Normal Controls Research Articles

Neural deterioration and compensation in visual short-term memory among individuals with amnestic mild cognitive impairment.

Visual short-term memory (VSTM) is a critical indicator of Alzheimer's disease (AD), but whether its neural substrates could adapt to early disease progression and contribute to cognitive resilience in amnestic mild cognitive impairment (aMCI) has been unclear. Fifty-five aMCI patients and 68 normal controls (NC) performed a change-detection task and underwent multimodal neuroimaging scanning. Among the atrophic brain regions in aMCI, VSTM performance correlated with the volume of the right prefrontal cortex (PFC) but not the medial temporal lobe (MTL), and this correlation was mainly present in patients with greater MTL atrophy. Furthermore, VSTM was primarily correlated with frontal structural connectivity in aMCI but was correlated with more distributed frontal and MTL connectivity in NC. This study provided evidence on neural adaptation in the precursor stages of AD, highlighting the compensatory role of PFC as MTL deteriorated and suggesting potential targets in early intervention for cognitive preservation. Atrophic left medial temporal lobe (MTL) no longer correlated with visual short-term memory (VSTM) in amnestic mild cognitive impairment (aMCI). Atrophic right middle frontal area continued to correlate with VSTM in aMCI. Frontal brain-behavior correlation was mainly present in the aMCI subgroup with greater medial temporal lobe (MTL) atrophy. Reliance of VSTM on frontal connectivity increased in compensation for MTL dysfunction.

Discovery of Methylated DNA Biomarkers for Potential Non-Endoscopic Detection of Barrett's Esophagus and Esophageal Adenocarcinoma.

We sought to develop a minimally-invasive, robust, accessible nonendoscopic strategy to diagnose Barrett's esophagus (BE), esophageal adenocarcinoma (EAC), and its immediate precursor lesion, high-grade dysplasia (HGD) based on methylated DNA biomarkers applied to a retrievable sponge-capsule device in a cohort representative of the BE population (i.e., mostly short-segment, non-dysplastic BE, NDBE). We identified 12 candidate methylation markers to distinguish normal vs. abnormal esophagus. These 12 markers were first assayed in 21-paired matched NDBE-normal esophageal tissues, then assessed in a case-control study of 234 esophageal samples collected using a sponge-capsule device. A classification algorithm was developed using Least Absolute Shrinkage and Selection Operator (LASSO) in a 199-patient training set and tested in an independent 35-patient test set. Twelve markers (A1BG, C9orf50, cg00720137, FLI1, GRAMD1B, HOXB13, IRF4, KCNQ3, NTNG1, SPX, TBC1D30, and USP44) were significantly hypermethylated (i.e., all P<0.05) in BE vs. matched normal esophageal biopsies. A discriminatory three-gene LASSO panel (USP44, TBCD1D30, NELL1), adjusted for age and sex, accurately distinguished HGD or EAC from normal control patients in both training (AUC=0.911, 95%CI=0.863-0.959) and test (AUC=0.969, 95%CI=0.911-1.00) sets. In normal vs. NDBE/LGD/HGD/EAC patients, this algorithm exhibited AUCs of 0.862 (95%CI=0.812-0.912) and 0.864 (95%CI=0.745-0.982) in training and test sets, respectively. In normal vs. NDBE patients, the algorithm yielded AUCs of 0.819 (95%CI=0.748-0.889) and 0.776 (95%CI=0.583-0.968) in training and test sets, respectively. This discriminatory biomarker panel algorithm exemplifies a practical nonendoscopic strategy to diagnose BE, HGD, and EAC using a minimally-invasive sponge-capsule device coupled with DNA methylation markers.

Altered Sensorimotor Striatal Network Connectivity in Women With Anorexia Nervosa.

Anorexia nervosa (AN) is associated with disturbances in reward processing, cognitive control, and body image perception, implicating striatal dysfunction. Evidence suggests that underweight may modulate brain function in AN. We aimed to investigate whole-brain resting-state functional connectivity (rsFC) of the striatum in patients with AN while controlling for the acute effects of underweight. Using theoretically selected striatal sub-regions, whole-brain rsFC patterns of the striatum were compared among patients with AN (n=39, BMI=16.19±1.48kg/m2), normal weight healthy controls (NHC) (n=31, BMI=20.98±1.72kg/m2), and underweight healthy controls (UHC) (n=22, BMI=16.68±0.69kg/m2). Correlation analysis between rsFC and clinical measures was conducted for the patients with AN. Compared with the NHC group, AN patients showed increased striatal rsFC with the fronto-parietal network (FPN) and reduced striatal rsFC with sensorimotor and visual regions. Compared with the UHC group, AN patients exhibited reduced striatal rsFC solely with sensorimotor and visual regions. No significant correlations were found between striatal rsFC and clinical variables in the patients with AN. Our findings suggest that decreased striatal rsFC with sensorimotor and visual areas may represent illness-specific neural correlates in patients with AN.

Regulation of reactive oxygen species and the role of mitochondrial apoptotic-related genes in rheumatoid arthritis

Previous research suggests mitochondrial apoptosis alleviates rheumatoid arthritis (RA), but the role of mitochondrial apoptosis-related genes (MARGs) is unclear. Urgent exploration of RA-related mitochondrial apoptosis biomarkers is needed. Gene Expression Ontology (GEO)-derived RA datasets were used to identify differentially expressed genes (DEGs) compared to normal controls, intersected with MARGs to obtain differentially expressed mitochondrial apoptosis-related genes (DE-MARGs). Three ML algorithms screened diagnostic biomarkers. A nomogram was built and validated by receiver operating characteristic (ROC) analysis. Gene Set Enrichment Analysis (GSEA), regulatory network, and drug prediction explored biomarker mechanisms. Finally, key cells analysis included clustering, type annotation, pseudo-temporal study, and interaction, focusing on validated biomarker expression in those cells. A total of 147 DE-MARGs linked to energy & ROS metabolism were identified. Four validated biomarkers (MRPS10, EEF2, HSPA9, TUFM) formed a new RA diagnostic model. Moreover, GSEA linked them to oxidative phosphorylation. YY1 regulates EEF2, HSPA9, MRPS10; FOXO3 regulates EEF2, TUFM. Drugs like Nonoxynol-9, Nedocromil, Gadobutrol target these biomarkers. In addition, biomarkers are expressed in plasmablasts, with CD74 as a key receptor binding multiple ligands. RA biomarkers (MRPS10, EEF2, HSPA9, TUFM) linked to energy & ROS, progression tied to AMPK/mTOR, CD74-MIF crucial. Study advances RA pathogenesis knowledge, supporting clinical diagnosis.

Single-cell and bulk RNA sequencing analysis reveals CENPA as a potential biomarker and therapeutic target in cancers.

Cancer remains one of the most significant public health challenges worldwide. A widely recognized hallmark of cancer is the ability to sustain proliferative signaling, which is closely tied to various cell cycle processes. Centromere Protein A (CENPA), a variant of the standard histone H3, is crucial for selective chromosome segregation during the cell cycle. Despite its importance, a comprehensive pan-cancer bioinformatic analysis of CENPA has not yet been conducted. Data on genomes, transcriptomes, and clinical information were retrieved from publicly accessible databases. We analyzed CENPA's genetic alterations, mRNA expression, functional enrichment, association with stemness, mutations, expression across cell populations and cellular locations, link to the cell cycle, impact on survival, and its relationship with the immune microenvironment. Additionally, a prognostic model for glioma patients was developed to demonstrate CENPA's potential as a biomarker. Furthermore, drugs targeting CENPA in cancer cells were identified and predicted using drug sensitivity correlations and protein-ligand docking. CENPA exhibited low levels of gene mutation across various cancers. It was found to be overexpressed in nearly all cancer types analyzed in TCGA, relative to normal controls, and was predominantly located in the nucleus of malignant cells. CENPA showed a strong association with the cancer cell cycle, particularly as a biomarker for the G2 phase. It also emerged as a valuable diagnostic and prognostic biomarker across multiple cancer types. In glioma, CENPA demonstrated reliable prognostic potential when used alongside other prognostic factors. Additionally, CENPA was linked to the immune microenvironment. Drugs such as CD-437, 3-Cl-AHPC, Trametinib, BI-2536, and GSK461364 were predicted to target CENPA in cancer cells. CENPA serves as a crucial biomarker for the cell cycle in cancers, offering both diagnostic and prognostic value.

Dysregulation of the molecular clock by blood-borne factors in Alzheimer's disease patients.

Circadian disruptions are increasingly recognized in Alzheimer's disease (AD) patients and may influence disease onset and progression. This study examines how AD pathology affects blood-borne factors that regulate circadian rhythms. Eighty-five participants from the Sino Longitudinal Study on Cognitive Decline were enrolled: 35 amyloid-beta negative normal controls (Aβ- NCs), 23 amyloid-beta positive normal controls (Aβ+ NCs), 15 patients with amnestic mild cognitive impairment (aMCI), and 12 with Alzheimer's disease dementia (ADD). Patients with aMCI and ADD were grouped as cognitively impaired (CI). Cellular circadian period length was assessed using a serum-based assay. Expression levels of clock genes in serum-treated cells and in leukocytes of participants were measured via real-time PCR. Plasma biomarkers were quantified using a single-molecule array immunoassay. Pineal parenchymal and hippocampal volumes were determined by magnetic resonance imaging. The cellular circadian period length was significantly extended by serum from CI patients than by that from Aβ- NCs (p < 0.01). Treatment of cells with serum from the CI patients resulted in suppressed expression of the clock genes Bmal1 and Nr1d1. Strong relationships between the expression levels of clock genes observed in leukocytes of the Aβ- NC group did not appear in those of the Aβ+ NC or CI groups. The significant correlation of cellular circadian period length and the pineal volume was only observed in the Aβ- NC group, but not in the Aβ+ NC or CI groups. This study indicates the presence of significant changes in blood-borne factors that could affect the circadian rhythms in AD, starting even at preclinical stages. These alterations could precede cognitive decline and contribute to AD pathogenesis. The cohort is registered at ClinicalTrials.gov (SILCODE: NCT03370744; Registered on Mar 15th, 2017).

MmuPV1 infection of Tmc6/Ever1 or Tmc8/Ever2 deficient FVB mice as a model of βHPV in typical epidermodysplasia verruciformis.

Typical epidermodysplasia verruciformis (EV) is a rare, autosomal recessive disorder characterized by an unusual susceptibility to infection with specific skin-trophic types of human papillomavirus, principally betapapillomaviruses, and a propensity for developing malignant skin tumors in sun exposed regions. Its etiology reflects biallelic loss-of-function mutations in TMC6 (EVER1), TMC8 (EVER2) or CIB1. A TMC6-TMC8-CIB1 protein complex in the endoplasmic reticulum is hypothesized to be a restriction factor in keratinocytes for βHPV infection. However, the complex is also present in lymphocytes and its loss may compromise cellular immune control of βHPV infection. Indeed, certain primary immunodeficiencies, iatrogenic immunosuppression and AIDS are associated with the atypical form of EV. While well controlled in immunocompetent mice, murine papillomavirus MmuPV1 was first isolated from immunodeficient mice with florid skin warts, modeling atypical EV. To examine their potential as a model of typical EV, Tmc6-/-, Tmc8-/- or wildtype FVB mice were challenged with MmuPV1. At day 16 post vaginal challenge with MmuPV1, the levels of viral transcripts were similar in Tmc6-/- and Tmc8-/- mice and wildtype FVB mice, arguing against Tmc6/8 acting as intracellular restriction factors. Thereafter, greater clearance of MmuPV1 by the wildtype that the Tmc6-/- and Tmc8-/- FVB mice was evident, supporting the hypothesis that typical EV reflects a subtle cellular immune deficit. Indeed, Tmc6-/- or Tmc8-/- mice exhibit partial CD8 T cell deficits and elevated Treg. While interferon-γ production and surface CD25 were similarly elevated in CD8 T cells upon in vitro stimulation with anti-CD3/CD28, the fraction of Tmc6-/- or Tmc8-/- CD8 T cells that were dividing was lower compared to wildtype. Typical EV patients exhibit normal control of most viral infections; Tmc6-/-, Tmc8-/- and wildtype FVB mice similarly controlled vaccinia virus after skin challenge and induced neutralizing antibodies.

Peripapillary and Macular Microvasculature of the Retina in Primary Angle Closure Suspect

Purpose: To compare the macular and peripapillary vascular parameters between the primary angle closure suspect (PACS) eyes and normal control eyes using optical coherence tomography angiography (OCTA).Methods: In this retrospective study, 42 PACS subjects and 38 normal individuals are included. Vessel density (VD) and perfusion density (PD) of the macular area and peripapillary area, and fovea avascular zone parameter were analyzed using OCTA and compared between two groups after adjustment for the axial length.Results: There were no statistically significant differences in sex ratio, age, refractive errors and intraocular pressures between both groups. In the peripapillary area, inferior VD and PD in the outer zone were significantly lower in the PACS eyes, while the retinal nerve fiber layer thicknesses were similar between groups (&lt;i&gt;p&lt;/i&gt; = 0.032, 0.026). In the macular superficial capillary plexus, inferior VD and PD in the inner zone, inferior VD and PD, nasal VD and PD in the outer zone were significantly lower in the PACS eyes, whereas ganglion cell inner plexiform layer thickness were similar between both groups (all &lt;i&gt;p&lt;/i&gt; &lt; 0.005).Conclusions: The VDs and PDs of retinal capillaries in PACS eyes, which have no glaucomatous changes in the retinal nerve fiber layer and optic nerve disc, were significantly lower compared to normal eyes.

Effects of acupuncture at the Taichong (LIV3) and Hegu (LI4) points on functional connectivity with the retrosplenial cortex in patients with Alzheimer’s disease

BackgroundAcupuncture has been demonstrated to have a promising effect on Alzheimer’s disease (AD), but the underlying neural mechanisms remain unclear. The retrosplenial cortex (RSC) is one of the earliest brain regions affected in AD, and changes in its functional connectivity (FC) are reported to underlie disease-associated memory impairment. The aim of this study was to examine the effect of acupuncture on FC with the RSC in patients with AD.MethodsDemographic data, neuropsychological assessments, and resting-state functional magnetic resonance imaging (fMRI) data were collected from 14 AD patients and 14 normal controls (NCs) matched by age, sex, and educational level at baseline. After the baseline MRI scan, acupuncture stimulation on the Taichong (LIV3) and Hegu (LI4) points was performed for 3 min. Then, another 10 min of fMRI data were acquired after the needle was withdrawn. A dataset that included 100 healthy participants was also included to construct a reliable FC map of the RSC. Two sets of regions of interest (ROIs) in the RSC were selected to assess the sustained effect of acupuncture on FC with the RSC in AD patients and NCs.ResultsTwo sets of RSC ROI-based analyses demonstrated robust positive connectivity with the hippocampus (HPC). Furthermore, multiple brain regions, including the bilateral thalamus, bilateral posterior cingulate cortex (PCC), bilateral subcallosal cingulate gyrus (SCG), bilateral orbitofrontal cortex (OFC), and right precuneus, showed decreased FC with the RSC in the AD group and increased FC with the RSC in the NC group after acupuncture compared to that at baseline. Acupuncture also specifically elicited increased FC between the RSC and the HPC as well as between the RSC and the parahippocampal gyrus in AD patients and decreased FC between the RSC and the visual cortices in NCs. Additionally, diminished FC with the RSC was correlated with neuropsychological scale scores in the AD group before acupuncture treatment.ConclusionThese findings confirm and extend previous studies suggesting that acupuncture at Taichong (LIV3) and Hegu (LI4) can exert bidirectional and benign regulatory effects on RSC connectivity in AD patients.

NDUFA11 may be the disulfidptosis-related biomarker of ischemic stroke based on integrated bioinformatics, clinical samples, and experimental analyses

BackgroundProgrammed cell death plays an important role in neuronal injury and death after ischemic stroke (IS), leading to cellular glucose deficiency. Glucose deficiency can cause abnormal accumulation of cytotoxic disulfides, resulting in disulfidptosis. Ferroptosis, apoptosis, necroptosis, and autophagy inhibitors cannot inhibit this novel programmed cell death mechanism. Nevertheless, the potential mechanisms of disulfidptosis in IS remain unclear.MethodsThe GSE16561 dataset was used to screen for differentially expressed disulfidptosis-related biomarkers (DE-DRBs). A correlation between the DE-DRBs was detected. The optimal machine-learning (ML) model and predictor molecules were determined. The GSE58294 dataset was used to verify the accuracy of the optimal ML model. The DE-DRB expression was detected in the blood of patients with IS. Based on IS models, experimental analyses were performed to verify DE-DRB expression and the correlation between DE-DRBs.ResultsLeucine-rich pentatricopeptide repeat-containing (LRPPRC) and NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 (NDUFA11) were identified as DE-DRBs. The NADH: ubiquinone oxidoreductase core subunit S1 (NDUFS1) interacted with NDUFA11 and LRPPRC. The support vector machine (SVM) model was identified as the optimal ML model. The NDUFA11 expression level in the blood of patients with IS was 20.9% compared to that in normal controls. NDUFA11 expression was downregulated in the in vitro/in vivo models of IS. The number of formed complexes of NDUFS1 and NDUFA11 decreased in the in vitro/in vivo models of IS.ConclusionThis research suggests that NDUFA11 is a specific DRB for IS and demonstrates alterations in the disulfidptosis-related protein complexes NDUFS1-NDUFA11.

Single cell transcriptomics in blood of patients with chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Single-cell RNA sequencing (scRNA-seq) provides gene expression profiles at the single-cell level. Hence, we evaluated gene expression in the peripheral blood of patients with COPD.MethodsPeripheral blood samples from seven healthy controls and eight patients with COPD were obtained in this study. The 10X Genomics Chromium Instrument and cDNA synthesis kit were utilized to generate a barcoded cDNA library for single cell RNA-sequencing. We compared the scRNA-seq data between the COPD and control groups using computational analysis. Functional analyses were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses.ResultsscRNA-seq was used to analyze the transcriptome of peripheral blood mononuclear cells from seven normal controls and eight patients with COPD. We found an increased number of monocyte/macrophages in the COPD group compared to the normal control group. Among the differentially expressed genes (DEGs) in monocyte/macrophages, we identified 15 upregulated genes (EGR1, NR4A1, CCL3, CXCL8, PTGS2, CD83, BCL2A1, SGK1, IL1B, BTG2, NFKBIZ, DUSP2, MAFB, PLAUR and CCL3L1) and 7 downregulated genes (FOLR3, RPS4Y1, HLA-DRB5, NAMPT, CD52, TMEM176A and TMEM176B) in the COPD group compared to the normal control group.ConclusionsUsing scRNA-seq, we found differences in cell type distribution, especially in monocyte/ macrophages. Several upregulated and downregulated genes were found in the monocyte/macrophages of the COPD group.

Pathology of Red Blood Cells in Patients with SARS-CoV-2

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been associated with various hematological disorders. Understanding the pathology of erythrocytes (red blood cells) in coronavirus infection may provide insights into disease severity and progression. Objective: To review and analyze the general pathology of erythrocytes in patients infected with SARS-CoV-2, focusing on clinical and laboratory findings across different severity groups. Methods: Patients were classified into four groups based on clinical criteria: Group 1: Regular group (fever, respiratory symptoms, and radiographic evidence of pneumonia). Group 2: Severe group (shortness of breath &gt;30 breaths/min, peripheral blood oxygen saturation &lt;92% at rest, extensive pneumonia, respiratory failure requiring mechanical ventilation, and/or organ failure necessitating intensive care). Group 3: Low saturation group (peripheral blood oxygen saturation &lt;85% at rest). Group 4: Erythroblastosis group (erythroblast count &gt;0.5% among total nucleated blood cells). Clinical laboratory investigations included major routine studies and scanning microspectrophotometry to measure hemoglobin (Hb) spectra in unstained erythrocytes. Results: Erythroblasts were detected in approximately 30% of SARS-CoV-2 patients, predominantly in the severe group. Serum ferritin, C-reactive protein (CRP), and anisocytosis were strongly correlated with disease severity. Microspectrophotometric studies revealed significant changes in hemoglobin adsorption spectra, with an increase in Hb absorbance at 420 nm in severe cases compared to normal controls. Conclusions: Elevated serum ferritin, CRP levels, anisocytosis, and altered hemoglobin absorption at 420 nm wavelength are associated with adverse outcomes in SARS-CoV-2 infection. These findings highlight the potential utility of hematological parameters as markers for disease severity and prognosis in viral infections.

Biochemical characteristics, genetic variants and treatment outcomes of 55 Chinese cases with neonatal intrahepatic cholestasis caused by citrin deficiency

BackgroundThe diagnostic criteria of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) have not been established due to non-specific clinical manifestations, and our understanding on the treatment outcome is still limited. We aim to investigate the biochemical characteristics, genetic variants, and treatment outcome of NICCD patients.MethodsWe compared the nutritional status and biochemical characteristics of 55 NICCD infants and 27 idiopathic neonatal cholestasis (INC) infants. SLC25A13 gene variant analysis was performed for definitive diagnosis of NICCD. NICCD infants received 12 months of lactose-free and/or medium-chain triglyceride-enriched (LF/MCT) formula treatment. The treatment efficacy was evaluated by comparing the outcome of NICCD with the 24 healthy infants that were selected as normal controls. All NICCD patients were followed up until death or at least 1 year of age.ResultsCompared to INC group, significant increase was found in levels of total bilirubin, indirect bilirubin, total bile acid, gamma-glutamyl transpeptidase, alkaline phosphatase, prothrombin time, thrombin time, international normalized ratio, alpha-fetoprotein (AFP), Vitamin D, and Vitamin E of NICCD group, while alanine aminotransferase, albumin, fibrinogen, glucose, and Vitamin A levels showed significant decrease in the NICCD group (P &amp;lt; 0.05). There were 7 novel variants among 19 SLC25A13 variant types. No significant differences were found between NICCD patients treated for 12 months and normal controls. In long term follow-up, 2 cases developed FTTDCD, 8 cases had special dietary habits, and 1 case died from cirrhosis.ConclusionsNICCD showed more severe impairments in liver, coagulation, and metabolic function than INC. Significantly increased AFP levels could provide reference for the differential diagnosis of NICCD. The newly discovered variants may be meaningful for the individualized treatment of NICCD patients. LF/MCT formula was recommended for NICCD patients.

Mechanism Study on the Regulation of Th1/Th2 in the Treatment of Idiopathic Membranous Nephropathy by Shengyang Yiwei Decoction.

Shengyang Yiwei Decoction showed efficacy in idiopathic membranous nephropathy treatment, and this study aimed to assess the underlying molecular mechanisms. Rats with passive Heymann nephritis were divided into the model group, the Shengyang Yiwei Decoction group, the JAK2 inhibitor group, and the STAT3 inhibitor group. Healthy rats served as the normal control. 24-hour urinary protein excretion, IgG deposition, renal histopathology, the expression levels of synaptopodin, nephrin, podocalyxin, interferon-γ, interleukin- 4, T-box expressed in T cells, GATA binding protein-3, and relevant pathway proteins were measured. Within the model group, a notable elevation in the 24-h urinary protein level was observed, accompanied by evident IgG deposition, increased glomerular volume, eosinophilic deposits, diminished expression of podocyte marker proteins, and a discernible imbalance in Th1/Th2 cellular immunity. Conversely, in Shengyang Yiwei Decoction and both inhibitor groups, enhancements were observed across the aforementioned indexes. Shengyang Yiwei Decoction may reduce glomerular podocyte injury through the suppression of the JAK2/STAT3 signaling pathway and modulation of the Th1/Th2 immune balance.

Identification of key genes associated with oxidative stress in ischemic stroke via bioinformatics integrated analysis

BackgroundIschemic stroke (IS) is a common cerebrovascular disease. Although the formation of atherosclerosis, which is closely related to oxidative stress (OS), is associated with stroke-related deaths. However, the role of OS in IS is unknown.MethodsOS-related key genes were obtianed by overlapping the differentially expressed genes (DEGs) between IS and normal control (NC) specimens, IS-related genes, and OS-related genes. Then, we investigated the mechanism of action of key genes. Subsequently, protein–protein interaction (PPI) network and machine learning algorithms were utilized to excavate feature genes. In addition, the network between feature genes and microRNAs (miRNAs) was established to investigate the regulatory mechanism of feature genes. Finally, quantitative PCR (qPCR) was utilized to validate the expression of feature genes with blood specimens.ResultsA total of 42 key genes related to OS were acquired. Enrichment analysis indicated that the key genes were associated with oxidative stress, reactive oxygen species, lipid and atherosclerosis, and cell migration-related pathways. Then, 6 feature genes (HSPA8, NCF2, FOS, KLF4, THBS1, and HSPA1A) related to OS were identified for IS. Besides, 6 feature genes and 255 miRNAs were utilized to establish a feature genes-miRNA network which contained 261 nodes and 277 edges. At last, qPCR results revealed that there was a trend for higher expression of FOS, KLF4, and HSPA1A in IS specimens than in NC specimens. Additionally, HSPA8 expression was significantly decreased in the IS specimens, which was consistent with the findings of the GEO database analysis.ConclusionIn conclusion, 6 feature genes (HSPA8, NCF2, FOS, KLF4, THBS1, and HSPA1A) related to OS were mined by bioinformatics analysis, which might provide a new insights into the evaluation and treatment of IS.Clinical trial number: Not applicable.

Specific plasma metabolite profile in intestinal Behçet’s syndrome

BackgroundIntestinal Behçet’s syndrome (IBS) has high morbidity and mortality rates with serious complications. However, there are few specific biomarkers for IBS. The purposes of this study were to investigate the distinctive metabolic changes in plasma samples between IBS patients and healthy people, active IBS and inactive IBS patients, and to identify candidate metabolic biomarkers which would be useful for diagnosing and predicting IBS.MethodsIn this study, we performed a global untargeted metabolomics approach in plasma samples from 30 IBS patients and 20 healthy subjects. P value < 0.05 and variable importance projection (VIP) values > 1 were considered to be statistically significant metabolites. Univariate receiver operating characteristic (ROC) curve analysis was plotted as a measure for assessing the clinical performance of metabolites, and area under curve (AUC) were assessed.ResultsA total of 147 differentially abundant metabolites (DAMs) were identified between IBS patients and normal control (NC) group. The potential pathways involved in the pathogenesis of IBS include linoleic acid metabolism; GABAergic synapse; biosynthesis of unsaturated fatty acids; valine, leucine and isoleucine biosynthesis; ovarian steroidogenesis; and others. In addition, a total of 103 significant metabolites were selected to distinguish active IBS from inactive IBS patients. Tyrosine metabolism, dopaminergic synapse and neuroactive ligand-receptor interaction were found to be closely related to the disease activity of IBS. Furthermore, three potential metabolites including quinate, stearidonic acid (SDA) and capric acid (CA) could significantly differ IBS patients from NC group. On the other hand, 1-methyladenosine (m1A), genipin, methylmalonic acid (MMA) and ascorbate could significantly differentiated active IBS from inactive IBS patients.ConclusionIn conclusion, this study demonstrated the characteristic plasma metabolic profiles between IBS group and NC group, as well as between active and inactive IBS patients by using an untargeted LC/MS metabolomics profiling approach. In this study, quinate, SDA and CA were identified as potential diagnostic biomarkers for IBS. Additionally, m1A, genipin, MMA and ascorbate could serve as potential biomarkers for evaluating IBS activity. These findings might provide potential valuable insights for developing therapeutic strategies to manage IBS in the future.

Common Variants in PLXNA4 and Correlation to Neuroimaging Phenotypes in Healthy, Mild Cognitive Impairment, and Alzheimer's Disease Cohorts.

A comprehensive genome-wide association study (GWAS) has validated the identification of the Plexin-A 4 (PLXNA4) gene as a novel susceptibility factor for Alzheimer's disease (AD). Nonetheless, the precise role of PLXNA4 gene polymorphisms in the pathophysiology of AD remains to be established. Consequently, this study is aimed at exploring the relationship between PLXNA4 gene polymorphisms and neuroimaging phenotypes intimately linked to AD. This study encompassed 812 subjects with PLXNA4 genotype data, procured from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Employing a tagging strategy, we identified five common variant sites within the PLXNA4 gene and assessed their associations with glucose metabolism, atrophy in AD-related brain regions (including the medial temporal lobe, hippocampus, and parahippocampal gyrus), and intracerebral Aβ deposition. We conducted a comprehensive analysis using a multiple linear regression model, with neuroimaging phenotypes as the dependent variable and PLXNA4 gene polymorphisms as the independent variable while incorporating APOE e4 carrier status, education level, age, and gender as covariates. The subjects were stratified into three groups based on their disease status: the Alzheimer's disease (AD) group, the mild cognitive impairment (MCI) group, and the cognitively normal healthy control (CN) group. Within each group, we examined the associations between PLXNA4 gene polymorphisms and various neuroimaging phenotypes. Our study identified significant associations between the rs156676-A and rs78036292-G alleles and the baseline volumes of the anterior cingulate and middle temporal gyrus, respectively, across the entire population. After 1year of follow-up, a significant correlation was observed between the rs6467431-G allele and accelerated volumetric atrophy of the parahippocampal gyrus in the overall population. Additionally, at the 2-year follow-up, significant correlations were observed between three PLXNA4 loci (rs1863015, rs6467431, rs67468325) and volumetric atrophy in the anterior cingulate, middle temporal gyrus, and hippocampus across the entire population. Specifically, the rs1863015-G allele notably accelerated atrophy of the left middle temporal gyrus and bilateral hippocampus, whereas the A alleles of rs6467431 and rs67468325 markedly accelerated atrophy specifically in the bilateral hippocampus. Subgroup analysis further validated these findings. Additionally, in the baseline CN group, the rs78036292 allele showed a significant correlation with intracerebral Aβ deposition, while in the 2-year follow-up CN group, rs67468325 was significantly associated with alterations in glucose metabolism rates in the right cingulate gyrus. Our findings indicate that PLXNA4 genotypes may modulate the development of AD through their regulation of intracerebral Aβ deposition. Additionally, PLXNA4 genotypes are strongly associated with AD-related brain atrophy and glucose metabolism, suggesting that they may alter susceptibility to AD by modulating neurodegenerative biomarkers.

Boswellic acid synergizes with low-dose ionizing radiation to mitigate thioacetamide-induced hepatic encephalopathy in rats

Hepatic encephalopathy (HE) is a syndrome that arises from acute or chronic liver failure. This study was devised to assess the impact of a combination of boswellic acid (BA) and low doses of gamma radiation (LDR) on thioacetamide (TAA)-induced HE in an animal model. The effect of daily BA treatment (175 mg/kg body weight, for four weeks) and/or fractionated low-dose γ-radiation (LDR; 0.25 Gy, twice the total dose of 0.5 Gy) was evaluated against TAA (200 mg/kg, intraperitoneal) twice-weekly for four weeks to induce liver damage and HE in rats. TAA-exposed rats exhibited a significant elevation in serum activities of liver enzymes (GGT, ALP) and plasma ammonia levels at P < 0.05 (Duncan’s test) compared to the control group. Moreover, there was an increase in the levels of proinflammatory cytokines (IL6, IL12, IL18) in the TAA-exposed animals accompanied by a depletion in the activities of paraoxonase-1 and neurotransmitter contents compared with normal control rats (P < 0.05). However, the administration of BA alone or in combination with LDR led to improvements in liver and brain parameter indices. Furthermore, the histopathological assessments of liver and brain tissues supported the findings of the biochemical investigations. From the statistical analysis, it can be concluded that the combined administration of BA and exposure to LDR may possess potential hepatoprotective effects against hepatic encephalopathy-associated hyperammonemia and the consequent damage to the liver and brain. This study proposes that a combination of therapeutic approaches, LDR and BA could be a new therapeutic candidate for the management of hepatic encephalopathy.

In vivo antidiabetic and ex-vivo antioxidant activities of dichloromethane extract of Xerophyta spekei

BackgroundThe medicinal plant Xerophyta spekei is used among Embu and Mbeere communities to manage diabetes mellitus. However, its efficacy has never been evaluated in vivo. The purpose of this study was to investigate its quantitative phytochemical and antidiabetic potential. Extraction was done using Dichloromethane (DCM). Quantitative phytochemical analysis was conducted using GC-MS. To evaluate antidiabetic activity, groups of mice which included normal control, diabetic control, positive control, and extract-administered groups (50, 100, 150, and 200 mg/kg body weight) were used. Alloxan monohydrate was used to induce diabetes. Blood glucose of the mice was determined hourly for the first six hours, and once after 12 and 24 h on the first day. Thereafter, the blood glucose in mice was determined once a week for three weeks. During the experimental period of three weeks, body weights were determined. After 21 days, lipid profiles, kidney and liver function tests as well as ex vivo antioxidant assays were carried out.ResultsThe phytochemicals classes identified included flavonoids, phenolic compounds, phytosterols, terpenoids, fatty acids, tocopherols and alkaloids. Stigmasterol had the highest concentration (12.99 ± 2.56 mg/g). The extract decreased blood glucose dose-dependently, with 200 mg/kg bw dose resulting in the highest % mean change (40.10 ± 0.95). The extract gradually decreased blood glucose during 21 days of treatment. It attenuated loss of body weight and aberrant biochemical parameters including liver and renal function tests as well as lipid profiles in diabetic mice. Furthermore, it reduced levels of malondialdehyde and enhanced enzymatic antioxidant activities in diabetic mice.ConclusionsThe study confirms that DCM extract X. spekei contains phytochemicals with antioxidant and antidiabetic properties. The findings authenticate the folkloric use of X. spekei in managing diabetes mellitus. The medicinal plant also serves as a potential source for developing antidiabetic agents.

ATXN2 polyglutamine intermediate repeats length expansions in Malaysian patients with amyotrophic lateral sclerosis (ALS).

Intermediate CAG repeats from 29 to 33 in the ATXN2 gene contributes to the risk of amyotrophic lateral sclerosis (ALS) in European and Asian populations. In this study, 148 ALS patients of multiethnic descent: Chinese (56.1%), Malay (24.3%), Indian (12.8%), others (6.8%) and 100 neurologically normal controls were screened for the ATXN2 CAG repeat expansion. The most common repeat length in both the controls and patients was 22. No familial ALS patients were positive for the intermediate repeat sizes (29-33), while four sporadic patients (2.8%) were positive, with one harbouring a rare ATXN2 homozygous 32 repeat expansion, and a likely pathogenic variant in SPAST. All four patients had limb-onset ALS. Despite representing the smallest ethnic group in our patient cohort, three of the four patients with intermediate repeat sizes were of Indian ancestry. This study, which is the first in Malaysia and Southeast Asia, shows that ATXN2 intermediate risk expansions are relevant to ALS in these populations and will help to inform future genetic testing strategies in the clinic.