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MiRNA-124 has been considered to play a significant role in the formation of memory and a variety of neurodegenerative diseases. In this study, the aim is to verify whether miRNA-124 is involved in memory impairment induced by d-galactose, and explore the underlying neuroprotective mechanism. The results revealed that rapid administration of d-galactose (1000 mg/kg subcutaneously) in mice caused memory impairments, as determined by Novel Object Recognition test, Morris Water Maze test, and histological assessments. MiRNA-124 agomir is stereotactic injected into hippocampus, thus alleviated memory impairment induced by d-galactose and reversed the neural damage and neuroinflammation. Furthermore, the results of molecular biological analysis and immunohistochemistry revealed that miRNA-124 markedly reduced neuroinflammation induced by d-galactose through polarization of microglia as determined by detection of ionized calcium binding adapter molecule 1 (Iba-1), inducible nitric oxide synthase (iNOS) and arginase-1(Arg-1), which also downregulated inflammatory mediators, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), and upregulated IL-4 and IL-10. Hence, taken together, the results of the present study suggested that miRNA-124 showed a significant negative correlation with memory impairment and neuroinflammation induced by d-galactose rapidly, possibly via polarization of microglia from M1 to M2. It is possible that miRNA-124 can be used as a new target for the pathogenesis of memory impairment, including age-associated neurodegenerative diseases such as Alzheimer's disease.

With the rapid development of information technology, researchers have paid attention to the pump-driven two-phase cooling loop technology for data centers, which imposes requirements on the efficiency and size of the pump. A fluid self-lubricating centrifugal pump with R134a refrigerant was developed to reach a higher rotation speed and oil-free system, resulting in a more diminutive size. Due to the high rotation speed and refrigerant pressure approaching saturated vapor pressure, the internal flow characteristics and cavitating characteristics are critical and complex. This paper focuses on the prototype’s head and cavitation performance based on experimental and numerical data. The experiments indicated that the head coefficient of the pump under design conditions is 0.9881, and the pump’s critical cavitation number and breakdown number are 0.551 and 0.412, respectively. The numerical results can predict the head and cavitation with deviations less than 2.6%. To study changing patterns in flow characteristics under the different operating conditions in the refrigerant centrifugal pump, the numerical model based on a modified Sauer-Schnerr cavitation model was built to analyze the distributions of pressure, temperature, relative velocity, and bubble volume across every hydraulic component and different degrees of cavitation, and proposed the influence of the thermal effect on refrigerant cavitating. The cavitating flow characteristics were obtained with the aim of providing guidance for the hydraulic design of a refrigerant centrifugal pump.

Sertoli cells (SCs), the only somatic cells in the seminiferous tubules, facilitate the maintenance of testicular immune privilege through the formation of the blood-testis barrier (BTB) and the expression of immunoregulatory factors. Rho guanosine exchange factor 15 (ARHGEF15) is a member of the guanosine exchange factors, which are involved in cell migration, cell polarity, and cell cycle progression via activation of Rho GTPases. This study investigated the functional role of ARHGEF15 in SCs during spermatogenesis using SC–specific Arhgef15 knockout mice. The results revealed that Arhgef15 deficiency in SCs affected the localization of SC nuclei, disrupted BTB integrity, and led to premature shedding of germ cells. In Arhgef15flox/flox/Amh-Cre+ mice, the ultrastructure of the round spermatids was impaired, accompanied by acrosome degeneration, acrosomal vesicle shedding, and atrophic nuclei. Consequently, the percentage of abnormal sperm in the Arhgef15flox/flox/Amh-Cre+ epididymis was markedly elevated. RNA-sequencing analysis revealed that most of the differentially expressed genes in SCs of Arhgef15flox/flox/Amh-Cre+ mice were associated with immunity. Further study revealed that the sera of Arhgef15flox/flox/Amh-Cre+ mice showed immunoreactivity against testicular lysate of wild-type mice, indicating the production of antibodies against testicular autoantigens in Arhgef15flox/flox/Amh-Cre+ mice. In conclusion, the specific deletion of Arhgef15 in SCs of mice leads to sperm abnormality, probably by disrupting the testicular immune homeostasis.

Although childhood maltreatment confers a high risk for the development of major depressive disorder, the neurobiological mechanisms underlying this connection remain unknown. The present study sought to identify the specific resting-state networks associated with childhood maltreatment. We recruited major depressive disorder patients with and without a history of childhood maltreatment (n = 31 and n = 30, respectively) and healthy subjects (n = 80). We used independent component analysis to compute inter- and intra- network connectivity. We found that individuals with major depressive disorder and childhood maltreatment could be characterized by the following network disconnectivity model relative to healthy subjects: (i) decreased intra-network connectivity in the left frontoparietal network and increased intra-network connectivity in the right frontoparietal network, (ii) decreased inter-network connectivity in the posterior default mode network-auditory network, posterior default mode network-limbic system, posterior default mode network-anterior default mode network, auditory network-medial visual network, lateral visual network - medial visual network, medial visual network-sensorimotor network, medial visual network - anterior default mode network, occipital pole visual network-dorsal attention network, and posterior default mode network-anterior default mode network, and (iii) increased inter-network connectivity in the sensorimotor network-ventral attention network, and dorsal attention network-ventral attention network. Moreover, we found significant correlations between the severity of childhood maltreatment and the intra-network connectivity of the frontoparietal network. Our study demonstrated that childhood maltreatment is integrally associated with aberrant network architecture in patients with major depressive disorder.

Due to the significant increase in cesarean section rates worldwide, cesarean scar pregnancy (CSP) has attracted extensive attention. This study aimed to investigate the global research status and developmental directions of CSP to discern promising research hotspots by means of bibliometrics and visualized analyses.The English CSP-related literature from 2001 to 2020 was retrieved from The Web of Science Core Collection (WOSCC) database. Microsoft Excel 2019 was used to analyze the years, countries, institutions, journals, authors, citations, H indices, titles, abstracts, and keywords of related literature, and VOSviewer software was used to visualize developmental directions and promising hotspots in CSP.The study included 1,186 articles in total. The number of CSP articles has presented an overall increasing trend over the last two decades. China has the maximum number of publications, but America's H-index is higher than that of China, with the average number of citations per item ranking fourth. The Journal of Obstetrics and Gynaecology Research published the most on the subject, while Zhejiang University from China published the largest number of articles; Jurkovic D, Timor-Tritsch IE, and Monteagudo A have achieved considerable progress in the CSP domain. There are 5 clusters that the current research orientation can fall into: "selection of the delivery mode with a scarred uterus after cesarean section", "risk factors", "diagnosis", "treatment" and "related basic and clinical experiments". High-intensity focused ultrasound (HIFU) and the formulation of consensus guidelines are the focus of the current research.The analysis of global trends shows that CSP research is being actively studied and that the number of published studies is continuously increasing. According to the comprehensive quality and quantity of the literature, the United States maintains a leading position in CSP research. In recent years, the research directions have mainly focused on "diagnosis", "treatment" and "risk factors", while HIFU and the formulation of consensus guidelines may become research hotspots in the field of CSP.

Purpose This paper aims to represent an empirical study of what role does structural empowerment play in the relationship between multi-stakeholder value co-creation (VCC) and the success of new product development (NPD). Design/methodology/approach The hypotheses developed in this paper are tested by using data from 243 manufacturing companies worldwide. Findings The results show that the VCC activities have significant positive effects on NPD success, and structural empowerment moderates the impact of VCC activities on NPD success, but the moderating effect is not significant for customer involvement. Originality/value This study contributes to the research of VCC and discusses the positive role of structural empowerment to enhance the impact of VCC activities on NPD success.

Due to its tumor-specificity and limited side effects, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown great potential in cancer treatments. However, the short half-life of TRAIL protein and the poor death receptor (DR) expression of cancer cells severely compromise the therapeutic outcomes of TRAIL in clinical studies. Herein, a novel ROS-dependent TRAIL-sensitizing nanoplatform, CPT MV, with a Ce6-PLGA core and a TRAIL-modified cell membrane shell was explored to improve the

1. Overview of the reaction mechanism, thermodynamics and kinetics of WGSR. 2. In-depth discussion of the modification strategies and structure–performance relationships.

Background CircRNAs, new non-coding RNA as miRNA sponge, play crucial roles in tumor initiation and development. The present study aimed to identify hsa_circ_0001451 and its related molecules for the progression of gastric cancer. Methods The expression of hsa_circ_0001451 was determined in 66 cases of paired gastric cancer and their adjacent normal gastric tissues by qRT-PCR. The cellular localization of hsa_circ_0001451 was detected with FISH analysis. The biofunction alterations of hsa_circ_0001451 were assessed by its overexpression or knockdown in gastric cancer cell lines. MTS and cloning assay were used to detect cell proliferation. Flow cytometry was used to detect cell cycle. The wound healing and transwell assays were used for cell migration and invasion. Western Blotting was used to detect the expression of a set of genes related proliferation and migration. RNA immunoprecipitation (RIP), biotinylated RNA pull-down and dual luciferase reporter tests were used to detect the interactions of hsa_circ_0001451with mir-197-3p / MT3. The in vivo proliferation and migration ability of hsa_circ_0001451infected cells were determined in zebrafish system. Results Hsa_circ_0001451 was decreased in 66 cases of gastric cancer tissues and cell lines, and significantly related to tumor invasion. The in vitro and in vivo studies indicated that over-expression of hsa_circ_0001451 inhibited the gastric cancer cell proliferation, invasion and migration via suppression of PCNA, CCND1 and BCL-2, and decreased in the S-phase. The results of pull-down, RNA immunoprecipitation and dual-luciferase reporter tests revealed that hsa_circ_0001451 could sponge miR-197-3p, targeting MT3 and affecting the malignancy of gastric cancer cells via regulating EMT related E-cadherin, N-cadherin, MMP7 and VIMENTIN. Conclusion This study revealed that hsa-circ-0001451 inhibited proliferation, invasion and metastasis and modulated EMT of gastric cancer cells via sponging of miR-197-3p and regulatng the downstream MT3. The circ_0001451 / miR-197-3p / MT3 axis are likely to be the biomarkers for prognosis and targets for drug of gastric cancer.

Context Antenatal hyperglycemia is associated with increased risk of future adverse health outcomes in both mother and child. Variations in offspring’s epigenome can reflect the impact and response to in utero glycemic exposure, and may have different consequences for the child. Objective We examined possible differences in associations of basal glucose status and glucose handling during pregnancy with both clinical covariates and offspring cord tissue DNA methylation. Research Design and Methods This study included 830 mother-offspring dyads from the Growing Up in Singapore Towards Healthy Outcomes cohort. The fetal epigenome of umbilical cord tissue was profiled using Illumina HumanMethylation450 arrays. Associations of maternal mid-pregnancy fasting (fasting plasma glucose [FPG]) and 2-hour plasma glucose (2hPG) after a 75-g oral glucose challenge with both maternal clinical phenotypes and offspring epigenome at delivery were investigated separately. Results Maternal age, prepregnancy body mass index, and blood pressure measures were associated with both FPG and 2hPG, whereas Chinese ethnicity (P = 1.9 × 10-4), maternal height (P = 1.1 × 10-4), pregnancy weight gain (P = 2.2 × 10-3), prepregnancy alcohol consumption (P = 4.6 × 10-4), and tobacco exposure (P = 1.9 × 10-3) showed significantly opposite associations between the 2 glucose measures. Most importantly, we observed a dichotomy in the effects of these glycemic indices on the offspring epigenome. Offspring born to mothers with elevated 2hPG showed global hypomethylation. CpGs most associated with the 2 measures also reflected differences in gene ontologies and had different associations with offspring birthweight. Conclusions Our findings suggest that 2 traditionally used glycemic indices for diagnosing gestational diabetes may reflect distinctive pathophysiologies in pregnancy, and have differential impacts on the offspring’s DNA methylome.

Early myocardial ischemia-induced sudden cardiac deaths (EMI-SCD) remain a great diagnostic challenge for forensic pathologists due to no gross or non-specific histological pathology. The goal of this study was to assess whether three secretory proteins, related with cellular endoplasmic reticulum stress, can be applied in forensic diagnosis of EMI-SCD. These markers included LMAN2, CAPN-1, and VCP and were compared with two clinically used markers (CK-MB and cTnI). A total of 21 EMI-SCD cases with a mean age of 53.0 (± 10.5) years and a mean ischemia interval of

In recent years, local antibiotic-loaded bone substitutes (ALBS) have been used increasingly in the treatment of diabetic foot infection (DFI). The meta-analysis aimed to analyse the efficacy of ALBS on patients with moderate to severe DFI (with or without osteomyelitis). With an appropriate search strategy, 7 studies were selected for analysis (2 RCTs and 5 cohort studies). The result showed that the application of ALBS effectively reduced the length of hospital stay (WMD -5.55; 95% CI: -9.85 to -1.26; P = 0.01), the recurrence rates (RR 0.33; 95% CI: 0.15 to 0.69; P = 0.003) and the mortality rates (RR 0.22; 95% CI: 0.06 to 0.82; P = 0.02). Compared to the control groups, however, there was no difference in healing rates (RR 1.06; 95% CI: 0.96 to 1.18; P = 0.26), healing time (WMD -1.44; 95% CI: -3.37 to -0.49; P = 0.14), the number of debridement (WMD -1.98; 95% CI: -4.08 to 0.12; P = 0.06) and major amputation rates (RR 0.76; 95% CI: 0.35 to 1.61; P = 0.47). The ALBS appears to have some beneficial effects as an adjunct to standard surgery in the treatment of DFI with or without osteomyelitis, as it reduces recurrence rates, mortality rates, and length of hospital stay, but there was no statistically significant difference in enhancing wound healing.

Childhood maltreatment has been related to various disadvantageous lifetime outcomes. However, the brain structural alterations that occur in major depressive disorder (MDD) patients with childhood maltreatment are incompletely investigated.We extensively explored the cortical abnormalities including cortical volume, surface area, thickness, sulcal depth, and curvature in maltreated MDD patients. Twoway ANOVA was performed to distinguish the effects of childhood maltreatment and depression on structural abnormalities. Partial correlation analysis was performed to explore the relationship between childhood maltreatment and cortical abnormalities. Moreover, we plotted the receiver operating characteristic curve to examine whether the observed cortical abnormalities could be used as neuro biomarkers to identify maltreated MDD patients.We reach the following findings: (i) relative to MDD without childhood maltreatment, MDD patients with childhood maltreatment existed increased cortical curvature in inferior frontal gyrus; (ii) compared to HC without childhood maltreatment, decreased cortical thickness was observed in anterior cingulate cortex and medial prefrontal cortex in MDD patients with childhood maltreatment; (iii) we confirmed the inseparable relationship between cortical curvature alterations in inferior frontal gyrus as well as childhood maltreatment; (iv) cortical curvature abnormality in inferior frontal gyrus could be applied as neural biomarker for clinical identification of MDD patients with childhood maltreatment.Childhood maltreatment have a significant effects on cortical thickness and curvature abnormalities involved in inferior frontal gyrus, anterior cingulate cortex and medial prefrontal cortex, constituting the vulnerability to depression.

Hydrogen evolution reaction (HER) and hydrogen oxidation reaction (HOR) have aroused great interest, but the high price of platinum group metals (PGMs) limits their development. The electronic reconstruction at the interface of a heterostructure is a promising strategy to enhance their catalytic performance. Here, MoO2/Ni heterostructure was synthesized to provide effective HER in an alkaline electrolyte and exhibit excellent HOR performance. Theoretical and experimental analyses prove that the electron density around the Ni atom is reduced. The electron density modulation optimizes the hydrogen adsorption and hydroxide adsorption free energy, which can effectively improve the activity of both HER and HOR. Accordingly, the prepared MoO2/Ni@NF catalyst reveals robust HER activity (η10 = 50.48 mV) and HOR activity (j0 = ∼1.21 mA cm-2). This work demonstrates an effective method to design heterostructure interfaces and tailor the surface electronic structure to improve HER/HOR performance.

Opinion statementMelanoma is caused by a variety of somatic mutations, and among these mutations, BRAF mutation occurs most frequently and has routinely been evaluated as a critical diagnostic biomarker in clinical practice. The introduction of targeted agents for BRAF-mutant melanoma has significantly improved overall survival in a large proportion of patients. However, there is BRAF inhibitor resistance in most patients, and its mechanisms are complicated and need further clarification. Additionally, treatment approaches to overcome resistance have evolved rapidly, shifting from monotherapy to multimodality treatment, which has dramatically improved patient outcomes in clinical trials and practice. This review highlights the mechanisms of BRAF inhibitor resistance in melanoma and discusses the current state of its therapeutic approaches that can be further explored in clinical practice.

Thin-walled cylindrical shell structures are widely used in various engineering fields due to their highly efficient load carrying capacity. This kind of structures is prone to buckling failure when subjected to axial compression loads. Machining the shell into corrugated shape is an effective method to prevent buckling. Rational design of corrugated shells can improve the load carrying efficiency of shell structures. However, there are few studies focused on the effects of various parameters on the longitudinal corrugated cylindrical shell buckling. In this paper, numerical studies are performed to analyze the factors affecting the buckling behaviors of thin-walled longitudinal corrugated cylindrical shells under axial compression loads. The cross section of the corrugated shell is obtained by superposing the sine curve on the reference circle. The critical buckling load, buckling mode and imperfection sensitivity of the longitudinal corrugated cylindrical shells are examined and compared with ordinary cylindrical shells. The effects of shell dimensions and material yield strength are taken into account. In addition, the influence of cross section shape parameters on the critical buckling load is considered, including the amplitude A and wave number k. Results show that the axial load carrying capacity of longitudinal corrugated cylindrical shells is better than ordinary cylindrical shells, and rational design of cross section shape can enhance the stability of corrugated shells. This work can provide some reference for relevant experimental studies. Furthermore, it can also give some guides for the application of thin-walled longitudinal corrugated cylindrical shells in actual engineering.

Summary Background COBRA-BPS (Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan, Sri Lanka), a multi-component hypertension management programme that is led by community health workers, has been shown to be efficacious at reducing systolic blood pressure in rural communities in Bangladesh, Pakistan, and Sri Lanka. In this study, we aimed to assess the budget required to scale up the programme and the incremental cost-effectiveness ratios. Methods In a cluster-randomised trial of COBRA-BPS, individuals aged 40 years or older with hypertension who lived in 30 rural communities in Bangladesh, Pakistan, and Sri Lanka were deemed eligible for inclusion. Costs were quantified prospectively at baseline and during 2 years of the trial. All costs, including labour, rental, materials and supplies, and contracted services were recorded, stratified by programme activity. Incremental costs of scaling up COBRA-BPS to all eligible adults in areas covered by community health workers were estimated from the health ministry (public payer) perspective. Findings Between April 1, 2016, and Feb 28, 2017, 11 510 individuals were screened and 2645 were enrolled and included in the study. Participants were examined between May 8, 2016, and March 31, 2019. The first-year per-participant costs for COBRA-BPS were US$10·65 for Bangladesh, $10·25 for Pakistan, and $6·42 for Sri Lanka. Per-capita costs were $0·63 for Bangladesh, $0·29 for Pakistan, and $1·03 for Sri Lanka. Incremental cost-effectiveness ratios were $3430 for Bangladesh, $2270 for Pakistan, and $4080 for Sri Lanka, per cardiovascular disability-adjusted life year averted, which showed COBRA-BPS to be cost-effective in all three countries relative to the WHO-CHOICE threshold of three times gross domestic product per capita in each country. Using this threshold, the cost-effectiveness acceptability curves predicted that the probability of COBRA-BPS being cost-effective is 79·3% in Bangladesh, 85·2% in Pakistan, and 99·8% in Sri Lanka. Interpretation The low cost of scale-up and the cost-effectiveness of COBRA-BPS suggest that this programme is a viable strategy for responding to the growing cardiovascular disease epidemic in rural communities in low-income and middle-income countries where community health workers are present, and that it should qualify as a priority intervention across rural settings in south Asia and in other countries with similar demographics and health systems to those examined in this study. Funding The UK Department of Health and Social Care, the UK Department for International Development, the Global Challenges Research Fund, the UK Medical Research Council, Wellcome Trust.

Digital multiplexed homogeneous immunoassay is supposed to have the advantages of high sensitivity, high analytical throughput, small sampling errors, and low consumption. We present a spectral imaging-based multiplex, homogenous immunoassay by counting sandwich-structured immunocomplexes in the form of quantum dot (QD) aggregates. As a proof of concept, the method was utilized to detect two tumor biomarkers: carcino-embryonic antigen (CEA) and α-fetoprotein (AFP). The immunocomplex induced by CEA contained QD 655 and QD 585 and were recognized by the spectral pattern of dual-color QD aggregates under a transmission-grating-based spectral imaging microscope. Immunocomplexes induced by AFP were labeled with the QD 585 aggregate and were identified by the spectral blue-shift pattern of same-color QD aggregates. Limits of detection for AFP and CEA were calculated to be 0.02 and 0.10 pM at a signal-to-noise ratio of 3, respectively. Further successful quantification of the model proteins in human plasma demonstrated the accuracy and reliability of our approach.

Three-dimensional nitrogen-doped graphene (3D-NG) networks, yielded by hydrothermal reaction and freeze-drying treatment, were used as building blocks to construct a metal-free quadruplet electrochemical sensor for simultaneous detection of ascorbic acid (AA), dopamine (DA), uric acid (UA), and acetaminophen (AP). The introduced 3D-NG materials with a 3D porous structure and a nitrogen doping effect were beneficial for the generation of multidimensional electron transfer pathways and the improvement of electrocatalytic activities by modulating their electronic properties, which could contribute to the effective differentiation of the four analytes in their quaternary mixture. Well-resolved oxidation peaks and enhanced response currents of AA, DA, UA, and AP were obtained from the 3D-NG-based electrodes. For the individual determination of one analyte, the linear concentration ranges of AA, DA, UA, and AP were 20-10 000, 1-1000, 0.5-1000, and 0.1-600 μM with detection limits of 3.91, 0.26, 0.12, and 0.02 μM (S/N = 3), respectively. After the synchronous change of the concentrations of AA, DA, UA, and AP, desirable linear relationships were observed in the ranges of 100-7000, 2-600, 1-800, and 10-550 μM with detection limits of 24.33, 0.37, 0.21, and 1.87 μM (S/N = 3), respectively. This sensitive sensing platform was successfully used to monitor AA, DA, UA, and AP in human urine samples, which indicated that 3D-NG could become a promising electrode material for the simultaneous monitoring of multiple electroactive species.

Recently, photothermal therapy (PTT) in the second near-infrared (NIR-II) biowindow has emerged as a promising treatment modality; however, its therapeutic outcomes are still limited by heterogeneous heat distribution and insufficient control of metastatic lesions. Tremendous efforts have been made to overcome the PTT's shortcomings by combining PTT with immunotherapy, but unfortunately current strategies still suffer from low response rates, primary/acquired resistance or severe immune-related adverse events. Herein, a novel photothermal agent and gene co-delivery nanoparticle (CSP), with CuS inside the SiO2 pore channels and PDMAEMA polycation on the outside of SiO2 surface, is explored for tumor localized NIR-II PTT and in situ immunotherapy through local generation of IL-12 cytokine. The resulting CSP integrated with the plasmid encoding IL-12 gene (CSP@IL-12) exhibited good gene transfection efficiency, outstanding NIR-II PTT effect and excellent therapeutic outcomes both in vitro and in vivo. Meanwhile, such an in situ joint therapy modality could significantly induce systemic immune responses including promoting DC maturation, CD8+ T cell proliferation and infiltration to efficiently eliminate possible metastatic lesions through abscopal effects. Hence, this creative combinational strategy of NIR-II PTT and IL-12 cytokine therapy might provide a more efficient, controllable and safer alternative strategy for future photo-immunotherapy.