the source of iNOS is unknown. Besides NO pathway, other pathways also should be considered. More prospective random studies are needed in order to certify our results.

Abstract Background TAB2 is an activator of MAP 3 K7/TAK1, which is required for the IL-1 induced signal pathway. Microdeletions encompassing TAB2 have been detected in various patients with congenital heart defects (CHD), indicating that haploinsufficiency of TAB2 causes CHD. To date, seven variants within TAB2 were reported associated with CHD, only two of them are nonsense mutations. Case presentation Here we describe a three-generation Chinese family that included five CHD patients with heart valvular defects, such as mitral or tricuspid valves prolapse or regurgitation, and aortic valve stenosis or regurgitation. Our proband was a pregnant woman presenting with mitral, tricuspid, and aortic defects; her first child experienced sudden cardiac death at the age of 2 years. Whole-exome sequencing of the proband revealed a novel nonsense variant in TAB2 (c.C446G, p.S149X), which results in the elimination of the majority of C-terminal amino acids of TAB2, including the critical TAK1-binding domain. The variant was identified in five affected patients but not in the eight unaffected family members using Sanger sequencing and was classified as “pathogenic” according to the latest recommendation on sequence variants laid out by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Conclusion We described a family with CHD caused by a novel TAB2 nonsense mutation. Our study broadens the mutation spectrum of TAB2; to the best of our knowledge, this is the first report of a pathogenic mutation within TAB2 in a Chinese population.

Background: Given the limited effectiveness of pharmacological treatments in mitigating cognitive decline in individuals with mild cognitive impairment (MCI), there is a pressing need for developing effective non-pharmacological intervention programs to counteract MCI-related cognitive decline. Acupressure and cognitive training are safe and cost-effective; however, evidence of the effect of acupressure or the combined effect of acupressure and cognitive training on cognitive functions of older adults with MCI is limited.Objective: To evaluate both the individual and combined effects of acupressure and cognitive training on cognitive functions of older adults with MCI.Methods: One hundred and eighty older adults with MCI were recruited and randomly assigned to combined acupressure and cognitive training group (n = 45), acupressure group (n = 45), cognitive training group (n = 45), or control group (n = 45). Participants in the experimental groups received self-administered and group-based training sessions, while those in the control group received routine community education. The intervention lasted for 6 months. The cognitive functions of all the participants were assessed at multiple stages, including pre-intervention, at the end of the third and sixth months.Results: One hundred and fifty-one participants completed the study, and all participants analyzed in intervention groups completed at least 85% of all practice sessions recommended. Repeated measures analysis of variance of the scores of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at different time points among the four groups revealed that the group effect, time effect, and interaction effect were all significant (p < 0.01). Pairwise comparisons with Bonferroni correction showed that the scores of MMSE and MoCA in acupressure group, cognitive training group, and combined group were significantly raised compared with control group (p < 0.01). Compared with acupressure or cognitive training groups, the scores of MMSE and MoCA in combined group were significantly higher (p < 0.05). The scores of MMSE and MoCA in acupressure group had no significant differences with those in cognitive training group (p > 0.05).Conclusion: Acupressure and cognitive training both could improve the cognitive functions of older adults with MCI, and when used together, the effects were enhanced.Clinical Trial Registration: This study was registered in the Chinese Clinical Trial Registry (No.ChiCTR2100049955).

Simvastatin (SIM) particles are liposoluble drugs with large particle sizes, resulting in poor compatibility with electrospun polycaprolactone (PCL)/polyethylene glycol (PEG) nanofibers, so that part of them will be exposed to the electrospun nanofiber surface, which is easy to cause the burst release of drugs. Therefore, in this paper, stearic acid (SA) with good biocompatibility was innovatively added to increase the dispersion uniformity of SIM in the spinning solution, thus improving the performances of SIM-loaded PCL/PEG nanofiber membranes (NFMs). Accordingly, the effects of SA addition on the morphologies, mechanical properties, wettability, and drug release properties of the SIM-loaded NFMs were studied. The results showed that after SIM was dissolved in SA solution, the particle size of SIM was significantly reduced and could be evenly dispersed in the polymer spinning solution, thus obtaining the SIM-loaded composite NFMs with the best morphology and performance.

Due to active geological resurfacing, the record of large impact basins (e.g. in Chryse Planitia) on Mars seems to be widely absent. Based on high-quality global datasets, the authors here propose a buried impact basin, covered by up to 1 km of sediments or lava flows after its formation more than 4 billion years ago.

Background: Exposure to airborne fine particulate matter (PM2.5) has been associated with a variety of adverse health outcomes including chronic obstructive pulmonary disease (COPD). However, the linkages between PM2.5 exposure, PM2.5-related biomarkers, COPD-related biomarkers and COPD remain poorly elucidated. Objectives: To investigate the linkages between PM2.5 exposure and COPD outcome by using the meet-in-middle strategy based on urinary metabolic biomarkers. Methods: A cross-sectional study was designed to illustrate the mentioned quadripartite linkages. Indoor PM2.5 and its element components were assessed in 41 Chinese elderly participants including COPD patients and their healthy spouses. Metabolic biomarkers involved in PM2.5 exposure and COPD were identified by using urinary metabolomics. The associations between PM2.5- and COPD-related biomarkers were investigated by statistics and metabolic pathway analysis. Results: Seven metabolites were screened and identified with significant correlations to PM2.5 exposure, which were majorly involved in purine and amino acid metabolism as well as glycolysis. Ten COPD-related metabolic biomarkers were identified, which suggested that amino acid metabolism, lipid and fatty acid metabolism, and glucose metabolism were disturbed in the patients. Also, PM2.5 and its many elemental components were significantly associated with COPD-related biomarkers. We observed that the two kinds of biomarkers (PM2.5- and COPD-related) integrated in a locally connected network and the alterations of these metabolic biomarkers can biologically link PM2.5 exposure to COPD outcome. Conclusions: Our study indicated the modification of PM2.5 to COPD via both modes of action of lowering participants' antioxidation capacity and decreasing their lung energy generation; this information would be valuable for the prevention strategy of COPD. Keywords: Urinary metabolomics, PM2.5, Chronic obstructive pulmonary disease, Adverse outcome pathway

Abstract Pakistan is highly exposed to climate-induced disasters, especially floods. Flooding history shows that educational establishments have been disproportionately hard-hit by flooding events. In Pakistan, school safety and preparedness is still a choice, rather than a mandatory requirement for all schools. But schools in Pakistan do have a responsibility to keep safe the students in their care, especially during and after the catastrophic events. This implies the need to maintain the environment in and around school property, so as to minimize the impacts of floods and to have the mechanisms in place to maximize a school’s resilience. This study examined the emergency preparedness activities of 20 schools in four districts of Khyber Pakhtunkhwa Province that had recently been severely affected by floods. Through face to face interviews and a structured questionnaire (n = 100) we collected data on the four pillars of emergency preparedness: emergency planning, preparation measures, safe school facilities, and hazard education and training. The study revealed that the majority of the sample schools had experienced more than one natural hazard-induced disaster, predominantly flooding, yet despite this had not undertaken adequate emergency preparedness activities. There are particular gaps with regard to plans for students with disabilities, the continuity of school operations after a disaster, the presence of maps to identify evacuation routes, the availability of emergency equipment and resources, disaster preparedness guidelines, and psychological first aid and crisis counseling. The strengths, weaknesses, opportunities, and threats analysis that our researchers carried out indicates that, although schools in the survey have taken many steps towards flood preparedness, many weaknesses still exist and there remain significant opportunities to strengthen the preparedness level of many schools. The goal of this study is to inform policy decisions that improve school safety in Pakistan and to suggest the priority areas for future school disaster preparedness and management efforts.

Abstract Background Desmoplastic small round cell tumor (DSRCT) is a rare malignant sarcoma with poor prognosis due to lack of effective treatments. Apatinib is a new potent oral small-molecule tyrosine kinase inhibitor, and targets the intracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2). In this study, we presented a case of intra-abdominal DSRCT which was effectively treated by apatinib. Case presentation A 32-year-old man was admitted due to increasing urination frequency and palpable mass in right lower abdomen for 2 months. The mass was resected and diagnosed DSRCT. The patient refused chemotherapy and radiotherapy,and used Chinese medicine only. Six months after the surgery, the patient re-hospitalized due to growing abdominal mass and ascites. Intraperitoneal cisplatin treatment showed little effect. Apatinib was then recommended. Apatinib revealed outstanding effect on reducing mass size and ascites during 2-month treatment. Apatinib therapy continued for additional 2 months, and the patient was in good condition. The only toxicity was hand-food syndrome, which was controllable and well tolerated. Conclusion It is the first report that apatinib is effective on DSRCT. This report may provide an additional option for the treatment of metastatic DSRCT.

Taking the new type of protuberant foil hydrodynamic thrust gas bearing as the research object,the finite element method and the Newton-Raphson iterative method are used to solve the numerical model of fluid-solid coupling by MATLAB software. The film pressure distribution,the thickness distribution and the carrying capacity of the bearing under different temperature of the same lubricating gas and the same lubricating gas at different temperatures were obtained. And the influence of the physical properties of the lubricating gas on the static characteristics of the foil dynamic pressure thrust bearing in the aircraft turbo cooler is studied. The results show that the lubricating gas with large dynamic viscosity has a large gas film pressure and thickness distribution,and the higher carrying capacity. With the high temperature of the bearing running at high speed for a long time,the change of the physical parameters of the lubricating gas is conducive to improving the carrying capacity.