Bioinformatics and machine learning approaches reveal key genes and underlying molecular mechanisms of atherosclerosis: A review.

Atherosclerosis (AS) causes thickening and hardening of the arterial wall due to accumulation of extracellular matrix, cholesterol, and cells. In this study, we used comprehensive bioinformatics tools and machine learning approaches to explore key genes and molecular network mechanisms underlying AS in multiple data sets. Next, we analyzed the correlation between AS and immune fine cell infiltration, and finally performed drug prediction for the disease. We downloaded GSE20129 and GSE90074 datasets from the Gene expression Omnibus database, then employed the Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts algorithm to analyze 22 immune cells. To enrich for functional characteristics, the black module correlated most strongly with T cells was screened with weighted gene co-expression networks analysis. Functional enrichment analysis revealed that the genes were mainly enriched in cell adhesion and T-cell-related pathways, as well as NF-κ B signaling. We employed the Lasso regression and random forest algorithms to screen out 5 intersection genes (CCDC106, RASL11A, RIC3, SPON1, and TMEM144). Pathway analysis in gene set variation analysis and gene set enrichment analysis revealed that the key genes were mainly enriched in inflammation, and immunity, among others. The selected key genes were analyzed by single-cell RNA sequencing technology. We also analyzed differential expression between these 5 key genes and those involved in iron death. We found that ferroptosis genes ACSL4, CBS, FTH1 and TFRC were differentially expressed between AS and the control groups, RIC3 and FTH1 were significantly negatively correlated, whereas SPON1 and VDAC3 were significantly positively correlated. Finally, we used the Connectivity Map database for drug prediction. These results provide new insights into AS genetic regulation.

An enhancer-AAV toolbox to target and manipulate distinct interneuron subtypes.

In recent years, we and others have identified a number of enhancers that, when incorporated into rAAV vectors, can restrict the transgene expression to particular neuronal populations. Yet, viral tools to access and manipulate fine neuronal subtypes are still limited. Here, we performed systematic analysis of single cell genomic data to identify enhancer candidates for each of the cortical interneuron subtypes. We established a set of enhancer-AAV tools that are highly specific for distinct cortical interneuron populations and striatal cholinergic neurons. These enhancers, when used in the context of different effectors, can target (fluorescent proteins), observe activity (GCaMP) and manipulate (opto- or chemo-genetics) specific neuronal subtypes. We also validated our enhancer-AAV tools across species. Thus, we provide the field with a powerful set of tools to study neural circuits and functions and to develop precise and targeted therapy.

Photoinduced oxidation of chromium picolinate to hexavalent chromium in the presence of ferric ions.

The occurrence of chromium picolinate (Cr(pic)3) in environment has attracted raising concerns on its fate and the associated risks. Herein, the photoinduced oxidation of Cr(pic)3 in the presence of ferric ions (Fe(III)) under simulated sunlight and natural solar light irradiation were investigated. Cr(pic)3 was stable under dark or without Fe(III). 87.9 % of Cr(pic)3 (C0 = 1.0 µM) was degraded in the presence of 50 µM Fe(III) after 90 min simulated sunlight irradiation at initial pH of 4.0. •OH was the main cause for Cr(pic)3 oxidation, it attacked the chromium center to generate hexavalent chromium (Cr(VI)) and picolinic acid (k = 5.9 ×108 M-1·s-1). Picolinic acid could be further oxidized to NH4+ and small organics. Relative higher Fe(III) content (25 - 75 µM) and Cr(pic)3 concentration (0.5 - 2.0 µM) promoted both of Cr(pic)3 degradation and Cr(VI) accumulation. While, the degradation of Cr(pic)3 decreased with pH at the range of 3.0 - 8.0, more Cr(VI) was accumulated at pH 5.0 and 6.0. The co-existence of inorganic ions and dissolved organic matter (DOM) in river water inhibited Cr(pic)3 oxidation by scavenging the •OH formed and shielding the light. 8.0 - 16.7 µg/L of Cr(VI) was accumulated after 9.0 h simulated sunlight irradiation of Cr(pic)3 in river water matrix ([Fe(III)]0 = 50 - 100 µM). The generation of Cr(VI) under solar light was slower than that under simulated sunlight due to the weaker light intensity (43.2 - 85.0 mW/cm2 vs. 750 - 1300 mW/cm2). These results consistently suggest photoinduced oxidation of Cr(pic)3 in environment generates the toxic Cr(VI), which deserves significant attention.

Selenium-Chelating Peptide Derived from Wheat Gluten: In Vitro Functional Properties.

The efficacy of selenium-chelating polypeptides derived from wheat protein hydrolysate (WPH-Se) includes enhancing antioxidant capacity, increasing bioavailability, promoting nutrient absorption, and improving overall health. This study aimed to enhance the bioavailability and functional benefits of exogenous selenium by chelating with wheat gluten protein peptides, thereby creating bioactive peptides with potentially higher antioxidant capabilities. In this study, WPH-Se was prepared with wheat peptide and selenium at a mass ratio of 2:1, under a reaction system at pH 8.0 and 80 °C. The in vitro antioxidant activity of WPH-Se was evaluated by determining the DPPH, OH, and ABTS radical scavenging rate and reducing capacity under different conditions, and the composition of free amino acids and bioavailability were also investigated at various digestion stages. The results showed that WPH-Se possessed significant antioxidant activities under different conditions, and DPPH, OH, and ABTS radical scavenging rates and reducing capacity remained high at different temperatures and pH values. During gastrointestinal digestion in vitro, both the individual digestate and the final digestate maintained high DPPH, OH, and ABTS radical scavenging rates and reducing capacity, indicating that WPH-Se was able to withstand gastrointestinal digestion and exert antioxidant effects. Post-digestion, there was a marked elevation in tryptophan, cysteine, and essential amino acids, along with the maintenance of high selenium content in the gastrointestinal tract. These findings indicate that WPH-Se, with its enhanced selenium and amino acid profile, serves as a promising ingredient for dietary selenium and antioxidant supplementation, potentially enhancing the nutritional value and functional benefits of wheat gluten peptides.

Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma.

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development. However, it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors (TFs) except for the nuclear receptor family of TFs. Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma (GEA) or the therapeutic effects of targeting TF and transcription cofactor complexes. In this study, we found that ETS homologous factor (EHF) expression is promoted by a core transcriptional regulatory circuitry (CRC), specifically ELF3-KLF5-GATA6, and interference with its expression suppressed the malignant biological behavior of GEA cells. Importantly, we identified Ajuba LIM protein (AJUBA) as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA. Furthermore, we identified KRAS signaling as a common pathway downstream of EHF and AJUBA. Applicably, dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo. In conclusion, EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway. Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

Machine learning-based prediction and experimental validation of heavy metal adsorption capacity of bentonite.

As a natural adsorbent material, bentonite is widely used in the field of heavy metal adsorption. The heavy metal adsorption capacity of bentonite varies significantly in studies due to the differences in the properties of bentonite, solution, and heavy metal. To achieve accurate predictions of bentonite's heavy metal adsorption capacity, this study employed six machine learning (ML) regression algorithms to investigate the adsorption characteristics of bentonite. Finally, an eXtreme Gradient Boosting Regression (XGB) model with outstanding predictive performance was constructed. Explanation analysis of the XGB model further reveal the importance and influence manner of each input feature in predicting the heavy metal adsorption capacity of bentonite. The feature categories influencing heavy metal adsorption capacity were ranked in order of importance as adsorption conditions > bentonite properties > heavy metal properties. Furthermore, a web-based graphical user interface (GUI) software was developed, facilitating researchers and engineers to conveniently use the XGB model for predicting the heavy metal adsorption capacity of bentonite. This study provides new insights into the adsorption behaviors of bentonite for heavy metals, offering guidance and support for enhancing its application efficiency and addressing heavy metal pollution remediation.

Hyperuricemia research progress in model construction and traditional Chinese medicine interventions.

Hyperuricemia (HUA), a severe metabolic disease derived from purine metabolism disorder, will lead to abnormally increased serum uric acid (SUA) levels in the body. Studies have shown that HUA is highly related to gout, hypertension, diabetes, coronary heart disease, chronic kidney diseases, and so on. Traditional Chinese medicine (TCM) shows excellent results in treating HUA because of its unique advantages of multi-metabolites and multi-targets. This article reports on the use of TCM components for uric acid (UA)-lowering activity with excellent efficacy and low side effects based on established HUA models. This work summarizes the advantages and limitations of various HUA disease models for efficacy evaluation. Applications of TCM in HUA treatment have also been discussed in detail. This paper reveals recent research progress on HUA in constructing evaluation models and systematic TCM interventions. It will provide a scientific reference for establishing the HUA model and suggest future TCM-related HUA studies.

Activation of Bivalent Gene POU4F1 Promotes and Maintains Basal-like Breast Cancer.

Basal-like breast cancer (BLBC) is the most aggressive molecular subtype of breast cancer with worse prognosis and fewer treatment options. The underlying mechanisms upon BLBC transcriptional dysregulation and its upstream transcription factors (TFs) remain unclear. Here, among the hyperactive candidate TFs of BLBC identified by bioinformatic analysis, POU4F1 is uniquely upregulated in BLBC and is associated with poor prognosis. POU4F1 is necessary for the tumor growth and malignant phenotypes of BLBC through regulating G1/S transition by direct binding at the promoter of CDK2 and CCND1. More importantly, POU4F1 maintains BLBC identity by repressing ERα expression through CDK2-mediated EZH2 phosphorylation and subsequent H3K27me3 modification in ESR1 promoter. Knocking out POU4F1 in BLBC cells reactivates functional ERα expression, rendering BLBC sensitive to tamoxifen treatment. In-depth epigenetic analysis reveals that the subtype-specific re-configuration and activation of the bivalent chromatin in the POU4F1 promoter contributes to its unique expression in BLBC, which is maintained by DNA demethylase TET1. Together, these results reveal a subtype-specific epigenetically activated TF with critical role in promoting and maintaining BLBC, suggesting that POU4F1 is a potential therapeutic target for BLBC.

Predictors of High Cardiovascular Risk Among Nonobese Patients with Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease in a Chinese Population.

Purpose: This study aims to investigate cardiovascular risk factors in nonobese patients with type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD) and to determine whether they might be used to predict high-risk individuals effectively. Patients and Methods: This cross-sectional study included 245 nonobese patients with T2DM who underwent FibroTouch in the National Metabolic Management Center of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from January 2021 to December 2022. All individuals were divided into NAFLD and non-NAFLD groups. Patients with NAFLD were further grouped by UAP tertiles (T1, T2 and T3). We created a Cardiovascular Score (total scale: 0-5 points; ≥3 points was defined as high-risk individual) based on baPWV, carotid ultrasound, and urinary microalbumin creatinine ratio (UA/CR) to assess the risk of cardiovascular disease in non-obese T2DM patients with NAFLD. Risk factors were evaluated using univariate and multivariate analysis. The performance of risk factors was compared according to the area under the receiver operating characteristic (ROC) curve. Results: Atherogenic index of plasma (AIP), atherosclerosis index (AI), prevalence of hypertension, body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR) were higher in the NAFLD group compared to the non-NAFLD group. In T3 group, AIP, AI, BMI and HOMA-IR were higher than those of T1 group. Multivariate logistic regression showed that age, systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C) and AIP were risk factors for cardiovascular disease among nonobese patients with T2DM and NAFLD. The area under the ROC curve for age, systolic blood pressure, LDL-C and AIP were 0.705, 0.688, 0.738 and 0.642, respectively. The area under the ROC curve was 0.895 when combining them. Conclusion: Age, systolic blood pressure, AIP and LDL-C are all independent risk factors for cardiovascular disease in non-obese individuals with T2DM and NAFLD, which can be combined to identify high-risk populations and carry out intervention.

Divergent opioid-mediated suppression of inhibition between hippocampus and neocortex across species and development.

Opioid receptors within the CNS regulate pain sensation and mood and are key targets for drugs of abuse. Within the adult rodent hippocampus (HPC), µ-opioid receptor agonists suppress inhibitory parvalbumin-expressing interneurons (PV-INs), thus disinhibiting the circuit. However, it is uncertain if this disinhibitory motif is conserved in other cortical regions, species, or across development. We observed that PV-IN mediated inhibition is robustly suppressed by opioids in HPC but not neocortex in mice and nonhuman primates, with spontaneous inhibitory tone in resected human tissue also following a consistent dichotomy. This hippocampal disinhibitory motif was established in early development when immature PV-INs and opioids already influence primordial network rhythmogenesis. Acute opioid-mediated modulation was partially occluded with morphine pretreatment, with implications for the effects of opioids on hippocampal network activity during circuit maturation as well as learning and memory. Together, these findings demonstrate that PV-INs exhibit a divergence in opioid sensitivity across brain regions that is remarkably conserved across evolution and highlights the underappreciated role of opioids acting through immature PV-INs in shaping hippocampal development.

Metabolic reprogramming directed by super-enhancers in tumors: An emerging landscape.

Metabolic reprogramming is an essential hallmark of tumors, and metabolic abnormalities are strongly associated with the malignant phenotype of tumor cells. This is closely related to transcriptional dysregulation. Super-enhancers are extremely active cis-regulatory regions in the genome, and can amalgamate a complex set of transcriptional regulatory components that are crucial for establishing tumor cell identity, promoting tumorigenesis, and enhancing aggressiveness. In addition, alterations in metabolic signaling pathways are often accompanied by changes in super-enhancers. Presently, there is a surge in interest in the potential pathogenesis of various tumors through the transcriptional regulation of super-enhancers and oncogenic mutations in super-enhancers. In this review, we summarize the functions of super-enhancers, oncogenic signaling pathways, and tumor metabolic reprogramming. In particular, we focus on the role of the super-enhancer in tumor metabolism and its impact on metabolic reprogramming. This review also discusses the prospects and directions in the field of super-enhancer and metabolic reprogramming.

Potential Effects of Orally Ingesting Polyethylene Terephthalate Microplastics on the Mouse Heart.

Polyethylene terephthalate microplastics (PET MPs) are widespread in natural environment, and can enter organisms and accumulate in the body, but its toxicity has not been well studied. Therefore, in order to investigate the toxic effects of PET microplastics on mammals, this study investigated the toxic effects of PET MPs on ICR mice and H9C2 cells by different treatment groups. The results indicated the cardiac tissue of mice in the PET-H (50 µg/mL) group showed significant capillary congestion, myocardial fiber breakage, and even significant fibrosis compared to the PET-C (control) group (P < 0.01). Results of the TUNEL assay demonstrated significant apoptosis in myocardial tissue in the PET-H and PET-M (5 µg/mL) groups (P < 0.01). Meanwhile, Western blotting showed increased expression of the apoptosis-related protein Bax and decreased expression of PARP, caspase-3, and Bcl-2 proteins in both myocardial tissues and H9C2 cells. In addition, flow cytometry confirmed that PET MPs decreased the mitochondrial membrane potential and apoptosis in H9C2 cells; however, this trend was reversed by N-acetylcysteamine application. Moreover, PET MP treatment induced the accumulation of reactive oxygen species (ROS) in H9C2 cells, while the MDA level in the myocardial tissue was elevated, and the activities of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were decreased (P < 0.01), indicating a change in the redox environment. In conclusion, PET MPs promoted cardiomyocyte apoptosis by inducing oxidative stress and activating mitochondria-mediated apoptotic processes, ultimately leading to myocardial fibrosis. This study provides ideas for the prevention of PET MP toxicity and promotes thinking about enhancing plastic pollution control.

Tiliroside disrupted iron homeostasis and induced ferroptosis via directly targeting calpain-2 in pancreatic cancer cells.

BACKGROUND: Tiliroside (TIL) is a flavonoid compound that exists in a variety of edible plants. These dietary plants are widely used as food and medicine to treat various diseases. However, the effect of TIL on pancreatic cancer (PC) and its underlying mechanisms are unclear. PURPOSE: This study aims to reveal the anti-PC effect of TIL and clarify its mechanism. METHODS: The inhibitory effects of TIL on PC growth were studied both in vitro and in vivo. Flow cytometry, transmission electron microscopy, immunofluorescence, biochemical analyses, RT-qPCR, genetic ablation, and western blotting were employed to evaluate ferroptosis, autophagy, and iron regulation. Additionally, RNA sequencing (RNA-seq), biomolecular layer interferometry (BLI), and molecular simulation analysis were combined to identify TIL molecular targets. The clinicopathological significance of Calpain-2 (CAPN2) was determined through immunohistochemistry (IHC) on a PC tissue microarray. RESULTS: Herein, we showed that TIL was an effective anti-PC drug. CAPN2 was involved in the TIL - induced elevation of the labile iron pool (LIP) in PC cells. TIL directly bound to and inhibited CAPN2 activity, resulting in AKT deactivation and decreased expression of glucose transporters (GLUT1 and GLUT3) in PC cells. Consequently, TIL impaired ATP and NADPH generation, inducing autophagy and ROS production. The accumulation of TIL-induced ROS combined with LIP iron causes the Fenton reaction, leading to lipid peroxidation. Meanwhile, TIL-induced reduction of free iron ions promoted autophagic degradation of ferritin to regulate cellular iron homeostasis, which further exacerbated the death of PC cells by ferroptosis. As an extension of these in vitro findings, our murine xenograft study showed that TIL inhibited the growth of PANC-1 cells. Additionally, we showed that CAPN2 expression levels were related to clinical prognoses in PC patients. CONCLUSION: We identify TIL as a potent bioactive inhibitor of CAPN2 and an anti-PC candidate of natural origin. These findings also highlight CAPN2 as a potential target for PC treatment.

The Correlation Between Leg Muscle Mass Index and Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus.

Objective: To analyze the relationship between leg skeletal muscle mass index (LSMI) and non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) and the ability of LSMI to predict NAFLD. Methods: Two hundred patients with T2DM and NAFLD treated at Changzhou Second People's Hospital Affiliated with Nanjing Medical University and the National Metabolic Management Center from June 2022 to June 2023 were divided into four LSMI quartiles. The clinical information from the four patient groups was compared, and the relationship between type 2 diabetes and LSMI and NAFLD was examined. We used receiver operating characteristic curves to determine how well the LSMI predicts NAFLD in T2DM. Results: The lowest quartile (Q1) had a higher prevalence of NAFLD than group Q4 (P < 0.05). LSMI was negatively associated with body mass index, LS, CAP, and other markers (P < 0.05). Receiver operating characteristic curve analysis LSMI predicted NAFLD with an ideal critical value of 0.64 and an area under the curve of 70.9%. The combined predictive value of the LSMI and the appendicular skeletal muscle mass index was more significant. Conclusion: Reduced LSMI is associated with NAFLD.

Applying Machine Learning Analysis Based on Proximal Femur of Abdominal Computed Tomography to Screen for Abnormal Bone Mass in Femur.

RATIONALE AND OBJECTIVES: To evaluate the performance of machine learning analysis based on proximal femur of abdominal computed tomography (CT) scans in screening for abnormal bone mass in femur. MATERIALS AND METHODS: 222 patients aged 50 years or older who underwent abdominal CT and dual-energy X-ray absorptiometry scans within 14 days were retrospectively enrolled. The patients were randomly assigned to a training cohort (n = 155) and a testing cohort (n = 67) in a ratio of 7:3. A total of 2288 candidate radiomic features were extracted from the volume region of interest - the left proximal femur of the abdominal CT scans. The most valuable radiomic features were selected using minimum-Redundancy Maximum-Relevancy and the least absolute shrinkage and selection operator to construct the radiomics model. The predictive performance was assessed with receiver operating characteristic curve. RESULTS: 13 features were chosen to establish the radiomics model. The radiomics model using logistic regression displayed excellent prediction performance in distinguishing normal bone mass and abnormal bone mass, with the area under the curve (AUC), accuracy, sensitivity and specificity of 0.917 (95% CI, 0.867-0.967), 0.826, 0.935 and 0.780 in the training cohort. The testing cohort indicated a better performance with AUC, accuracy, sensitivity and specificity of 0.963 (95% CI, 0.919-0.999), 0.851, 0.923 and 0.889. CONCLUSION: The radiomics model based on proximal femur of abdominal CT scans had a high predictive performance to identify abnormal bone mass in femur, which can be used as a tool for opportunistic osteoporosis screening.

Long noncoding RNA lnc_217 regulates hepatic lipid metabolism by modulating lipogenesis and fatty acid oxidation.

Nonalcoholic fatty liver disease (NAFLD) is considered a major health epidemic with an estimated 32.4% worldwide prevalence. No drugs have yet been approved and therapeutic nodes remain a major unmet need. Long noncoding RNAs are emerging as an important class of novel regulators influencing multiple biological processes and the pathogenesis of NAFLD. Herein, we described a novel long noncoding RNA, lnc_217, which was liver enriched and upregulated in high-fat diet-fed mice, and a genetic animal model of NAFLD. We found that liver specific knockdown of lnc_217 was resistant to high-fat diet-induced hepatic lipid accumulation and decreased serum lipid in mice. Mechanistically, we demonstrated that knockdown of lnc_217 not only decreased de novo lipogenesis by inhibiting sterol regulatory element binding protein-1c cleavage but also increased fatty acid ß-oxidation through activation of peroxisome proliferator-activated receptor α and carnitine palmitoyltransferase-1α. Taken together, we conclude that lnc_217 may be a novel regulator of hepatic lipid metabolism and a potential therapeutic target for the treatment of hepatic steatosis and NAFLD-related metabolic disorders.

Expression level and clinical significance of LncRNA PVT1 in the serum of patients with LEASO.

Objective: Our study aims to investigate the long non-coding RNA plasmacytoma variant translocation 1 (lncRNA PVT1) in lower extremity arteriosclerosis obliterans (LEASO) patient serum and its clinical significance in LEASO. Patients and Methods: From July 2021 to April 2022, 133 LEASO patients diagnosed at the Qingdao Municipal Hospital were included. Among them, 44 complicated with coronary artery disease (CAD) were classified as the LEASO with CAD group. The remaining 89 were marked as the LEASO group, which was classified into single (n = 48) and double (n = 41) lower limb groups, with the former being subclassified into the left (n = 28) and right (n = 20) lower limb groups based on the affected sites. Fifty healthy individuals who came to our hospital for physical examination during the same period were randomly included and defined as the Healthy Control group. PVT1 expression was detected in serum samples from each group using a quantitative reverse transcriptase-polymerase chain reaction , and differences in expression levels were calculated. The ankle-brachial index (ABI) of patients in the LEASO group was measured using a sphygmomanometer, and its correlation with PVT1 was analyzed. Clinical data and laboratory test results (including blood routine, liver and renal function, and blood lipids) were collected for all patients upon admission. Logistic regression analyses were performed to determine the influence of PVT1 and laboratory test results on LEASO. The diagnosis and prediction of LEASO were obtained by combing PVT1 with laboratory test indicators. Results: It was found that lncRNA PVT1 expression was the highest in the serum of the LEASO with CAD group, followed by the LEASO and control groups (P < 0.05). Within the LEASO group, no significant difference in PVT1 expression was seen between the left and right limbs (P > 0.05), nor between the single and double lower limb groups. Furthermore, the PVT1 expression increased with the Rutherford grades, indicating a negative correlation between PVT1 and ABI. Logistic regression analysis revealed that triglycerides (OR = 2.972, 95% CI [1.159-7.618]), cholesterol (OR = 6.655, 95% CI [1.490-29.723]), C-reactive protein (OR = 1.686, 95% CI [1.218-2.335]), and PVT1 (OR = 2.885, 95% CI [1.350-6.167]) were independent risk factors for LEASO. Finally, strong sensitivity was observed in the receiver operating characteristic curve when combining PVT1 with meaningful laboratory indicators to diagnose and predict LEASO. Conclusion: lncRNA PVT1 promotes LEASO occurrence and progression and is related to atherosclerosis severity. The expression of PVT1 was negatively correlated with ABI. Logistic regression analysis suggested that blood lipid levels and inflammatory reactions might be related to LEASO occurrence. PVT1 was incorporated into laboratory indicators to predict LEASO. The subject's working curve area was large, and the prediction results were highly sensitive.

Evolutionary conservation of hippocampal mossy fiber synapse properties.

Various specialized structural/functional properties are considered essential for contextual memory encoding by hippocampal mossy fiber (MF) synapses. Although investigated to exquisite detail in model organisms, synapses, including MFs, have undergone minimal functional interrogation in humans. To determine the translational relevance of rodent findings, we evaluated MF properties within human tissue resected to treat epilepsy. Human MFs exhibit remarkably similar hallmark features to rodents, including AMPA receptor-dominated synapses with small contributions from NMDA and kainate receptors, large dynamic range with strong frequency facilitation, NMDA receptor-independent presynaptic long-term potentiation, and strong cyclic AMP (cAMP) sensitivity of release. Array tomography confirmed the evolutionary conservation of MF ultrastructure. The astonishing congruence of rodent and human MF core features argues that the basic MF properties delineated in animal models remain critical to human MF function. Finally, a selective deficit in GABAergic inhibitory tone onto human MF postsynaptic targets suggests that unrestrained detonator excitatory drive contributes to epileptic circuit hyperexcitability.

Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons.

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a+/- and Grin2a-/- mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a+/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a+/- mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a-/- mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients.