Dysregulated Transcript Expression but Not Function of the Glutamate Transporter EAAT2 in the Dorsolateral Prefrontal Cortex in Schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a serious mental illness with complex pathology, including abnormalities in the glutamate system. Glutamate is rapidly removed from the synapse by excitatory amino acid transporters (EAATs). Changes in the expression and localization of the primary glutamate transporter EAAT2 are found in the brain in central nervous system (CNS) disorders including SCZ. We hypothesize that neuronal expression and function of EAAT2 are increased in the frontal cortex in subjects diagnosed with SCZ. STUDY DESIGN: EAAT2 protein expression and glutamate transporter function were assayed in synaptosome preparations from the dorsolateral prefrontal cortex (DLPFC) of SCZ subjects and age- and sex-matched nonpsychiatrically ill controls. EAAT2 splice variant transcript expression was assayed in enriched populations of neurons and astrocytes from the DLPFC. Pathway analysis of publicly available transcriptomic datasets was carried out to identify biological changes associated with EAAT2 perturbation in different cell types. RESULTS: We found no significant changes in EAAT2 protein expression or glutamate uptake in the DLPFC in SCZ subjects compared with controls (n = 10/group). Transcript expression of EAAT2 and signaling molecules associated with EAAT2b trafficking (CaMKIIa and DLG1) were significantly altered in enriched populations of astrocytes and pyramidal neurons (P < .05) in SCZ (n = 16/group). These changes were not associated with antipsychotic medications. Pathway analysis also identified cell-type-specific enrichment of biological pathways associated with perturbation of astrocyte (immune pathways) and neuronal (metabolic pathways) EAAT2 expression. CONCLUSIONS: Overall, these data support the growing body of evidence for the role of dysregulation of the glutamate system in the pathophysiology of SCZ.

Clinicopathological features of two cases of ETV6-NTRK3 rearranged papillary thyroid carcinoma: a case report.

Rearrangements involving the neurotrophic-tropomyosin receptor kinase (NTRK) gene family (NTRK1, NTRK2, and NTRK3) have been identified as drivers in a wide variety of human cancers. However, the association between NTRK rearranged thyroid carcinoma and clinicopathological characteristics has not yet been established. In our study, we retrospectively reviewed medical records of thyroid cancer patients and identified 2 cases with NTRK rearrangement, no additional molecular alterations were observed in either of these cases. The fusion of the rearrangement in both cases was ETV6(E4)::NTRK3(E14). By analyzing the clinicopathological features of these two cases, we found that both were characterized by multiple tumor nodules, invasive growth, and central lymph node metastases, indicating the follicular subtype of papillary thyroid carcinoma. Immunohistochemical staining profiles showed CD56-, CK19+, Galectin-3+, HBME1+. These clinicopathological features suggest the possibility of ETV6-NTRK3 rearranged thyroid carcinoma and highlight the importance of performing gene fusion testing by FISH or NGS for these patients.

Associations between body mass index and all-cause mortality among individuals with psoriasis: results from the NHANES database retrospective cohort study.

Background: Previous findings imply a potential positive association between BMI and all-cause mortality in individuals with psoriasis, yet direct evidence remains absent. This study aimed to fill this gap. Methods: We utilized data from the National Health and Nutrition Examination Survey (NHANES) for the periods 2003-2006 and 2009-2014. Participants' BMI was categorized as lean (<25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30). Psoriasis status was determined through self-reporting. The main outcome measured was all-cause mortality up to December 2019. We accounted for multiple covariates, such as sociodemographic factors and histories of smoking and alcohol consumption. Our statistical analyses mainly included Kaplan-Meier survival analysis, Restricted Cubic Spline (RCS) and Multivariate Cox Regression (MCR). We also applied propensity score matching (PSM) to verify the robustness of our findings. Results: Among 22,876 participants, 618 (2.70%) reported a history of psoriasis. An overall effect from the MCR analysis showed that, among individuals with psoriasis, a higher baseline BMI was independently associated with an increased risk of all-cause mortality, noting a 5.5% rise in mortality risk per BMI unit [hazard ratio (HR) = 1.055, 95% CI: 1.004-1.110, p = 0.035]. This significant relationship persisted after PSM. A statistically significant positive correlation was consistent among males, smokers, and individuals younger than 60. However, no such association was found in individuals without a history of psoriasis. Additionally, no significant difference in mortality risk was found between lean and overweight groups with psoriasis, according to the RCS regression and stratified analysis. Conclusion: Our findings indicated a trend that, higher BMIs significantly correlated with increased risks of all-cause mortality in people with psoriasis, particularly among obese ones. However, the impact of being overweight on this relationship remains underexplored. Moreover, the necessity to employ alternative metrics beyond BMI for body fat assessment to further investigate these associations is critical.

Overexpression of ATP5F1A in Cardiomyocytes Promotes Cardiac Reverse Remodeling.

BACKGROUND: The mechanism of cardiac reverse remodeling (CRR) mediated by the left ventricular assist device remains unclear. This study aims to identify the specific cell type responsible for CRR and develop the therapeutic target that promotes CRR. METHODS: The nuclei were extracted from the left ventricular tissue of 4 normal controls, 4 CRR patients, and 4 no cardiac reverse remodeling patients and then subjected to single-nucleus RNA sequencing for identifying key cell types responsible for CRR. Gene overexpression in transverse aortic constriction and dilated cardiomyopathy heart failure mouse model (C57BL/6J background) and pathological staining were performed to validate the results of single-nucleus RNA sequencing. RESULTS: Ten cell types were identified among 126 156 nuclei. Cardiomyocytes in CRR patients expressed higher levels of ATP5F1A than the other 2 groups. The macrophages in CRR patients expressed more anti-inflammatory genes and functioned in angiogenesis. Endothelial cells that elevated in no cardiac reverse remodeling patients were involved in the inflammatory response. Echocardiography showed that overexpressing ATP5F1A through cardiomyocyte-specific adeno-associated virus 9 demonstrated an ability to improve heart function and morphology. Pathological staining showed that overexpressing ATP5F1A could reduce fibrosis and cardiomyocyte size in the heart failure mouse model. CONCLUSIONS: The present results of single-nucleus RNA sequencing and heart failure mouse model indicated that ATP5F1A could mediate CRR and supported the development of therapeutics for overexpressing ATP5F1A in promoting CRR.

Anemoside B4 attenuates abdominal aortic aneurysm by limiting smooth muscle cell transdifferentiation and its mediated inflammation.

Abdominal aortic aneurysm (AAA) is a degenerative disease characterized by local abnormal dilation of the aorta accompanied by vascular smooth muscle cell (VSMC) dysfunction and chronic inflammation. VSMC dedifferentiation, transdifferentiation, and increased expression of matrix metalloproteinases (MMPs) are essential causes of AAA formation. Previous studies from us and others have shown that Anemoside B4 (AB4), a saponin from Pulsatilla chinensis, has anti-inflammatory, anti-tumor, and regulatory effects on VSMC dedifferentiation. The current study aimed to investigate whether AB4 inhibits AAA development and its underlying mechanisms. By using an Ang II induced AAA model in vivo and cholesterol loading mediated VSMC to macrophage transdifferentiation model in vitro, our study demonstrated that AB4 could attenuate AAA pathogenesis, prevent VSMC dedifferentiation and transdifferentiation to macrophage-like cells, decrease vascular inflammation, and suppress MMP expression and activity. Furthermore, KLF4 overexpression attenuated the effects of AB4 on VSMC to macrophage-like cell transition and VSMC inflammation in vitro. In conclusion, AB4 protects against AAA formation in mice by inhibiting KLF4 mediated VSMC transdifferentiation and inflammation. Our study provides the first proof of concept of using AB4 for AAA management.

Individualized survival prediction and surgery recommendation for patients with glioblastoma.

Background: There is a lack of individualized evidence on surgical choices for glioblastoma (GBM) patients. Aim: This study aimed to make individualized treatment recommendations for patients with GBM and to determine the importance of demographic and tumor characteristic variables in the selection of extent of resection. Methods: We proposed Balanced Decision Ensembles (BDE) to make survival predictions and individualized treatment recommendations. We developed several DL models to counterfactually predict the individual treatment effect (ITE) of patients with GBM. We divided the patients into the recommended (Rec.) and anti-recommended groups based on whether their actual treatment was consistent with the model recommendation. Results: The BDE achieved the best recommendation effects (difference in restricted mean survival time (dRMST): 5.90; 95% confidence interval (CI), 4.40-7.39; hazard ratio (HR): 0.71; 95% CI, 0.65-0.77), followed by BITES and DeepSurv. Inverse probability treatment weighting (IPTW)-adjusted HR, IPTW-adjusted OR, natural direct effect, and control direct effect demonstrated better survival outcomes of the Rec. group. Conclusion: The ITE calculation method is crucial, as it may result in better or worse recommendations. Furthermore, the significant protective effects of machine recommendations on survival time and mortality indicate the superiority of the model for application in patients with GBM. Overall, the model identifies patients with tumors located in the right and left frontal and middle temporal lobes, as well as those with larger tumor sizes, as optimal candidates for SpTR.

Lipids, apolipoproteins and gestational diabetes mellitus: a Mendelian randomization study.

BACKGROUND: This study investigates the causal relationship between lipid traits and GDM in an effort to better understand the aetiology of GDM. METHODS: Employing a two-sample Mendelian Randomization (MR) framework, we used Single Nucleotide Polymorphisms (SNPs) as instrumental variables to examine the impact of lipids and apolipoproteins on GDM. The research comprised univariable and multivariable MR analyses, with a prime focus on individual and combined effects of lipid-related traits. Statistical techniques included the fixed-effect inverse variance weighted (IVW) method and supplementary methods such as MR-Egger for comprehensive assessment. RESULTS: Our findings revealed the following significant associations: apoA-I and HDL cholesterol were inversely correlated with GDM risk, while triglycerides showed a positive correlation. In multivariable analysis, apoA-I consistently exhibited a strong causal link with GDM, even after adjusting for other lipids and Body Mass Index (BMI). CONCLUSION: The study demonstrates a significant causal relationship between apoA-I and GDM risk.

Effects of plant diversity and community structure on ecosystem multifunctionality under different grazing potentials in the eastern Eurasian steppe.

Grazing potential represents the potential carrying capacity of steppe livestock production. Understanding the impact of changes in plant diversity and community structure on ecosystem multifunctionality (EMF) at different grazing potentials is crucial for the sustainable management of steppe ecosystems. We examined the associations between plant diversity, community structure, above-ground ecosystem multifunctionality (AEMF), and below-ground ecosystem multifunctionality (BEMF) at various grazing potentials. Our assessment employed generalized linear mixed-effects models and structural equation models to determine the impact of these factors on ecosystem multifunctionality. Our study results indicated that ecosystem multifunctionality differed depending on the level of grazing potential and decreased as grazing potential declined. The impact of plant diversity and community structure on above- and below-ground ecosystem multifunctionality varied. Plant diversity and community structure correlated more with AEMF than BEMF. Plant diversity had the most significant effect on EMF under high grazing potential, while community structure had the greatest effect on EMF under moderate and low grazing potential. These improve our understanding of the correlation between steppe plant diversity, community structure, and above- and below-ground ecosystem multifunctionality. This understanding is necessary to develop strategies to increase plant diversity or regulate community structure and the sustainability of steppes.

Single-Cell Transcriptomic Analysis Reveals Myocardial Fibrosis Mechanism of Doxorubicin-Induced Cardiotoxicity.

Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the specific cellular and molecular mediators driving doxorubicin-induced cardiac fibrosis, and the relative impact of different cell populations on cardiac fibrosis, remain unclear.This study aimed to explore the mechanism of doxorubicin-induced cardiotoxicity and myocardial fibrosis and to find potential therapeutic targets. Single-cell RNA sequencing was used to analyze the transcriptome of non-cardiomyocytes from normal and doxorubicin-induced chronic cardiotoxicity in mouse model heart tissue.We established a mouse model of doxorubicin-induced cardiotoxicity with a well-defined fibrotic phenotype. Analysis of single-cell sequencing results showed that fibroblasts were the major origin of extracellular matrix in doxorubicin-induced myocardial fibrosis. Further resolution of fibroblast subclusters showed that resting fibroblasts were converted to matrifibrocytes and then to myofibroblasts to participate in the myocardial remodeling process in response to doxorubicin treatment. Ctsb expression was significantly upregulated in fibroblasts after doxorubicin-induced.This study provides a comprehensive map of the non-cardiomyocyte landscape at high resolution, reveals multiple cell populations contributing to pathological remodeling of the cardiac extracellular matrix, and identifies major cellular sources of myofibroblasts and dynamic gene-expression changes in fibroblast activation. Finally, we used this strategy to detect potential therapeutic targets and identified Ctsb as a specific target for fibroblasts in doxorubicin-induced myocardial fibrosis.

Removal of Pb pollution using alginate-coupled magnetic sludge biochar: Solidification and stabilization behavior and electron promotion mechanisms.

Environmental and human health problems caused by Pb pollution have attracted much attention, and solidification and stabilization are effective means for its remediation. Improving the ability of biochar to remediate heavy metals through modification is the focus of current biochar research. This study used calcium-alginate gel (GB) and Fe3+ (magnetic) to encapsulate and improve sludge biochar (SB), and explored the adsorption behavior and passivation mechanism of Pb2+ on it from outside to inside. The magnetic-biochar (MB) in magnetic-biochar-gel microspheres (MBGB) showed a homogeneous dispersion and part of the Fe ion was detached from the MB into the three-dimensional pores of the gel. The results of kinetic, isothermal and pH adsorption experiments showed that the MBGB has 108.4 % and 200 % higher Pb2+ adsorption capacity and rate than SB and can be applied to pH 3-9. The adsorption of Pb2+ by MBGB is a multilayer adsorption with both physical and chemical mechanisms. Mineralogical and electrochemical results demonstrate that the cross-linking of the gel with magnetic-biochar (MB) can provide a directional diffusion channel for Pb2+ from the outside to the inside. The electron transfer rate of MBGB was significantly higher than that of SB (222.2 %) after the reaction. The dissolved cations and electrons on the MB guide Pb2+ from the MBGB surface to the internal MB quickly via accelerating the electron transfer and migration rate between Pb2+ and MB. Subsequently, the abundance of PO43- on the MB ensures stable mineral precipitation (Pyromorphite). Moreover, four-step extraction analysis confirmed that most of Pb2+ in MBGB was stable (36.2 % acid-soluble and 47.6 % non-bioavailable). Meanwhile, the Pb adsorption efficiency of MBGB was still >93.0 % after three cycles of adsorption-desorption. Excellent reuse performance and stability guarantee the environmental security of MBGB. The results of the study provide theoretical support for the efficient treatment of Pb2+ polluted water assisted by gel materials.

Characterization of ovarian progenitor cells for their potential to generate steroidogenic theca cells in vitro.

In brief: Progenitor cells with ovulation-related tissue repair activity were identified with defined markers (LGR5, EPCR, LY6A, and PDGFRA), but their potentials to form steroidogenic cells were not known. This study shows that the cells can generate progenies with different steroidogenic activities. Abstract: Adult mammalian ovaries contain stem/progenitor cells necessary for folliculogenesis and ovulation-related tissue rupture repair. Theca cells are recruited and developed from progenitors during the folliculogenesis. Theca cell progenitors were not well defined. The aim of current study is to compare the potentials of four ovarian progenitors with defined markers (LY6A, EPCR, LGR5, and PDGFRA) to form steroidogenic theca cells in vitro. The location of the progenitors with defined makers was determined by immunohistochemistry and immunofluorescence staining of ovarian sections of adult mice. Different progenitor populations were purified by magnetic-activated cell sorting (MACS) and/or fluorescence-activated cell sorting (FACS) techniques from ovarian cell preparation and were tested for their abilities to generate steroidogenic theca cells in vitro. The cells were differentiated with a medium containing LH, ITS, and DHH agonist for 12 days. The results showed that EPCR+ and LGR5+ cells primarily distributed along the ovarian surface epithelium (OSE), while LY6A+ cells distributed in both the OSE and parenchyma. However, PDGFRA+ cells were exclusively located in interstitial compartment. When the progenitors were purified by these markers and differentiated in vitro, LY6A+ and PDGFRA+ cells formed steroidogenic cells expressing both CYP11A1 and CYP17A1 and primarily producing androgens, showing characteristics of theca-like cells, while LGR5+ cells generated steroidogenic cells devoid of CYP17A1 expression and androgen production, showing a characteristic of progesterone-producing cells (granulosa- or lutea-like cells). In conclusion, progenitors from both OSE and parenchyma of adult mice are capable of generating steroidogenic cells with different steroidogenic capacities, showing a possible lineage preference.

Source Tracing of Kidney Injury via the Multispectral Fingerprint Identified by Machine Learning-Driven Surface-Enhanced Raman Spectroscopic Analysis.

Early diagnosis of drug-induced kidney injury (DIKI) is essential for clinical treatment and intervention. However, developing a reliable method to trace kidney injury origins through retrospective studies remains a challenge. In this study, we designed ordered fried-bun-shaped Au nanocone arrays (FBS NCAs) to create microarray chips as a surface-enhanced Raman scattering (SERS) analysis platform. Subsequently, the principal component analysis (PCA)-two-layer nearest neighbor (TLNN) model was constructed to identify and analyze the SERS spectra of exosomes from renal injury induced by cisplatin and gentamycin. The established PCA-TLNN model successfully differentiated the SERS spectra of exosomes from renal injury at different stages and causes, capturing the most significant spectral features for distinguishing these variations. For the SERS spectra of exosomes from renal injury at different induction times, the accuracy of PCA-TLNN reached 97.8% (cisplatin) and 93.3% (gentamicin). For the SERS spectra of exosomes from renal injury caused by different agents, the accuracy of PCA-TLNN reached 100% (7 days) and 96.7% (14 days). This study demonstrates that the combination of label-free exosome SERS and machine learning could serve as an innovative strategy for medical diagnosis and therapeutic intervention.

Could the YEARS algorithm be applied to evaluate suspected pulmonary embolism in hospitalized women after cesarean section?

OBJECTIVE: To evaluate the effectiveness of the YEARS algorithm for excluding pulmonary embolism (PE) in hospitalized women after cesarean section. METHODS: This retrospective study included postpartum women who gave birth by cesarean section and received computed tomography pulmonary angiography (CTPA) because of suspected PE in the obstetric department between 2015 and 2021. We used the YEARS algorithm in these women retrospectively and assessed its performance to evaluate whether the algorithm could be reliably applied in such cases. RESULTS: In all, 225 women were included in the study, of whom 29 (12.9%) women were positive for PE according to the results of CTPA. Upon retrospective application of the YEARS algorithm, 188 (83.6%) women had no YEARS items, while 37 (16.4%) women had YEARS items. Combining the results with D-dimer levels revealed that only 12 (5.3%) women did not need to undergo CTPA, and none showed PE. CONCLUSION: The YEARS algorithm could be applied to exclude PE in hospitalized women in the early post-cesarean period. However, the specificity of the YEARS algorithm was very low, and the D-dimer cut-off for ruling out PE in women after early cesarean section should be further studied and optimized.

Cesarean section "en caul" in preterm twin pregnancy: experience of a single center.

PURPOSE: The "en caul" cesarean section (CS) is a method to keep the amnion intact during CS. This amnion protection effect may have benefits in preterm twin pregnancy. This study aimed to explore the benefits and risks of this method in preterm twin pregnancy. METHODS: This study is a retrospective analysis of preterm twin pregnancies underwent CS in West China Second University Hospital of Sichuan University from January 2011 to December 2022. Data on maternal and fetal outcomes were collected. Univariable analyses and multivariate logistic regression analyses were applied. The level of significance was set at p < 0.05. RESULTS: A total of 182 patients were included (90 in the "en caul" group, 92 in the conventional group). "en caul" CS was associated with lower incidence for respiratory distress (aOR 0.47, 95% CI 0.25-0.88, for the first fetus; aOR 0.42, 95% CI 0.21-0.82, for the second fetus). This method was proved to have beneficial effects in improving the Apgar scores at 1st minute and reducing the mechanical ventilation rate in the second neonates (aOR 0.41, 95% CI 0.19-0.88). CONCLUSION: "En caul" CS is an easy and safe technique to perform during CS for preterm twin pregnancy. The efficacy and safety of this method could be tested by future studies with larger sample size.

An Aerial Image Detection Algorithm Based on Improved YOLOv5.

To enhance aerial image detection in complex environments characterized by multiple small targets and mutual occlusion, we propose an aerial target detection algorithm based on an improved version of YOLOv5 in this paper. Firstly, we employ an improved Mosaic algorithm to address redundant boundaries arising from varying image scales and to augment the training sample size, thereby enhancing detection accuracy. Secondly, we integrate the constructed hybrid attention module into the backbone network to enhance the model's capability in extracting pertinent feature information. Subsequently, we incorporate feature fusion layer 7 and P2 fusion into the neck network, leading to a notable enhancement in the model's capability to detect small targets. Finally, we replace the original PAN + FPN network structure with the optimized BiFPN (Bidirectional Feature Pyramid Network) to enable the model to preserve deeper semantic information, thereby enhancing detection capabilities for dense objects. Experimental results indicate a substantial improvement in both the detection accuracy and speed of the enhanced algorithm compared to its original version. It is noteworthy that the enhanced algorithm exhibits a markedly improved detection performance for aerial images, particularly under real-time conditions.

Low-molecular-weight heparin and preeclampsia - does the sword cut both ways? Three case reports and review of literature.

BACKGROUND: Low-molecular-weight heparins (LMWH) are the most commonly used anticoagulants during pregnancy. It is considered to be the drug of choice due to its safety in not crossing placenta. Considering the beneficial effect in the improvement of microcirculation, prophylactic application of LMWH in patients with preeclampsia became a trend. However, the bleeding risk related with LMWH in preeclampsia patients has seldomly been evaluated. This current study aimed to identify the potential risks regarding LMWH application in patients with preeclampsia. CASE SUMMARY: Herein we present a case series of three pregnant women diagnosed with preeclampsia on LMWH therapy during pregnancy. All the cases experienced catastrophic hemorrhagic events. After reviewing the twenty-one meta-analyses, the bleeding risk related with LMWH seems ignorable. Only one study analyzed the bleeding risk of LMWH and found a significantly higher risk of developing PPH in women receiving LMWH. Other studies reported minor bleeding risks, none of these were serious enough to stop LMWH treatment. Possibilities of bleeding either from uterus or from intrabdominal organs in preeclampsia patients on LMWH therapy should not be ignored. Intensive management of blood pressure even after delivery and homeostasis suture in surgery are crucial. CONCLUSION: Consideration should be given to the balance between benefits and risks of LMWH in patients with preeclampsia.