Celastrol inhibits mouse B16-F10 melanoma cell survival by regulating the PI3K/AKT/mTOR signaling pathway and repressing HIF-1α expression.

OBJECTIVE: Melanoma, with its high degree of malignancy, stands as one of the most dangerous skin cancers and remains the primary cause of death from skin cancer. With studies demonstrating the potential of traditional Chinese medicine to intervene and treat melanoma, we turned our attention to celastrol. Celastrol is a triterpene compound extracted from the traditional Chinese medicine derived from Tripterygium wilfordii. Previous studies have shown that celastrol exerts inhibitory effects on various malignant tumors, including melanoma. Hence, our goal was to clarify the impact of celastrol on cell viability, apoptosis, and cell cycle progression by elucidating its effects on the PI3K/AKT/mTOR pathway. METHODS: CCK-8 and wound healing assays were used to determine the effect of celastrol on the viability and migration of B16-F10 cells. Changes in cell apoptosis, cell cycle, reactive oxygen species (ROS), and mitochondrial membrane potential were detected by flow cytometry. PI3K/AKT/mTOR pathway proteins and HIF-α mRNA expression in B16-F10 cells were detected by western blotting and qPCR. Moreover, the addition of a PI3K activator demonstrated that celastrol could inhibit the function of B16-F10 cells via the PI3K/AKT/mTOR pathway. RESULTS: Celastrol inhibited the viability and migration of B16-F10 cells. Through the inhibition of the PI3K/AKT/mTOR pathway down-regulates the expression of HIF-α mRNA, thereby causing an increase of ROS in cells and a decrease in the mitochondrial membrane potential to promote cell apoptosis and cell cycle arrest. The inhibitory effect of celastrol on B16-F10 cells was further demonstrated by co-culturing with a PI3K activator. CONCLUSION: Celastrol inhibits the function of B16-F10 cells by inhibiting the PI3K/AKT/mTOR cellular pathway and regulating the expression of downstream HIF-α mRNA.

Cellular nucleic acid binding protein facilitates cardiac repair after myocardial infarction by activating ß-catenin signaling.

The regenerative capacity of the adult mammalian heart is limited, while the neonatal heart is an organ with regenerative and proliferative ability. Activating adult cardiomyocytes (CMs) to re-enter the cell cycle is an effective therapeutic method for ischemic heart disease such as myocardial infarction (MI) and heart failure. Here, we aimed to reveal the role and potential mechanisms of cellular nucleic acid binding protein (CNBP) in cardiac regeneration and repair after heart injury. CNBP is highly expressed within 7 days post-birth while decreases significantly with the loss of regenerative ability. In vitro, overexpression of CNBP promoted CM proliferation and survival, whereas knockdown of CNBP inhibited these processes. In vivo, knockdown of CNBP in CMs robustly hindered myocardial regeneration after apical resection in neonatal mice. In adult MI mice, CM-specific CNBP overexpression in the infarct border zone ameliorated myocardial injury in acute stage and facilitated CM proliferation and functional recovery in the long term. Quantitative proteomic analysis with TMT labeling showed that CNBP overexpression promoted the DNA replication, cell cycle progression, and cell division. Mechanically, CNBP overexpression increased the expression of ß-catenin and its downstream target genes CCND1 and c-myc; Furthermore, Luciferase reporter and Chromatin immunoprecipitation (ChIP) assays showed that CNBP could directly bind to the ß-catenin promoter and promote its transcription. CNBP also upregulated the expression of G1/S-related cell cycle genes CCNE1, CDK2, and CDK4. Collectively, our study reveals the positive role of CNBP in promoting cardiac repair after injury, providing a new therapeutic option for the treatment of MI.

Recycling drinking water treatment sludge in construction and building materials: A review.

Drinking water treatment sludge (DWTS) is a by-product of water treatment, and it is difficult to recycle to high value and poses potential environmental risks. Recycling DWTS into cement-based materials is an effective measure to achieve its high-volume utilization and reduce its environmental load. DWTS is rich in silica-alumina phases and has potential pozzolanic activity after drying, grinding and calcination, giving it similar properties to traditional supplementary cementitious materials. Adjusting the sludge production process and coagulant type will change its physical and chemical properties. Adding a small amount of DWTS can generate additional hydration products and refine the pore structure of the cement sample, thus improving the mechanical properties and durability of the sample. However, adding high-volume DWTS to concrete causes microstructural deterioration, but it is feasible to use high-volume DWTS to produce artificial aggregates, lightweight concrete, and sintered bricks. Meanwhile, calcined DWTS has similar compositions to clay, which makes it a potential raw material for cement clinker production. Cement-based materials can effectively solidify heavy metal ions in DWTS, and alkali-activated binders, magnesium-based cement, and carbon curing technology can further reduce the risk of heavy metal leaching. This review provides support for the high-value utilization of DWTS in cement-based materials and the reduction of its potential environmental risks.

TransGCN: a semi-supervised graph convolution network-based framework to infer protein translocations in spatio-temporal proteomics.

Protein subcellular localization (PSL) is very important in order to understand its functions, and its movement between subcellular niches within cells plays fundamental roles in biological process regulation. Mass spectrometry-based spatio-temporal proteomics technologies can help provide new insights of protein translocation, but bring the challenge in identifying reliable protein translocation events due to the noise interference and insufficient data mining. We propose a semi-supervised graph convolution network (GCN)-based framework termed TransGCN that infers protein translocation events from spatio-temporal proteomics. Based on expanded multiple distance features and joint graph representations of proteins, TransGCN utilizes the semi-supervised GCN to enable effective knowledge transfer from proteins with known PSLs for predicting protein localization and translocation. Our results demonstrate that TransGCN outperforms current state-of-the-art methods in identifying protein translocations, especially in coping with batch effects. It also exhibited excellent predictive accuracy in PSL prediction. TransGCN is freely available on GitHub at https://github.com/XuejiangGuo/TransGCN.

scapGNN: A graph neural network-based framework for active pathway and gene module inference from single-cell multi-omics data.

Although advances in single-cell technologies have enabled the characterization of multiple omics profiles in individual cells, extracting functional and mechanistic insights from such information remains a major challenge. Here, we present scapGNN, a graph neural network (GNN)-based framework that creatively transforms sparse single-cell profile data into the stable gene-cell association network for inferring single-cell pathway activity scores and identifying cell phenotype-associated gene modules from single-cell multi-omics data. Systematic benchmarking demonstrated that scapGNN was more accurate, robust, and scalable than state-of-the-art methods in various downstream single-cell analyses such as cell denoising, batch effect removal, cell clustering, cell trajectory inference, and pathway or gene module identification. scapGNN was developed as a systematic R package that can be flexibly extended and enhanced for existing analysis processes. It provides a new analytical platform for studying single cells at the pathway and network levels.

Bio-Inspired Proprioceptive Touch of a Soft Finger with Inner-Finger Kinesthetic Perception.

In-hand object pose estimation is challenging for humans and robots due to occlusion caused by the hand and object. This paper proposes a soft finger that integrates inner vision with kinesthetic sensing to estimate object pose inspired by human fingers. The soft finger has a flexible skeleton and skin that adapts to different objects, and the skeleton deformations during interaction provide contact information obtained by the image from the inner camera. The proposed framework is an end-to-end method that uses raw images from soft fingers to estimate in-hand object pose. It consists of an encoder for kinesthetic information processing and an object pose and category estimator. The framework was tested on seven objects, achieving an impressive error of 2.02 mm and 11.34 degrees for pose error and 99.05% for classification.

Widespread Involvement of Acetylation in the Retinal Metabolism of Form-Deprivation Myopia in Guinea Pigs.

Myopia has become the major cause of visual impairment worldwide. Although the pathogenesis of myopia remains controversial, proteomic studies suggest that dysregulation of retinal metabolism is potentially involved in the pathology of myopia. Lysine acetylation of proteins plays a key role in regulating cellular metabolism, but little is known about its role in the form-deprived myopic retina. Hence, a comprehensive analysis of proteomic and acetylomic changes in the retinas of guinea pigs with form-deprivation myopia was performed. In total, 85 significantly differential proteins and 314 significantly differentially acetylated proteins were identified. Notably, the differentially acetylated proteins were markedly enriched in metabolic pathways such as glycolysis/gluconeogenesis, the pentose phosphate pathway, retinol metabolism, and the HIF-1 signaling pathway. HK2, HKDC1, PKM, LDH, GAPDH, and ENO1 were the key enzymes in these metabolic pathways with decreased acetylation levels in the form-deprivation myopia group. Altered lysine acetylation of key enzymes in the form-deprived myopic retina might affect the dynamic balance of metabolism in the retinal microenvironment by altering their activity. In conclusion, as the first report on the myopic retinal acetylome, this study provides a reliable basis for further studies on myopic retinal acetylation.

DeepSP: A Deep Learning Framework for Spatial Proteomics.

The study of protein subcellular localization (PSL) is a fundamental step toward understanding the mechanism of protein function. The recent development of mass spectrometry (MS)-based spatial proteomics to quantify the distribution of proteins across subcellular fractions provides us a high-throughput approach to predict unknown PSLs based on known PSLs. However, the accuracy of PSL annotations in spatial proteomics is limited by the performance of existing PSL predictors based on traditional machine learning algorithms. In this study, we present a novel deep learning framework named DeepSP for PSL prediction of an MS-based spatial proteomics data set. DeepSP constructs the new feature map of a difference matrix by capturing detailed changes between different subcellular fractions of protein occupancy profiles and uses the convolutional block attention module to improve the prediction performance of PSL. DeepSP achieved significant improvement in accuracy and robustness for PSL prediction in independent test sets and unknown PSL prediction compared to current state-of-the-art machine learning predictors. As an efficient and robust framework for PSL prediction, DeepSP is expected to facilitate spatial proteomics studies and contributes to the elucidation of protein functions and the regulation of biological processes.

Successful treatment of veno-arterial extracorporeal membrane oxygenation complicated with left ventricular thrombus by intravenous thrombolysis: A case report.

BACKGROUND: Left ventricular thrombus is a rare condition, for which appropriate treatments are not extensively studied. Although it can be treated by thrombectomy, such surgery can be difficult and risky, and not every patient can tolerate the surgery. CASE SUMMARY: We report a case of a middle-aged man receiving veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for acute myocardial infarction who developed left ventricular thrombus despite systemic anticoagulation. After systemic thrombolysis with urokinase, the left ventricular thrombus disappeared, ECMO was successfully withdrawn 9 days later, and the patient recovered and was discharged from hospital. CONCLUSION: Systemic thrombolysis is a treatment option for left ventricular thrombus in addition to anticoagulation and thrombectomy.

Successful treatment of near-fatal asthma with ECMO: A case report and literature review.

Near-fatal asthma (NFA) can lead to severe hypercapnia and sudden cardiac arrest; however, it can be reversed by extracorporeal membrane oxygenation (ECMO). We report a case of a 37-year-old male diagnosed with NFA. After fluid rehydaration, spasmolysis, and treatment with glucocorticoid and mechanical ventilation, the patient's condition improved temporarily. However, his condition worsened rapidly, and the patient presented with progressive respiratory distress, a sharp increase in airway pressure, decreased tidal volume, and barotrauma. The patient was treated with venovenous ECMO in the prone position. Five days later, the patient was successfully weaned from ECMO. Hence, ECMO could be used for NFA at the right time to provide adequate gas exchange for patients in order to reduce lung damage and prevent death.

Enhanced extracellular production of raw starch-degrading α-amylase in Bacillus subtilis through expression regulatory element modification and fermentation optimization.

BACKGROUND: Raw starch-degrading α-amylase (RSDA) can hydrolyze raw starch at moderate temperatures, thus contributing to savings in starch processing costs. However, the low production level of RSDA limits its industrial application. Therefore, improving the extracellular expression of RSDA in Bacillus subtilis, a commonly used industrial expression host, has great value. RESULTS: In this study, the extracellular production level of Pontibacillus sp. ZY raw starch-degrading α-amylase (AmyZ1) in B. subtilis was enhanced by expression regulatory element modification and fermentation optimization. As an important regulatory element of gene expression, the promoter, signal peptide, and ribosome binding site (RBS) sequences upstream of the amyZ1 gene were sequentially optimized. Initially, based on five single promoters, the dual-promoter Pveg-PylB was constructed by tandem promoter engineering. Afterward, the optimal signal peptide SPNucB was obtained by screening 173 B. subtilis signal peptides. Then, the RBS sequence was optimized using the RBS Calculator to obtain the optimal RBS1. The resulting recombinant strain WBZ-VY-B-R1 showed an extracellular AmyZ1 activity of 4824.2 and 41251.3 U/mL during shake-flask cultivation and 3-L fermenter fermentation, which were 2.6- and 2.5-fold greater than those of the original strain WBZ-Y, respectively. Finally, the extracellular AmyZ1 activity of WBZ-VY-B-R1 was increased to 5733.5 U/mL in shake flask by optimizing the type and concentration of carbon source, nitrogen source, and metal ions in the fermentation medium. On this basis, its extracellular AmyZ1 activity was increased to 49082.1 U/mL in 3-L fermenter by optimizing the basic medium components as well as the ratio of carbon and nitrogen sources in the feed solution. This is the highest production level reported to date for recombinant RSDA production. CONCLUSIONS: This study represents a report on the extracellular production of AmyZ1 using B. subtilis as a host strain, and achieved the current highest expression level. The results of this study will lay a foundation for the industrial application of RSDA. In addition, the strategies employed here also provide a promising way for improving other protein production in B. subtilis.

HLA-DR+ mucosal-associated invariant T cells predict poor prognosis in patients with sepsis: A prospective observational study.

Mucosal-associated invariant T (MAIT) cells are important in antibacterial immune responses; however, during sepsis, they are few in number and exhibit highly activated phenotypes. The relationship between MAIT cells in peripheral blood and the prognosis of sepsis is not well understood. Thus, this study aimed to examine the levels and phenotypes of MAIT cells in early sepsis, evaluate their clinical relevance, and investigate their association with patient prognosis. This prospective observational study enrolled 72 septic patients defined according to the Sepsis 3.0 criteria and 21 healthy controls matched for age and sex. Their peripheral blood samples were used to assay the expression of immune activation (CD69 and HLA-DR) and immune checkpoint (PD-1 and PD-L1) markers on MAIT cells. The systemic inflammatory response syndrome, acute physiology and chronic health evaluation (APACHE) II, and sequential organ failure assessment scores were recorded. Subsequently, the association between MAIT cell characteristics and clinical indicators was assessed using Spearman's rank correlation analysis, and binary logistic regression analysis with a forward stepwise approach assessed independent risk factors for 28-day mortality. We noted a decrease in the percentage of MAIT cells in the patients' peripheral blood, which exhibited an activated phenotype. Besides, HLA-DR+ MAIT cell percentage and the APACHE II score were independently associated with the 28-day mortality and, in combination, were the best indicators of mortality. Thus, the percentage of HLA-DR+ MAIT cells in early sepsis serves as a novel prognostic biomarker for predicting mortality and improves the predictive capacity of the APACHE II score.

Reproductive performance and transcriptome analysis of ovaries at different parities in female rabbits.

This study investigated the reproductive performance and ovarian molecular regulation associated with parity in commercial rabbit systems. The pregnancy data of 658 female rabbits from the first to sixth parities (P1 to P6) under the same mating pattern were analyzed, showing a significant decrease in the conception rate in P6. Compared to P1 (N = 120) and P2 (N = 105), P6 (N = 99) had significantly lower performance indices in terms of total litter size, live litter size, survival rate at birth, and weight of 3 and 5 wk old kits (P < 0.05). Using H&E staining, we found that the ovarian primordial follicle reservoir of P6 was significantly lower than that of P1 and P2, and the number of atretic follicles at P6 was significantly higher (P < 0.05). Blood (N = 30 per group) and ovaries (N = 6 per group) in P1, P2, and P6 were collected for measurement of the serum anti-oxidant capacity and indices of ovarian function by ELISA. It was found that serum glutathione, ovarian Klotho protein, and telomeres of P1 and P2 were significantly higher than those of P6 (P < 0.05). The serum levels of ROS and MDA at P1 and P2 were significantly lower than those at P6 (P < 0.05). Additionally, transcriptome analysis showed 213 up-regulated and 747 down-regulated differentially expressed genes (DEGs) between P2 and P6 ovaries. Several DEGs were related to reproduction, including CYP21A2, PTGFR, SGK1, PIK3R6, and SRD5A2. These results demonstrate the influence of parity on reproduction in female rabbits, reflected in a loss of follicle reservoir, disordered levels of anti-oxidants, and indices associated with ovarian function and molecular regulation. This study provides a basis for the strategies to increase reproductive rate in female rabbits.

The pregnancy data of 658 female rabbits from the first to sixth parities (P1 to P6) under the same mating pattern were used to assess the rate of conception at different parities. The reproductive performance and follicular development of P1, P2, and P6 female rabbits were analyzed. The results showed that conception rate was dramatically reduced in P6. Compared with P1 and P2, P6 rabbits showed evidence of lower fertility in terms of total litter size, live litter size, survival rate at birth, and weights of kits at 3 and 5-wk-old. The primordial follicle storage at P6 was significantly reduced, with greater numbers of atretic follicles compared with P1 and P2. In terms of serum glutathione, reactive oxygen species, malondialdehyde, and ovarian Klotho protein, telomeres, the anti-oxidant capacity and ovarian function at P6 was significantly affected by parity. Further, based on the ovarian transcriptomes at P2 and P6, several genes related to reproductive regulation were identified. These findings provide a basis for improving the reproductive rate of female rabbits.

Comparison of Efficacy and Safety of Different Doses of Dexmedetomidine for Epidural Labor Analgesia.

Objective: To explore the efficacy and safety of different doses of dexmedetomidine (DEX) for epidural labor analgesia (ELA). Methods: From June 2021 to June 2022, 147 parturients who underwent ELA in our hospital were selected and divided into low- (0.5 µg/kg DEX), medium- (0.75 µg/kg DEX), and high-dose (1.0 µg/kg DEX) groups (n = 49 for each) according to the random number table method. The analgesic effect was assessed using the Ramsay sedation score and Visual Analogue Scale (VAS), and the labor duration, mean arterial pressure (MAP), and heart rate (HR) before and after analgesia, vaginal bleeding within 2 h postpartum, and delivery outcomes (the cesarean section conversion rate and the neonatal Apgar score) were statistically analyzed. Furthermore, the incidence of adverse reactions was calculated, and maternal satisfaction with delivery was investigated. Results: After analgesia, the the Ramsay and labor duration were higher in the high-dose group than those in the low- and medium-dose groups, and the VAS scores was lowerin the high-dose group than those in the low- and medium-dose groups(P < 0.05), while no difference was identified among the three groups in terms of the cesarean section conversion rate and the neonatal Apgar score (P > 0.05). The high-dose group had the greatest fluctuations in MAP and HR levels before and after analgesia than the other two groups, with a higher incidence of adverse reactions (P < 0.05). Finally, the survey of delivery satisfaction showed no significant difference in delivery satisfaction among the three groups (P > 0.05). Conclusion: DEX has excellent performance in ELA, which can effectively relieve the pain of puerperae and shorten the labor process. Among them, low-dose DEX has higher safety and is recommended as the first choice. Trial Registrations. This trial is registered with ML2021073.

Regulation of Miwi-mediated mRNA stabilization by Ck137956/Tssa is essential for male fertility.

BACKGROUND: Sperm is formed through spermiogenesis, a highly complex process involving chromatin condensation that results in cessation of transcription. mRNAs required for spermiogenesis are transcribed at earlier stages and translated in a delayed fashion during spermatid formation. However, it remains unknown that how these repressed mRNAs are stabilized. RESULTS: Here we report a Miwi-interacting testis-specific and spermiogenic arrest protein, Ck137956, which we rename Tssa. Deletion of Tssa led to male sterility and absence of sperm formation. The spermiogenesis arrested at the round spermatid stage and numerous spermiogenic mRNAs were down-regulated in Tssa-/- mice. Deletion of Tssa disrupted the localization of Miwi to chromatoid body, a specialized assembly of cytoplasmic messenger ribonucleoproteins (mRNPs) foci present in germ cells. We found that Tssa interacted with Miwi in repressed mRNPs and stabilized Miwi-interacting spermiogenesis-essential mRNAs. CONCLUSIONS: Our findings indicate that Tssa is indispensable in male fertility and has critical roles in post-transcriptional regulations by interacting with Miwi during spermiogenesis.

Recycling of water treatment sludge in concrete: The role of water-binder ratio from a nanoscale perspective.

For eutrophic water bodies, potassium permanganate is an effective pre-oxidant to remove algae and its residue in water treatment sludge. Recycling water treatment sludge in concrete is an environmentally friendly and high-value utilization measure. However, little research has been done on the effect of manganese-rich drinking water sludge ash (DWSA) on concrete. The effect of water-binder ratio (w/b) on strength, shrinkage and microstructural characteristics of concrete containing DWSA was investigated, and the structural behavior was explained from a nanoscale perspective. The results show that recycling 10 % DWSA in concrete improved the strength and shrinkage resistance of the samples. Reducing the w/b effectively increased the strength of DWSA-modified concrete and reduced the shrinkage deformation. The paste with high w/b had higher contents of non-evaporated water and calcium hydroxide, as well as higher reaction degree of DWSA. Nanoscale characterization shows that reducing the w/b reduced the volume fraction of pore and unhydrated phases in the matrix and increased the proportion of high-density C-S-H. Meanwhile, reducing the w/b also reduced the interfacial transition zone width of DWSA-modified concrete. Recycling DWSA in concrete effectively reduced the total carbon footprint and cost of the mixture. The combined application of reducing the w/b and incorporating DWSA effectively improved the economic and environmental benefits of concrete material. For the concrete modified with 10 % DWSA (w/b = 0.3), its cost and carbon emissions are reduced by 14 %-21 % and 19 %-25 % compared with the reference sample, respectively. Overall, this study reveals the action mechanism of DWSA in cement system at different w/b from nanoscale perspective, and gives a new insight on determining the optimal w/b in full-scale application of DWSA concrete.

Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis.

Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n = 401) as well as a group with HS-aging without CTE (n = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.

Pleiotropy analysis between lobar intracerebral hemorrhage and CSF ß-amyloid highlights new and established associations.

BACKGROUND AND AIMS: Combining biologically related traits in genome-wide association studies (GWAS) increases the power for genetic discovery. Given the established relationship between lobar intracerebral hemorrhage (ICH) and cerebral amyloid angiopathy (CAA), and between the latter and levels of cerebrospinal fluid amyloid-ß 42 (CSF-Aß42), we leveraged genetic predisposition for lower CSF-Aß42 levels as a proxy phenotype for CAA to identify new genes associated with lobar ICH. METHODS: We used publicly available GWAS data for CSF-Aß42 levels (n = 3146) and for lobar ICH (n = 2094). First, we evaluated the association between lobar ICH risk and CSF-Aß42 in lobar ICH patients using a polygenic risk score (PRS) for CSF-Aß42. Next, we conducted multi-trait analysis of GWAS (MTAG) for pleiotropy analysis of lobar ICH and CSF-Aß42. MTAG results were further tested using Expression Quantitative Trait Locus and Differential Gene Expression Analyses. RESULTS: CSF-Aß42 PRS was associated with lobar ICH risk (p = 0.04). MTAG analysis identified a novel association within CDH9 (rs1007589; minor allele frequency = 0.09; MTAG p = 5.4 × 10-8; lobar ICH odds ratio = 1.4 and p = 2.4 × 10-3; CSF-Aß42 ß = -0.03 and p = 4.5 × 10-6). rs1007589 was significantly associated with the expression levels of CDH9 in temporal and occipital cortices, regions known to preferentially accumulate microhemorrhages in CAA. CONCLUSION: Our pleiotropy analysis suggested a variant possibly implicated with lobar ICH driven by amyloid-related mechanisms in CDH9 and associated with differential expression in brain regions characteristically affected by CAA. CDH9 is one subtype of the cadherin superfamily, which regulates intercellular adhesion, is involved in blood-brain barrier integrity, and is elevated in Alzheimer's disease patients. Further analyses are warranted to understand the effects of the variant on the pathogenesis of ICH and its clinical significance.

Inhibition of Phosphoinositide 3-Kinase Gamma Protects Endothelial Cells via the Akt Signaling Pathway in Sepsis-Induced Acute Kidney Injury.

INTRODUCTION: Sepsis is a primary cause of death in critically ill patients and is characterized by multiple organ dysfunction, including sepsis-induced acute kidney injury (AKI), which contributes to high mortality in sepsis. However, its pathophysiological mechanisms remain unclear. The kidney has one of the richest and most diversified endothelial cell populations in the body. This study was designed to investigate the effects of endothelial dysfunction in sepsis-induced AKI and explore possible intervention measures to offer new insight into the pathogenesis and treatment of sepsis-induced AKI. METHODS: The circulating levels of endothelial adhesion molecules were detected in patients with sepsis and healthy controls to observe the role of endothelial damage in sepsis and sepsis-induced AKI. A murine sepsis model induced by cecal ligation and perforation was pretreated with a phosphoinositide 3-kinase gamma (PI3Kγ) inhibitor (CZC24832), and survival, kidney damage, and renal endothelial injury were assessed by pathological examination, immunohistochemistry, quantitative polymerase chain reaction, and Western blotting. Lipopolysaccharides and CZC24832 were administered to human umbilical vein endothelial cells in vitro, and endothelial cell function and the expression of adhesion molecules were evaluated. RESULTS: Endothelial damage was more serious in sepsis-induced AKI than that in non-AKI, and the inhibition of PI3Kγ alleviates renal endothelial injury in a murine sepsis model, protecting endothelial cell function and repairing endothelial cell injury through the Akt signaling pathway. CONCLUSIONS: In this study, endothelial cell dysfunction plays an important role in sepsis-induced AKI, and the inhibition of PI3Kγ alleviates endothelial cell injury in sepsis-induced AKI through the PI3Kγ/Akt pathway, providing novel targets for treating sepsis and related kidney injury.

Association of APOE Genotypes and Chronic Traumatic Encephalopathy.

Importance: Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope. Objective: To test the association between APOE genotype and CTE neuropathology and related endophenotypes. Design, Setting, and Participants: This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022. Exposures: One or more APOEε4 or APOEε2 alleles. Main Outcomes and Measures: CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8+ pixel count per mm2), and dementia. Results: Of 364 consecutive brain donors (100% male; 53 [14.6%] self-identified as Black and 311 [85.4%] as White; median [IQR] age, 65 [47-77] years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio [OR], 2.34 [95% CI, 1.30-4.20]; false discovery rate [FDR]-corrected P = .01) and quantitative p-tau burden in the dorsolateral frontal lobe (ß, 1.39 [95% CI, 0.83-1.94]; FDR-corrected P = 2.37 × 10-5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 [95% CI, 1.06-6.61]; FDR-corrected P = .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race. Conclusions and Relevance: APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.