Healthy Control Individuals Research Articles

Mass spectrometry-based proteomics analysis of human globus pallidus from progressive supranuclear palsy patients discovers multiple disease pathways.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date.Unbiased global proteome analysis of patients' brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell. In this study, we conducted unbiased mass spectrometry-based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11-plex isobaric tandem mass tag (TMT)-based multiplexing experiments. The identified proteins were subjected to statistical analysis, such as a permutation-based statistical analysis in the significance analysis of microarray (SAM) method and bootstrap receiver operating characteristic curve (ROC)-based statistical analysis. Subsequently, we conducted bioinformatics analyses using gene set enrichment analysis, Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein-protein interaction (PPI) analysis, and weighted gene co-expression network analysis (WGCNA). We have identified 10,231 proteins with ∼1,000 differentially expressed proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non-alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b-c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent STRING PPI analysis and the WGCNA further supported that the mitochondrial proteins were the most highly enriched in PSP. Our study showed that the mitochondrial respiratory electron transport chain complex was the key proteins that were dysregulated in GP of PSP, suggesting that the mitochondrial respiratory electron transport chain complex could potentially be involved in the pathogenesis of PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the mechanistic pathogenesis of PSP.

Analysis of DYRK1B, PPARG, and CEBPB Expression Patterns in Adipose-Derived Stem Cells from Patients Carrying DYRK1B R102C and Healthy Individuals During Adipogenesis.

Background: Metabolic syndrome (MetS) is a group of signs and symptoms that are associated with a higher risk of type 2 diabetes mellitus and cardiovascular diseases. The major risk factor for developing MetS is abdominal obesity, which is caused by an increase in adipocyte size or quantity. Increased adipocyte quantity is a result of differentiation of stem cells into adipose tissue. Numerous studies have investigated the expression of key transcription factors, including PPARG and CEBPB during adipocyte differentiation in murine cells such as 3T3-L1 cell lines. To better understand the expression changes during the process of fat accumulation in adipose-derived stem cells (ASCs), we compared the expression of DYRK1B, PPARG, and ẟB in ASCs between the patient (harboring DYRK1B R102C) and control (healthy individuals) groups. Methods: Gene expression was evaluated on the eighth day before induction and days 1, 5, and 15 postinduction. The pluripotent capacity of ASCs and the potential for differentiation into adipocytes were confirmed by flow cytometry analysis of surface markers (CD34, CD44, CD105, and CD90), and Oil Red O staining, respectively. The Expression of DYRK1B, PPARG, and CEBPB were assessed by real-time-polymerase chain reaction in patients and normal individuals. The effects of AZ191, a potent small molecule inhibitor on DYRK1B and CEBPB expression in patients' samples were studied. Result: The expression of DYRK1B kinase and transcription factors (CEBPB and PPARG) are higher in ASCs harboring DYRK1B R102C compared with noncarriers on days 5 and 15 during adipocyte differentiation. These proteins may be helpful to elucidate the mechanisms underlying obesity and obesity-related disorders like MetS. Furthermore, the new compound AZ191 exhibited inhibitory activity toward DYRK1B and CEBPB. We suggest that AZ191 may be helpful in defining the potential roles of DYRK1B and CEBPB in adipogenesis.

Hippocampal Network Dysfunction in Early Psychosis: A 2-Year Longitudinal Study

BackgroundHippocampal abnormalities are among the most consistent findings in schizophrenia. Numerous studies have reported deficits in hippocampal volume, function, and connectivity in the chronic stage of illness. While hippocampal volume and function deficits are also present in the early stage of illness, there is mixed evidence of both higher and lower functional connectivity. Here, we use graph theory to test the hypothesis that hippocampal network connectivity is broadly lowered in early psychosis and progressively worsens over 2 years. MethodsWe examined longitudinal resting-state functional connectivity in 140 participants (68 individuals in the early stage of psychosis, 72 demographically similar healthy control individuals). We used an anatomically driven approach to quantify hippocampal network connectivity at 2 levels: 1) a core hippocampal-medial temporal lobe cortex (MTLC) network; and 2) an extended hippocampal-cortical network. Group and time effects were tested in a linear mixed effects model. ResultsEarly psychosis patients showed elevated functional connectivity in the core hippocampal-MTLC network, but contrary to our hypothesis, did not show alterations within the broader hippocampal-cortical network. Hippocampal-MTLC network hyperconnectivity normalized longitudinally and predicted improvement in positive symptoms but was not associated with increasing illness duration. ConclusionsThese results show abnormally elevated functional connectivity in a core hippocampal-MTLC network in early psychosis, suggesting that selectively increased hippocampal signaling within a localized cortical circuit may be a marker of the early stage of psychosis. Hippocampal-MTLC hyperconnectivity could have prognostic and therapeutic implications.

Signatures of Mitochondrial Dysfunction and Impaired Fatty Acid Metabolism in Plasma of Patients with Post-Acute Sequelae of COVID-19 (PASC).

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Shame and guilt activations: Associations and sociodemographic differences among ploysubstance abusers.

Shame and guilt in polysubstance abusers are still understudied despite their significance in substance use disorders (SUD). The goal of the current study is to develop a better understanding of how shame and guilt interact among polysubstance abusers who are receiving residential treatment. The sample of two hundred four males with SUD admitted to five rehabilitation centers from two cities in Pakistan participated in this study. For comparison, 215 age-matched healthy individuals were recruited (control). All participants reported their scores on the state shame and guilt scale (SSGS) and demographic form. A cross-sectional study design was adopted. The group with SUD reported greater activations on SGSS (r = 0.79, p < 0.001) as compared to healthy (control) individuals (r = 0.48, p < 0.001). Further, multivariate analysis indicated that people with SUD who were of older age, unemployed, living in a nuclear family system, with a higher level of education, and low income, experienced higher levels of shame and guilt. Multinomial logistic regression analysis revealed that people with SUD in the age group 41-60 years (OR 5.2, 95%CI 2.4-6.8), unemployed (OR 4.4, 95%CI 3.2-4.7), nuclear family system (OR 5.9, 95%CI 4.5-6.4) and low monthly income group (OR 5.4, 95%CI 3.5-5.8) had a significantly high risk of shame and guilt than the control group. Findings of the current study indicate an association between shame and guilt activation and SUD. These results suggest that polysubstance users may benefit from therapeutic interventions to avoid a generalization of shame and guilt toward their substance use. Reducing shame and guilt should be considered a priority in treating adults with multiple SUD.

Assessment of Depressionn, Anxiety and Stresss among a Samplee of patients with Chronic HepatitissB in Gastroenterology and Hepatology Center/ AL-Najaf Province

Objective: Hepatitis B has recently been identified as the primary cause of cirrhosis, chronic hepatitis, and hepatocellularr cancer (HCC) (1). stress, depression, anxiety, and other psychological problems accompanied with decay in social and work functionality along may occur in patients with CHB (2). The study's objective was to assess the prevalence and severity of depression, anxiety, and stress in a sampling of chronic hepatitis B patients at the gastroenterology and hepatology center in the Iraqi province of Al-Najaf.Subjects and methodd: ̏ The Gastroenterology and Hepatology Center/Al-Sader Medical City/Najaf treated 104 patients with chronic viral hepatitis B who had already been diagnosed with the disease between November 2018 and May 2019. 100 people who appeared to be in good health were also added as a control group. To evaluate mental health, the Depression, Anxiety, Stress scale (DASS-21) in Arabic was employed.Results: Depression, anxiety and stress which associated in patients with hepatitis B were significantly affected on quality of life of those patients where the prevalence rate of depression, anxiety and stress was significantly high in compared with healthy control group and within extremely severe stage.Conclusion: In conclusion, chronic hepatitis B patients have a higher significantly prevalence rate and level of severity of depression, anxiety and stress which consequently greatly affected on quality of life in comparison to healthy control individuals at the province of AL-gastroenterology Najaf's and hepatology center .

Infliximab and Tofacitinib Attenuate Neutralizing Antibody Responses Against SARS-CoV-2 Ancestral and Omicron Variants in Inflammatory Bowel Disease Patients After 3 Doses of COVID-19 Vaccine

Infliximab and Tofacitinib Attenuate Neutralizing Antibody Responses Against SARS-CoV-2 Ancestral and Omicron Variants in Inflammatory Bowel Disease Patients After 3 Doses of COVID-19 Vaccine

Key Genes Associated with Pyroptosis in Gout and Construction of a miRNA-mRNA Regulatory Network.

This study aimed to analyze key hub genes related to pyroptosis in gout and construct a miRNA-mRNA regulatory network using bioinformatic tools to elucidate the pathogenesis of gout and offer novel ideas to develop targeted therapeutic strategies for gout. Methods: The GSE160170 dataset was downloaded from the GEO database. The expression data extracted from the dataset were used to screen for differentially expressed genes (DEGs), which intersected with pyroptosis-related genes. These DEGs were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and a protein–protein interaction (PPI) network was constructed to identify pyroptosis-related hub DEGs. The relationship between upstream miRNAs and the hub genes was analyzed, miRNA-mRNA networks belonging to gout disease were constructed and samples from patients with gout were used for experimental verification. The CTDbase tool was used to analyze the identified hub genes and construct a molecular docking model. Results: A total of 943 DEGs (380 upregulated and 563 downregulated) were identified by analyzing the data of patients with early-stage gout and healthy control individuals in the GSE160170 dataset. DEGs and pyroptosis-related genes were intersected to obtain 17 pyroptosis-related DEGs associated with gout; of which, 12 were upregulated, and five were downregulated. The results of GO and KEGG analyses revealed that the DEGs were enriched in inflammatory and immune signaling pathways. Additionally, the DEGs were found to regulate inflammatory responses and were associated with apoptosis. TNF, IL-1β, NLRP3, CXCL8, PTGS2, NFE2L2, CASP8, and CD274 were identified as key hub genes in the PPI network, and a miRNA-mRNA network was constructed, which had 16 edges. Experimental validation revealed that PTGS2 and NFE2L2 were significantly upregulated, and CASP8 and CD274 were significantly downregulated in gout. In addition, miR-128-3p, miR-16-5p, miR-155-5p, and miR-20a-5p (associated with the miRNA-mRNA regulatory network) were significantly downregulated in gout. Five potential therapeutic drugs with stable PTGS2 binding were selected to develop a molecular docking model. Conclusion: A miRNA-mRNA potential regulatory network was constructed based on pyroptosis-related DEGs associated with gout. miR-16-5p, miR-128-3p, miR-20a-5p, and miR-155-5p can potentially influence pyroptosis and the occurrence and development of gout by affecting the expression of the PTGS2, CASP8, NFE2L2, and CD274 genes. Screening of celecoxib and resveratrol and other targeted drugs with stable binding. The findings of this study offer valuable insights into the regulatory mechanisms of gout and may help to identify Biomarkers and develop targeted therapeutic strategies for gout.

Correlation between serum trimethylamine-N-oxide concentration and protein energy wasting in patients on maintenance hemodialysis

Objectives Chronic kidney disease (CKD) is a serious health problem that is associated with several systemic changes, including protein energy wasting (PEW). However, the exact mechanism of PEW in CKD remains unclear. As one of the important intestinal flora metabolites and uremic toxins, trimethylamine-N-oxide (TMAO) is involved in CKD-associated mortality, which might play a role in the development of PEW in CKD patients especially in patients on maintenance hemodialysis (MHD). However, this possibility has not been investigated. Methods PEW was diagnosed in a group of CKD patients on MHD according to the criteria of the International Society of Renal Nutrition and Metabolism. Serum TMAO concentration was assessed by high-performance liquid chromatography and mass spectrometry. The association between TMAO concentration and PEW was assessed using linear regression and logistic analysis after adjustment for confounding factors, including basic characteristics, comorbidities, and laboratory findings. Results The circulating TMAO level was higher in the MHD patients than in control (healthy) individuals (5653.76 ± 2853.51 vs. 254.92 ± 197.88 ng/mL, p < 0.001). Further, after the MHD patients were screened for PEW, those with PEW were found to have significantly higher serum TMAO levels than those without PEW (6760.9 vs. 4016.1 ng/mL, p < 0.001). Further, the serum TMAO concentration exhibited a significant negative correlation with body mass index (BMI) and dietary protein intake. In the logistic regression analysis, after adjustment for confounding factors, the serum TMAO concentration was still significantly correlated with PEW occurrence. Conclusions The circulating TMAO level is significantly correlated with the prevalence of PEW in MHD patients. TMAO might be a potential target in the prevention and treatment of PEW in CKD especially ESRD.

Testing of Motor Coordination in Degenerative Neurological Diseases.

Parkinson’s disease (PD) is a progressive movement disorder caused by the death of dopamine-producing cells in the midbrain. PD is the most prevalent movement disorder of the central nervous system and affects more than 6.3 million people in the world. The changes in the motor functions of patients are not easy to be clearly and on-time observed by the clinicians and to make the most well-informed decisions for the treatment. The aim of this paper is the monitoring PD by designing, developing, and evaluating a prototype mobile App using a pressure pen, which collects quantitative and objective information about PD patients, thus allowing clinicians to understand better and make assumptions about the severity and the stage of Parkinson’s disease. This study presents a dynamic spiral test that can only be performed with tablet and pen pressure. Furthermore, the handwriting samples by PD patients and healthy controls individuals are collected by a computerized system, and the measurements of Spiral Deviation, Total Time, and Pen Pressure are processed. The results showed an accurate evaluation of the stage of Parkinson’s disease. Thus, the clinician may use the proposed PD telemonitoring system as a screening test, storing the history of all the patient’s measurements.

Oviductal Glycoprotein 1 Promotes Hypertension by Inducing Vascular Remodeling Through an Interaction With MYH9.

Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classic epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in patients with hypertension is important for investigating hypertension mechanisms. Differential genomic DNA methylation in patients with hypertension, individuals with prehypertension, and healthy control individuals was screened using Illumina 450K BeadChip and verified by pyrosequencing. Plasma OVGP1 (oviduct glycoprotein 1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein-protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays. We found a hypomethylated site at cg20823859 in the promoter region of OVGP1 and plasma OVGP1 levels were significantly increased in patients with hypertension. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, OVGP1 deficiency attenuated angiotensin II-induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that MYH9 (nonmuscle myosin heavy chain IIA) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling. Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.

Reduced brain activity and functional connectivity during creative idea generation in individuals with smartphone addiction.

Since the coronavirus disease 2019 outbreak, the frequency of smartphone use has surged, which has caused an increase in smartphone addiction among individuals. Smartphone addiction can impair various cognitive abilities. However, to date, the impact of smartphone addiction on creative cognition remains unclear. The current functional near-infrared spectroscopy study compared neural differences between smartphone addiction tendency (SAT) and healthy control (HC) individuals during creative idea generation. In particular, by manipulating a key component of creative cognition, that is, overcoming semantic constraints, we explored whether SAT individuals could overcome semantic constraints. Both the SAT and HC groups completed the alternate uses task (AUT) in semantic constraint and unconstraint conditions. The results indicated that the prefrontal cortex (PFC) and temporal regions were less active during AUT in the SAT group than in the HC group. In the SAT group, the PFC was less active under constraint than unconstraint conditions. Moreover, both task-related and resting-state functional connectivity analyses indicated weaker coupling between the PFC and temporal regions in the SAT than in the HC group. Furthermore, the left dorsolateral PFC mediated the effect of smartphone addiction on creative performance. These findings provide unprecedented neuroimaging evidence on the negative impact of smartphone addiction on creative cognition.

Decreased fecal calprotectin levels in Spondyloarthritis patients colonized by Blastocystis spp.

Spondyloarthritis (SpA) is a group of chronic inflammatory systemic diseases mainly characterized by inflammation in the spine and/or peripheral joints. Although a link between SpA-pathogenesis, intestinal inflammation and gut dysbiosis has been proposed, studies have been focused on bacteria-host interactions and very little has been reported regarding intestinal parasites. Here, intestinal parasitic infection of 51 SpA-patients were evaluated and compared to healthy control individuals. No significant differences in the frequency of any parasite between SpA-patients and control individuals were found. Significantly higher levels of fecal calprotectin (FCP) were found in the SpA-patients compared to the control individuals. However, FCP levels were the same when comparing SpA-patients and control individuals, both colonized by Blastocystis spp. On the other hand, when comparing Blastocystis spp. colonized and Blastocystis spp. free SpA-patients, FCP levels were significantly higher in those Blastocystis spp. free. Without ignoring the small sample size as a study limitation, the results showed that in the SpA-patients colonized by Blastocystis spp., the FCP levels were significantly lower than those in the Blastocystis spp. free group and comparable to those in the control group. These findings seem to suggest a relationship between Blastocystis spp. and intestinal inflammation in SpA-patients, but studies intended to explore that interaction specifically should be designed.

S10.3d Yeast Microbiome in patients with inflammatory bowel disease (IBD)

S10.3 The mycobiome characterization: future perspectives or just a trend?, September 24, 2022, 10:30 AM - 12:00 PMObjectiveThe intestinal microbiota plays major roles in host-protective functions and inflammatory bowel diseases (IBDs). Although some data suggest a role of the yeast microbiota in IBD pathogenesis, the available data are rare. The aim of this study was to evaluate the fecal yeast microbiota in patients with IBD.MethodsFungal isolates of the fecal microbiota of 120 patients with IBD and 30 healthy control individuals were determined using conventional and molecular (ITS sequencing and RFLP) methods.ResultsThe mean age of the patients was 37.4 ± 12.2 years (range 15-72 years). Of 120 patients included, 67 had ulcerative colitis (55.8%) and 53 had Crohn's disease (44.2%). Ulcerative colitis was more prevalent in women than Crohn's disease (61.7% vs 50.2%, P <.005). The median time between the onset of symptoms and diagnosis was 9.58 ± 8.56 years. In total, 73 colonies of Candida spp. were isolated from 60 patients with IBD. The most common identified species of Candida were C. albicans (42.4%), C. glabrata (20.5%), and C. krusei (6.8%). The incidence of non-albicans Candida species (57.6%) was higher than C. albicans (42.4%). We observed an increased proportion of C. albicans compared with healthy individuals (28.5% vs 21.6%). The frequencies of C. glabrata were significantly higher among IBD patients rather than the control group (20.5% vs 9.8%).Conclusion Candida albicans were found to be increased in abundance in the IBD samples. These data emphasize the potential importance of yeast microbiota signatures as biomarkers. Moreover, we unravel here disease-specific-Candida species network alterations in IBD, suggesting that, Candida species might play a role in IBD pathogenesis.

Motion energy analysis during speech tasks in medication-naïve individuals with at-risk mental states for psychosis

Movement abnormalities are commonly observed in schizophrenia and at-risk mental states (ARMS) for psychosis. They are usually detected with clinical interviews, such that automated analysis would enhance assessment. Our aim was to use motion energy analysis (MEA) to assess movement during free-speech videos in ARMS and control individuals, and to investigate associations between movement metrics and negative and positive symptoms. Thirty-two medication-naïve ARMS and forty-six healthy control individuals were filmed during speech tasks. Footages were analyzed using MEA software, which assesses movement by differences in pixels frame-by-frame. Two regions of interest were defined—head and torso—and mean amplitude, frequency, and coefficient of variability of movements for them were obtained. These metrics were correlated with the Structured Interview for Prodromal Syndromes (SIPS) symptoms, and with the risk of conversion to psychosis—inferred with the SIPS risk calculator. ARMS individuals had significantly lower mean amplitude of head movement and higher coefficients of movement variability for both head and torso, compared to controls. Higher coefficient of variability was related to higher risk of conversion. Negative correlations were seen between frequency of movement and most SIPS negative symptoms. All positive symptoms were correlated with at least one movement variable. Movement abnormalities could be automatically detected in medication-naïve ARMS subjects by means of a motion energy analysis software. Significant associations of movement metrics with symptoms were found, supporting the importance of movement analysis in ARMS. This could be a potentially important tool for early diagnosis, intervention, and outcome prediction.

Non Classical MHC presentation to Non-classical lymphocytesMR1-restricted T cell activation in physiopathology

Similarly to iNKT cells, mucosal associated invariant T (MAIT) cells express an invariant TCRalpha chain with a limited number of beta chains. These innate-like T cells recognize bacterial ligands presented by the non-polymorphic MR1 molecule. Metabolites derived from bacterial riboflavin synthesis pathway activate MAIT cells to produce granzyme B, Th1 and Th17 cytokines. The recognition of bacterial ligands by MAIT cells is further illustrated by the near absence of MAIT cells in germ-free mice. Most interestingly the riboflavin precursor needs to be modified by small molecules such as methylglyoxal, which level is elevated in obesity and diabetes. Moreover gut micro- biota alterations have been described in diabetes and obesity, both in humans and mouse models. Our recent studies have shown major alterations of MAIT cells in the blood of obese and diabetic patients as compared to healthy lean control individuals, suggesting their potential role in these pathologies. On going studies on the role and activation of MAIT cells in these pathologies will be presented.

Fas cell surface death receptor/Fas ligand genetic variants in gastric cancer patients: A case control study

Background &amp; objectives: Various studies have suggested a correlation between Fas Cell Surface Death Receptor/Fas Ligand (FAS/FASL) variants and multiple types of cancers. The present study aimed to investigate the association between FAS-670A/G and FASL-844C/T and the synergistic effects of both variants on the risk of Gastric Cancer (GC) in the Kurdish population of West of Iran. Methods: This study was conducted by polymerase chain reaction-restriction fragment length polymorphism technique using MvaI and BsrDI restriction enzymes in 98 GC patients and 103 healthy control individuals. Results: According to the obtained results, a significant association (P=0.008) of FASL polymorphism among GC patients and the control group was detected. Furthermore, no significant differences were found in the FAS polymorphism frequencies between GC patients and the control group. Codominant and dominant models in FASL polymorphism showed significant protective effects against GC [odds ratio (OR) =0.307, 95% confidence interval (CI) (0.134-0.705), P=0.005; OR=0.205, 95% CI (0.058-0.718), P=0.013 and OR=0.295, 95% CI (0.129-0.673), P=0.004 for models of codominant CC vs. CT, codominant CC vs. TT and dominant, respectively]. Furthermore, the presence of both FAS-670G and FASL-844T alleles represented a significant protective effect against GC occurrence [OR=0.420, 95% CI (0.181-0.975), P=0.043]. Interpretation &amp; conclusions: So far, we believe this is the first study the results of which suggest that FASL gene variation and its synergistic effects with FAS gene could be associated with the risk of GC in the Kurdish population in the west of Iran.

Higher cardiovascular activation, but normal heartbeat-evoked potentials and cardiac interoceptive accuracy in somatoform disorders and major depressive disorder

The perception-filter model posits that the generation of medically-unexplained symptoms is associated with (I.) more intense afferent bodily signals, (II.) impaired filter system activity to differentiate relevant from irrelevant signals, and (III.) altered perception of bodily signals. We tested these assumptions for cardiac perception in patients with somatoform disorders (SFD), patients with major depressive disorder (MDD) and healthy control (HC) individuals. Heart rate (variability; HR/HRV) and blood pressure served as indicators of bodily signals (I.); heartbeat-evoked potentials (HEPs) assessed during a heartbeat counting task (HCT) and a distraction task indicated filter system activity (II.); interoceptive accuracy (IAc) in the HCT was interpreted as an index of perception (III.). All indicators were assessed before and after a socially-evaluated cold pressor stress task (SECPT) and a control intervention. SFD patients (n ​= ​24) showed higher average HR and diastolic blood pressure, as well as lower HRV than HC individuals (n ​= ​22), but there were no differences in HEPs or IAc. Neither were there significant differences between the SFD and the MDD groups (n ​= ​24), nor any stress effect on HEPs or IAc. Our findings suggest that increased intensity of bodily signals (I.) is the only model assumption that could be supported for patients with fully-developed SFD. • We investigated interoception in somatoform disorders (SFD) and depression (MDD). • SFD and MDD patients had higher heart rate (HR) and blood pressure than controls. • Heartbeat-evoked potentials did not differ between SFD, MDD patients and controls. • Cardiac interoception did not differ between SFD, MDD patients and controls. • Acute stress did not affect heartbeat-evoked potentials and cardiac interoception.

Rationale and design of the “NEurodegeneration: Traumatic brain injury as Origin of the Neuropathology (NEwTON)” study: a prospective cohort study of individuals at risk for chronic traumatic encephalopathy

BackgroundRepetitive head injury in contact sports is associated with cognitive, neurobehavioral, and motor impairments and linked to a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). As the clinical presentation is variable, risk factors are heterogeneous, and diagnostic biomarkers are not yet established, the diagnostic process of CTE remains a challenge. The general objective of the NEwTON study is to establish a prospective cohort of individuals with high risk for CTE, to phenotype the study population, to identify potential fluid and neuroimaging biomarkers, and to measure clinical progression of the disease. The present paper explains the protocol and design of this case-finding study.MethodsNEwTON is a prospective study that aims to recruit participants at risk for CTE, with features of the traumatic encephalopathy syndrome (exposed participants), and healthy unexposed control individuals. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement. Exposed participants receive a comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain MRI for anatomical imaging, diffusion tensor imaging (DTI), resting-state functional MRI (rsfMRI), and quantitative susceptibility mapping (QSM). Questionnaires include topics on life-time head injury, subjective cognitive change, and neuropsychiatric symptoms. Optionally, blood and cerebrospinal fluid are obtained for storage in the NEwTON biobank. Patients are informed about our brain donation program in collaboration with the Netherlands Brain Brank. Follow-up takes place annually and includes neuropsychological assessment, questionnaires, and optional blood draw. Testing of control subjects is limited to baseline neuropsychological tests, MRI scan, and also noncompulsory blood draw.ResultsTo date, 27 exposed participants have finished their baseline assessments. First baseline results are expected in 2023.ConclusionsThe NEwTON study will assemble a unique cohort with prospective observational data of male and female individuals with high risk for CTE. This study is expected to be a primary explorative base and designed to share data with international CTE-related cohorts. Sub-studies may be added in the future with this cohort as backbone.

Microbiota dysbiosis in primary Sjögren's syndrome and the ameliorative effect of hydroxychloroquine.

The human microbiome plays an important role in autoimmune diseases. However, there is limited knowledge regarding the microbiota in individuals with primary Sjögren's syndrome (pSS). Here, we perform 16S ribosomal RNA gene sequencing of fecal, oral, and vaginal samples from a cohort of 133 individuals with pSS, 56 with non-pSS, and 40 healthy control (HC) individuals. Dysbiosis in the gut, oral, and vaginal microbiome is evident in patients with pSS, and oral samples demonstrate the greatest extent of microbial variation. Multiple key indicator bacteria and clinical characteristics are identified across different body sites, implying that microbial dysbiosis has important roles in the pathogenesis of pSS. Furthermore, we observe pSS-like dysbiosis in individuals with pre-clinical pSS or non-pSS-related disease, revealing that microbial shifts could appear prior to pSS. After hydroxychloroquine (HCQ) treatment, microbial dysbiosis in individuals with pSS is partially resolved, although the microbiota composition remain disordered. These results contribute to the overall understanding of the relationship between the microbiome and pSS.