Inhibition of PPP1R15A alleviates osteoporosis via suppressing RANKL-induced osteoclastogenesis.

Osteoporosis results from overactivation of osteoclasts. There are currently few drug options for treatment of this disease. Since the successful development of allosteric inhibitors, phosphatases have become attractive therapeutic targets. Protein phosphatase 1, regulatory subunit 15 A (PPP1R15A), is a stress-responsive protein, which promotes the UPR (unfolded protein response) and restores protein homeostasis. In this study we investigated the role of PPP1R15A in osteoporosis and osteoclastogenesis. Ovariectomy (OVX)-induced osteoporosis mouse model was established, osteoporosis was evaluated in the left femurs using micro-CT. RANKL-stimulated osteoclastogenesis was used as in vitro models. We showed that PPP1R15A expression was markedly increased in BMMs derived from OVX mice and during RANKL-induced osteoclastogenesis in vitro. Knockdown of PPP1R15A or application of Sephin1 (a PPP1R15A allosteric inhibitor in a phase II clinical trial) significantly inhibited osteoclastogenesis in vitro. Sephin1 (0.78, 3.125 and 12.5 µM) dose-dependently mitigated the changes in NF-κB, MAPK, and c-FOS and the subsequent nuclear factor of activated T cells 1 (NFATc1) translocation in RANKL-stimulated BMMs. Both Sephin1 and PPP1R15A knockdown increased the phosphorylated form of eukaryotic initiation factor 2α (eIF2α); knockdown of eIF2α reduced the inhibitory effects of Sephin1 on NFATc1-luc transcription and osteoclast formation. Furthermore, Sephin1 or PPP1R15A knockdown suppressed osteoclastogenesis in CD14+ monocytes from osteoporosis patients. In OVX mice, injection of Sephin1 (4, 8 mg/kg, i.p.) every two days for 6 weeks significantly inhibited bone loss, and restored bone destruction and decreased TRAP-positive cells. This study has identified PPP1R15A as a novel target for osteoclast differentiation, and genetic inhibition or allosteric inhibitors of PPP1R15A, such as Sephin1, can be used to treat osteoporosis. This study revealed that PPP1R15A expression was increased in osteoporosis in both human and mice. Inhibition of PPP1R15A by specific knockdown or an allosteric inhibitor Sephin1 mitigated murine osteoclast formation in vitro and attenuated ovariectomy-induced osteoporosis in vivo. PPP1R15A inhibition also suppressed pathogenic osteoclastogenesis in CD14+ monocytes from osteoporosis patients. These results identify PPP1R15A as a novel regulator of osteoclastogenesis and a valuable therapeutic target for osteoporosis.

The development and validation of a prediction model for imminent vertebral osteoporotic fracture in postmenopausal women.

PURPOSE: This study aimed to develop and validate a new model that focused on the risk of imminent vertebral fractures in women with osteoporosis. METHODS: Data from 2,048 patients were extracted from three hospitals, of which 1,720 patients passed the inclusion and exclusion screen. The patients from Nanfang Hospital (NFH) were randomized at a 2:1 ratio to create a training cohort (n = 709) and an internal validation cohort (n = 355), with the patients from the other two hospitals (n = 656) used for external validation. The risk factors included in the imminent osteoporotic vertebral compression fractures (OVCFs) prediction model (labelled TVF) were sorted by the least absolute shrinkage and selection operator and constructed by logistic regression. The area under the receiver operating characteristic curve (AUC), the decision curve, and the clinical impact curves of the optimal model were analyzed to verify the model. RESULTS: There were 138 and 161 fresh fractures in NFH and the other two hospitals, respectively. The lowest BMD T value and the history of vertebral fracture were integrated into the TVF model. The prediction power of TVF was demonstrated by the AUCs of 0.788 (95% confidence interval [CI], 0.728-0.849) in the training cohort and 0.774 (95% CI, 0.705-0.842) in the internal validation cohort, and 0.790 (95% CI, 0.742-0.839) and 0.741 (95% CI, 0.668-0.813) in the external validation cohorts. CONCLUSION: The TVF model demonstrated good discrimination to stratify the imminent risk of OVCFs. We therefore consider the model as a pertinent commencement in the search for more accurate imminent OVCFs prediction.

Spatially Resolved Metabolomics Combined with the 3D Tumor-Immune Cell Coculture Spheroid Highlights Metabolic Alterations during Antitumor Immune Response.

The metabolic cross-talk between tumor and immune cells plays key roles in immune cell function and immune checkpoint blockade therapy. However, the characterization of tumor immunometabolism and its spatiotemporal alterations during immune response in a complex tumor microenvironment is challenging. Here, a 3D tumor-immune cell coculture spheroid model was developed to mimic tumor-immune interactions, combined with mass spectrometry imaging-based spatially resolved metabolomics to visualize tumor immunometabolic alterations during immune response. The inhibition of T cells was simulated by coculturing breast tumor spheroids with Jurkat T cells, and the reactivation of T cells can be monitored through diminishing cancer PD-L1 expressions by berberine. This system enables simultaneously screening and imaging discriminatory metabolites that are altered during T cell-mediated antitumor immune response and characterizing the distributions of berberine and its metabolites in tumor spheroids. We discovered that the transport and catabolism of glutamine were significantly reprogrammed during the antitumor immune response at both metabolite and enzyme levels, corresponding to its indispensable roles in energy metabolism and building new biomass. The combination of spatially resolved metabolomics with the 3D tumor-immune cell coculture spheroid visually reveals metabolic interactions between tumor and immune cells and possibly helps decipher the role of immunometabolic alterations in tumor immunotherapy.

CT for the evaluation of myocardial extracellular volume with MRI as reference: a systematic review and meta-analysis.

OBJECTIVE: Myocardial extracellular volume (ECV) fraction is an important imaging biomarker in clinical decision-making. CT-ECV is a potential alternative to MRI for ECV quantification. We conducted a meta-analysis to comprehensively assess the reliability of CT for ECV quantification with MRI as a reference. METHODS: We systematically searched PubMed, EMBASE, and the Cochrane Library for relevant articles published since the establishment of the database in July 2022. The articles comparing CT-ECV with MRI as a reference were included. Meta-analytic methods were applied to determine the pooled weighted bias, limits of agreement (LOA), and correlation coefficient (r) between CT-ECV and MRI-ECV. RESULTS: Seventeen studies with a total of 459 patients and 2231 myocardial segments were included. The pooled mean difference (MD), LOA, and r for ECV quantification at the per-patient level was (0.07%; 95% LOA: - 0.42 to 0.55%) and 0.89 (95% CI: 0.86-0.91), respectively, while on the per-segment level was (0.44%; 95% LOA: 0.16-0.72%) and 0.84 (95% CI: 0.82-0.85), respectively. The pooled r from studies with the ECViodine method for ECV quantification was significantly higher compared to those with the ECVsub method (0.94 (95% CI: 0.91-0.96) vs. 0.84 (95% CI: 0.80-0.88), respectively, p = 0.03). The pooled r from septal segments was significantly higher than those from non-septal segments (0.88 (95% CI: 0.86-0.90) vs. 0.76 (95% CI: 0.71-0.90), respectively, p = 0.009). CONCLUSION: CT showed a good agreement and excellent correlation with MRI for ECV quantification and is a potentially attractive alternative to MRI. CLINICAL RELEVANCE STATEMENT: The myocardial extracellular volume fraction can be acquired using a CT scan, which is not only a viable alternative to myocardial extracellular volume fraction derived from MRI but is also less time-consuming and costly for patients. KEY POINTS: • Noninvasive CT-ECV is a viable alternative to MRI-ECV for ECV quantification. • CT-ECV using the ECViodine method showed more accurate myocardial ECV quantification than ECVsub. • Septal myocardial segments showed lower measurement variability than non-septal segments for the ECV quantification.

The Underappreciated Placebo Effects and Responses in Randomized Controlled Trials on Neck Pain: A Systematic Review With Meta-analysis.

OBJECTIVE: To quantify placebo effects and responses in randomized controlled trials (RCTs) on neck pain and explore how they would influence the treatment of neck pain. DATA SOURCES: We searched MEDLINE (PubMed), EMBASE (Ovid), CINAHL (EBSCO), Physiotherapy Evidence Database (PEDro), and World Health Organization International Clinical Trials Registry Platform from the inception of August 15, 2021, to identify relevant RCTs. STUDY SELECTION AND DATA EXTRACTION: The abstracts and full texts of potential studies were independently screened, and data extraction was also independently performed by 2 researchers. Scales of the score measuring neck pain and the scores both at baseline and the endpoint were extracted. DATA SYNTHESIS: A total of 60 RCTs were included. The mean improvement in the pain score after placebo treatment was 15.65 (mean difference [MD]=-15.65, 95% confidence interval; CI [-19.19, -12.12]; P<.05), which we defined as the placebo response. In the active groups, it was 25.91 (MD=-25.91, 95% CI [-29.15, -22.68]; P<.05), and in the no-treatment groups, it was 5.80 (MD=-5.80, 95% CI [13.28, 1.69]; P=.13). Using the 3 MDs from the 3 groups, the placebo effect was calculated to account for 38.0% of the pain score improvement in the active group. CONCLUSIONS: The pain scores of patients with neck pain were reduced after treatment with placebos, but the magnitude of pain score reduction was not clinically significant enough. The 38.0% amount of pain score reduction in patients treated with active interventions was caused by placebo. Interventions with considerable clinically significance for neck pain were still required.

Effectiveness of nurse-led multidisciplinary interventions in primary health care: A systematic review and meta-analysis.

AIM: This review aimed to synthesize the available evidence on the effectiveness of nurse-led multidisciplinary interventions in primary health care. METHODS: The following Chinese and English databases were searched for relevant articles: PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang and Chinese Biomedical Literature Database (CBM), from the establishment of the databases until the last updating search 1 April 2022. Two researchers screened the studies independently and extracted the data. Meta-analysis was performed using the RevMan 5.3 software. RESULTS: A total of 12 studies were included in this review. It was found that nurse-led multidisciplinary interventions significantly shortened patients' length of stay in hospital (standardized mean differences [SMD] = -1.28, 95%CI: -2.03 to -0.54; P<0.001) and decreased incidences of complications (RR = 0.24, 95%CI:0.10 to 0.54; P = 0.0006) compared to the control group, and lowered patients' anxiety levels (SMD = -1.21, 95%CI: -1.99 to -0.44; P<0.01) and depression levels (SMD = -1.85, 95%CI: -3.42 to -0.28; P<0.0001). Furthermore, the results of subgroup analysis indicated that nurse-led multidisciplinary interventions had significant effects on patients' self-management ability (SMD = 4.45, 95%CI:2.45 to 6.44; P<0.0001) and quality of life (SMD = 1.01, 95%CI: 0.63 to 1.40; P<0.0001) compared to the control group. CONCLUSIONS: Nurse-led multidisciplinary interventions had strong effects in primary health care, contributing to shorten patients' length of stay in hospital, decrease incidences of complications and reduce the levels of anxiety and depression. Moreover, nurse-led multidisciplinary interventions also improved patients' self-management ability and quality of life.

Regeneration of skin appendages and nerves: current status and further challenges.

Tissue-engineered skin (TES), as an analogue of native skin, is promising for wound repair and regeneration. However, a major drawback of TES products is a lack of skin appendages and nerves to enhance skin healing, structural integrity and skin vitality. Skin appendages and nerves are important constituents for fully functional skin. To date, many studies have yielded remarkable results in the field of skin appendages reconstruction and nerve regeneration. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients' quality of life. Current strategies to create skin appendages and sensory nerve regeneration are mainly based on different types of seeding cells, scaffold materials, bioactive factors and involved signaling pathways. This article provides a comprehensive overview of different strategies for, and advances in, skin appendages and sensory nerve regeneration, which is an important issue in the field of tissue engineering and regenerative medicine.

Associations between folate metabolism enzyme polymorphisms and breast cancer: A meta-analysis.

We performed this meta-analysis to explore associations between folate metabolism enzyme polymorphisms and breast cancer (BC) in a larger pooled population. Systematic literature research was performed to identify eligible studies for pooled analyses. Totally 92 genetic association studies were included for analyses. The pooled analyses revealed significant findings for MTRR rs1801394 polymorphism in South Asians, for MTR rs1805087 polymorphism in Caucasians and East Asians, and for MTHFR rs1801133 polymorphism in East Asians. In conclusion, the present meta-analysis indicated that MTRR rs1801394, MTR rs1805087, and MTHFR rs1801133 polymorphisms could be used to identify individuals at high risk of developing BC.

Unrevealing the coupling coordination degree between atmospheric CO2 concentration and human activities from geospatial and temporal perspectives.

Anthropogenic activities exhibit intricate and significant relationships with atmospheric CO2 concentration. Dissecting the spatiotemporal patterns and potential drivers of their coupling coordination relationships from geospatial and temporal perspectives contributes to the benign coordinating development between the two. The coupling coordination degree (D) and types, and their potential influencing factors in China were explored using a coupling coordination model, emerging hotspot analysis, and Multiscale Geographically Weighted Regression model. Results revealed D was dominated by basic coordination in China with notable spatial disparities. Generally, D exhibited higher values in the eastern regions and lower values in the western regions divided by the Hu Line. Furthermore, Central and East China exhibited lower coordination degrees compared to other eastern regions. A total of 15 spatiotemporal dynamic patterns were identified across China. Hot spot patterns were concentrated in the eastern regions of the Hu Line, while cold spots were mainly observed in the western regions. The coupling coordination types exhibited a distinct pattern of "coordination in the east and incoherence in the west, divided by the Hu Line". Over time, there was a shift from lower-level to more benign coordinated types. Additionally, the D and coupling coordination types demonstrated significant spatial agglomeration characteristics, and intercity alliances and enhanced collaborations are essential for sustaining low-carbon improvements. The mechanisms and intensities of various factors on D exhibited spatiotemporal differences. The key drivers influencing coupling coordination types varied depending on the specific type. Additionally, the scales of these drivers affecting D changed over time. It is essential to consider natural and meteorological factors and their scaling effects when developing policies to enhance coupling coordination level. These results have significant implications for assessing the relationship between atmospheric CO2 and human activities and provide guidance for implementing effective low-carbon development policies.

Spatiotemporal patterns of net regional productivity and its causes throughout Ordos, China.

A comprehensive understanding of the terrestrial carbon sink is essential for proficient regional carbon management. However, previous studies predominantly relied on net ecosystem productivity (NEP) as an indicator of regional carbon sink, overlooking the impacts of carbon emissions from physical processes and carbon leakage associated with anthropogenic activities. In this study, net region productivity (NRP), a vital metric representing carbon sink dynamics in regional multi-landscape ecosystems, was employed to systematically analyze the patterns, trends, and causes of carbon sink in Ordos. The results revealed that spatially averaged NRP in Ordos was 70.334 g·m-2·a-1, indicating a carbon sink effect. The coefficient of variation of NRP was 68.035%, with a higher NRP in the southern region. Normalized difference vegetation index (NDVI) predominantly controlled the spatial heterogeneity of NRP in Ordos, while precipitation emerged as the primary climatic factor influencing spatial differences in NRP. Regional variations in the impact of environmental factors on NRP were evident. In most areas, NRP showed a notable increasing trend influenced by various factors. Specifically, the simultaneous rise in NDVI and improvements in hydrothermal conditions contributed to the gradual elevation of NRP, each with varying degrees of influence across Ordos and its sub-regions.

Mass spectrometry imaging-based metabolomics highlights spatial metabolic alterations in three types of liver injuries.

Liver's distinctive function renders it highly susceptible to diverse damage sources. Characterizing the metabolic profiles and spatial signatures in different liver injuries is imperative for early diagnosis and etiology-oriented treatment. In this comparative study, we conducted whole-body spatial metabolomics on zebrafish with liver injury induced by ethanol (EtOH), acetaminophen (APAP), and thioacetamide (TAA). The two specific levels, the whole-body and liver-specific metabolic profiles, as well as their regional distributions, were systematically mapped in situ by mass spectrometry imaging, which is distinct from conventional LC-MS and GC-MS methods. We found that liver injury regions exhibited more pronounced metabolic reprogramming than the entire organism, leading to significant alterations in eight fatty acids, three phospholipids, and four low-molecular-weight metabolites. More importantly, fatty acids as well as small molecule metabolites including glutamine, glutamate, taurine and malic acid displayed contrasting changes between alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). In addition, phospholipids, including Lyso PC (16:0) and Lyso PE (18:0), demonstrated notable down-regulation in all damaged liver, whereas PC (34:1) underwent upregulation. This study not only deepens insights into distinct potential biomarkers for liver injuries, but also underscores spatial metabolomics as a powerful tool to elucidate possible pathogenic mechanisms in other metabolic diseases.

miRNAs in patients with alcoholic liver disease: a systematic review and meta-analysis.

INTRODUCTION: Alcoholic liver disease (ALD) encompasses a spectrum of liver conditions, including liver steatosis, alcoholic hepatitis (AH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). microRNAs (miRNAs) have garnered significant interest as potential biomarkers for ALD. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) systemically from inception to June 2024. All extracted data was stratified according to the stages of ALD. The vote-counting strategy performed a meta-analysis on miRNA expression profiles. RESULTS: We included 40 studies. In serum of individuals with alcohol-use vs. no alcohol-use, miRNA-122 and miRNA-155 were upregulated, and miRNA-146a was downregulated. In patients with ALD vs. healthy controls, miRNA-122 and miRNA-155 were also upregulated and miRNA-146a was downregulated. However, in patients with AH vs. healthy individuals, only the serum miRNA-122 level was upregulated. Due to insufficient data on diagnostic accuracy, we failed to conclude the ability of miRNAs to distinguish different stages of ALD-related liver fibrosis. The results for ALD-related HCC were also insufficient and controversial. CONCLUSIONS: Circulating miRNA-122 was the most promising biomarker to manage individuals with ALD. More studies were needed for the diagnostic accuracy of miRNAs in ALD. REGISTRATION: This protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) (www.crd.york.ac.uk/prospero/) with registration number CRD42023391931.

Identification of patients with internet gaming disorder via a radiomics-based machine learning model of subcortical structures in high-resolution T1-weighted MRI.

It is of vital importance to establish an objective and reliable model to facilitate the early diagnosis and intervention of internet gaming disorder (IGD). A total of 133 patients with IGD and 110 healthy controls (HCs) were included. We extracted radiomic features of subcortical structures in high-resolution T1-weighted MRI. Different combinations of four feature selection methods (analysis of variance, Kruskal-Wallis, recursive feature elimination and relief) and ten classification algorithms were used to identify the most robust combined models for distinguishing IGD patients from HCs. Furthermore, a nomogram incorporating radiomic signatures and independent clinical factors was developed. Calibration curve and decision curve analyses were used to evaluate the nomogram. The combination of analysis of variance selector and logistic regression classifier identified that the radiomic model constructed with 20 features from the right caudate nucleus and amygdala showed better IGD screening performance. The radiomic model produced good areas under the curves (AUCs) in the training, validation and test cohorts (AUCs of 0.961, 0.903 and 0.895, respectively). In addition, sex, internet addiction test scores and radiomic scores were included in the nomogram as independent risk factors for IGD. Analysis of the correction curve and decision curve showed that the clinical-radiomic model has good reliability (C-index: 0.987). The nomogram incorporating radiomic features of subcortical structures and clinical characteristics achieved satisfactory classification performance and could serve as an effective tool for distinguishing IGD patients from HCs.

Three types of dermal grafts in rats: the importance of mechanical property and structural design.

BACKGROUND: To determine how the mechanical property and micro structure affect tissue regeneration and angiogenesis, three types of scaffolds were studied. Acellular dermal matrices (ADM), produced from human skin by removing the epidermis and cells, has been widely used in wound healing because of its high mechanical strength. Collagen scaffolds (CS) incorporated with poly(glycolide-co-L-lactide) (PLGA) mesh forms a well-supported hybrid dermal equivalent poly(glycolide-co-L-lactide) mesh/collagen scaffolds (PMCS). We designed this scaffold to enhance the CS mechanical property. These three different dermal substitutes-ADM, CS and PMCSs are different in the tensile properties and microstructure. METHODS: Several basic physical characteristics of dermal substitutes were investigated in vitro. To characterize the angiogenesis and tissue regeneration, the materials were embedded subcutaneously in Sprague-Dawley (SD) rats. At weeks 1, 2, 4 and 8 post-surgery, the tissue specimens were harvested for histology, immunohistochemistry and real-time quantitative PCR (RT-qPCR). RESULTS: In vitro studies demonstrated ADM had a higher Young's modulus (6.94 MPa) rather than CS (0.19 MPa) and PMCS (3.33 MPa) groups in the wet state. Compared with ADMs and CSs, PMCSs with three-dimensional porous structures resembling skin and moderate mechanical properties can promote tissue ingrowth more quickly after implantation. In addition, the vascularization of the PMCS group is more obvious than that of the other two groups. The incorporation of a PLGA knitted mesh in CSs can improve the mechanical properties with little influence on the three-dimensional porous microstructure. After implantation, PMCSs can resist the contraction and promote cell infiltration, neotissue formation and blood vessel ingrowth, especially from the mesh side. Although ADM has high mechanical strength, its vascularization is poor because the pore size is too small. In conclusion, the mechanical properties of scaffolds are important for maintaining the three-dimensional microarchitecture of constructs used to induce tissue regeneration and vascularization. CONCLUSION: The results illustrated that tissue regeneration requires the proper pore size and an appropriate mechanical property like PMCS which could satisfy these conditions to sustain growth.

In vitro evaluation of Panax notoginseng Rg1 released from collagen/chitosan-gelatin microsphere scaffolds for angiogenesis.

BACKGROUND: The emergence of skin substitutes provides a new approach for the treatment of wound repair and healing. The consistent and steady release of angiogenic factors is an important factor in the promotion of angiogenesis in skin substitutes, which usually lack, yet need, a vascular network. METHODS: In this study, ginsenoside Rg1, a natural compound isolated from Panax notoginseng (PNS), was incorporated into a collagen/chitosan-gelatin microsphere (CC-GMS) scaffold. The cumulative release kinetics were evaluated, and the effects of the released Rg1 on human umbilical vein endothelial cells (HUVECs) behavior, including proliferation, migration, tube formation, cell-cycle progression, cell apoptosis, and vascular endothelial growth factor (VEGF) secretion, were investigated. Additionally, HUVECs were cultured on the CC-GMS scaffold to test its biocompatibility. Standard Rg1 and VEGF were used as positive controls. RESULTS: The results indicated that the CC-GMS scaffold had good release kinetics. The Rg1 released from the CC-GMS scaffold did not lose its activity and had a significant effect on HUVEC proliferation. Both Rg1 and VEGF promoted HUVEC migration and tube formation. Rg1 did not induce HUVEC apoptosis but instead promoted HUVEC progression into the S and G2/M phases of the cell cycle. Rg1 significantly increased VEGF secretion compared with that in the control group. HUVEC culture on the CC-GMS scaffold indicated that this scaffold has good biocompatibility and that CC-GMS scaffolds containing different concentrations of Rg1 promote HUVEC attachment in a dose- and time-dependent manner. CONCLUSIONS: Rg1 may represent a new class of angiogenic agent that can be encapsulated in CC-GMS scaffolds to exert angiogenic effects in engineered tissue.

Associations between the kynurenine pathway and the brain in patients with major depressive disorder-A systematic review of neuroimaging studies.

Previous studies have indicated that an imbalance in the kynurenine (KYN) pathway is an important pathophysiological mechanism of depression. Several studies have reported that an imbalance in the KYN pathway and its metabolites is associated with abnormalities in cerebral structure and function in depression, but the available evidence has been inconsistent. In this review, we systematically reviewed and integrated the findings concerning the associations between the KYN pathway and the brain in patients with major depressive disorder (MDD). A total of 22 neuroimaging studies were ultimately included in the present study. The neuroimaging modalities used in the studies included structural magnetic resonance imaging (MRI), diffusion tensor imaging, functional MRI, magnetic resonance spectroscopy, arterial spin labelling and positron emission tomography. The results revealed that an imbalance in the KYN pathway was associated with structural and functional abnormalities in several brain regions in patients with MDD. The brain regions most frequently associated with an imbalance in the KYN pathway were cortical regions (i.e., anterior cingulate cortex and orbitofrontal cortex), subcortical regions (i.e., striatum, thalamus and amygdala) and white matter fibres (i.e., inner capsule and left superior longitudinal tract). Our study provides robust evidence that cerebral abnormalities associated with the KYN pathway may be the underlying pathophysiological mechanisms of MDD. Future prospective studies are needed to further elucidate the causal relationships between the imbalanced KYN pathway and cerebral abnormalities in patients with MDD.

Involvement of Rictor/mTORC2/Akt/GLUT4 pathway in the regulation of energy metabolism in the gastric smooth muscle of diabetic rats.

Diabetes mellitus can be accompanied by a variety of complications. The purpose of the present study was to characterize the Rictor/mTOR complex 2 (mTORC2)/Akt/glucose transporter 4 (GLUT4) pathway and its effects on energy metabolism in the gastric smooth muscle of diabetic rats. Diabetes was induced in rats using streptozotocin and their phenotype was compared with untreated rats. The relationship between gastric motility and energy metabolism was analyzed by comparing the contraction and ATP metabolism of muscle strips. Western blotting was used to detect the expression of key proteins in the pathway. The diabetic rats demonstrated less frequent and less powerful gastric smooth muscle contractions. The concentrations of ADP, AMP, and ATP, and the energy charge in gastric smooth muscle changed in different periods of diabetes, and these changes were consistent with changes in mechanistic target of rapamycin (mTOR) protein content. The expression of the key intermediates in signal transduction in the Rictor/mTORC2/Akt/GLUT4 pathway also underwent significant changes. Rictor protein expression increased during the development of diabetes, but the activation of mTORC2 did not increase with the increase in Rictor expression. GLUT4 translocation is regulated by Akt and its expression change during the development of diabetes. These findings suggest that altered energy metabolism is present in gastric smooth muscle that is associated with changes in the Rictor/mTORC2/Akt/GLUT4 pathway. Rictor/mTORC2/Akt/GLUT4 pathway may be involved in the regulation of energy metabolism in the gastric smooth muscle of diabetic rats and the development of diabetic gastroparesis.

Abnormal neonatal brain microstructure in gestational diabetes mellitus revealed by MRI texture analysis.

To investigate the value of MRI texture analysis in evaluating the effect of gestational diabetes mellitus (GDM) on neonatal brain microstructure development, we retrospectively collected images of neonates undergoing head MRI scans, including a GDM group (N1 = 37) and a healthy control group (N2 = 34). MaZda texture analysis software was used to extract the texture features from different sequence images and perform dimensionality reduction, and then the texture features selected by the lowest misjudgement rate method were imported into SPSS software for statistical analysis. In our study, we found that GDM affects the development of the microstructure of the neonatal brain, and different combinations of texture features have different recognition performances, such as different sequences and different brain regions. As a consequence, texture analysis combining multiple conventional MRI sequences has a high recognition performance in revealing the abnormal development of the brain microstructure of neonates born of mothers with GDM.

The progress of silver nanoparticles in the antibacterial mechanism, clinical application and cytotoxicity.

Nanotechnology is a highly promising field, with nanoparticles produced and utilized in a wide range of commercial products. Silver nanoparticles (AgNPs) has been widely used in clothing, electronics, bio-sensing, the food industry, paints, sunscreens, cosmetics and medical devices, all of which increase human exposure and thus the potential risk related to their short- and long-term toxicity. Many studies indicate that AgNPs are toxic to human health. Interestingly, the majority of these studies focus on the interaction of the nano-silver particle with single cells, indicating that AgNPs have the potential to induce the genes associated with cell cycle progression, DNA damage and mitochondrial associated apoptosis. AgNPs administered through any method were subsequently detected in blood and were found to cause deposition in several organs. There are very few studies in rats and mice involving the in vivo bio-distribution and toxicity, organ accumulation and degradation, and the possible adverse effects and toxicity in vivo are only slowly being recognized. In the present review, we summarize the current data associated with the increased medical usage of nano-silver and its related nano-materials, compare the mechanism of antibiosis and discuss the proper application of nano-silver particles.

A review of burnout in college English teachers in China.

College English teachers' job burnout has become prominent in the field of education. Using China National Knowledge Infrastructure (CNKI) database, this review research on burnout of college English language teachers in China from 2006 to 2021. The review demonstrates key research areas including teacher burnout severity and influencing variables related to teacher burnout. Individual factors, such as age, gender, marital status, educational background, professional title, and years of teaching experience are associated with burnout rates. University type and level, teaching-related role overload, scientific research stress induced by promotion, limited job autonomy, a stern hierarchical organizational system, and opaque operating rules are influencing factors discussed. Possible ways to reduce burnout across micro, meso, and macro-levels, along with practical implications and limitations are discussed.