👤 Serge Brand

The effects of different exercise intensities on cognitive outcomes and brain-derived neurotrophic factor (BDNF) concentrations in adolescents with overweight/obesity are not yet fully elucidated. This study aimed: (a) to compare the prevalence of responders to cognitive function and BDNF concentration in adolescents with overweight/obesity participating in a 12-week intervention with high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), and (b) to analyze whether cardiorespiratory fitness (CRF) can explain differences in inter-individual variability between responders and non-responders. Adolescents with overweight/obesity were assigned to HIIT (n = 15), MICT (n = 14), or CG (n = 24). Anthropometrics, body composition, CRF, basal BDNF, and cognitive performance (Trial Making Test (TMT) and Stroop Test (ST)) were evaluated pre- and post-intervention. Training was performed on stationary bikes (3×/week for 12 weeks). The prevalence of responders in ST and TMT was higher in the HIIT group than in CG (93-62%, p = 0.029; 67-33%, p = 0.043), with no differences in MICT. No group differences were found for BDNF responders (HIIT:73%-MICT:71%-CG:46%, p = 0.263). ST and TMT responders had greater CRF improvements than non-responders. HIIT elicited a higher prevalence of cognitive responders than CG. CRF improvements may partially explain individual variability in responsiveness to cognitive outcomes. This is the first study to examine and compare inter-individual variability in cognitive function and BDNF levels following MICT and HIIT interventions in adolescents with overweight/obesity; Exercise intensity and improvements in cardiorespiratory fitness are key factors for optimizing the cognitive effects of interventions in youth with overweight; Twelve weeks of supervised HIIT and MICT training led to increased rates of cognitive responders among adolescents with overweight/obesity. Show less

Suicidal ideation is prevalent among university students and is associated with a complex interplay of psychological, interpersonal, and behavioral factors. While prior research has examined individual predictors such as sleep disturbances, depressive symptoms, and impulsivity, less is known about how these factors co-occur in clinically distinct profiles. This study aimed to identify latent profiles of suicide risk using a multidimensional model.We conducted a secondary data analysis using the Assessing Nocturnal Sleep/Wake Effects on Risk of Suicide (ANSWERS) dataset, which includes self-reported data from 971 U.S. university students aged 18 to 52 years (M = 20.10, SD = 2.41). Seven continuous variables were included as indicators: sleep quality (PSQI), insomnia severity (ISI), depressive symptoms (CES-D), suicidal ideation severity (C-SSRS), thwarted belongingness and perceived burdensomeness (INQ), and total impulsivity (UPPS-P). Latent Profile Analysis (LPA) was employed to identify subgroups, and model fit was assessed using the AIC, BIC, and entropy.Latent Profile Analysis identified five distinct profiles based on indicators of sleep, affect, interpersonal behavior, and impulsivity. These included a severely distressed profile characterized by elevated depressive symptoms, suicidal ideation, sleep disturbances, and interpersonal burden; an interpersonally burdened profile with mild affective symptoms; a moderately symptomatic profile; a psychologically resilient profile with minimal symptoms across domains; and a high impulsivity profile accompanied by emotional dysregulation.This study identified five clinically distinct profiles of suicide risk in a large sample of university students. These results may inform the development of tailored screening and intervention strategies in campus-based mental health settings. Show less

Adherence to antiretroviral therapy is essential for achieving viral suppression. Plasma separation cards (HemaSep; HS-DBS) provide advantages for pharmacokinetic (PK) analysis and adherence monitoring, including simplified sample collection. This study compared the PK of dolutegravir (DTG), nucleoside reverse transcriptase inhibitors (NRTIs), and their intracellular metabolites in the dried plasma and cellular fractions of HS-DBS against the appropriate gold-standard matrices: liquid plasma for parent drugs and Whatman DBS (WM-DBS) for NRTI metabolites. The APT-POCT-01 clinical trial (NCT04302896) is an open-label study assessing drug concentrations following cessation in healthy volunteers. Participants were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15 days. Paired liquid plasma (L-pL), HS-DBS, and WM-DBS samples were collected on Day 15 and following treatment cessation (0-336 hours post-final dose). 29 individuals were included in the PK analysis (15-TDF/14-TAF). Tenofovir diphosphate (TFV-DP) was quantifiable up to 14 days post-cessation in HS-DBS (TAF/TDF) and WM-DBS (TDF) (HS-DBS t½ > 17 days, WM-DBS t½ = 15 days). 3TC-TP and FTC-TP were eliminated more rapidly. Nucleoside di/triphosphate concentrations were 3-7-fold higher, with prolonged half-lives (TFV-DP, FTC-TP), compared with WM-DBS. TFV-DP levels were ~12-fold higher with TDF compared to TAF. For NRTI and DTG, HS-plasma resulted in 1.8-fold higher exposures compared to L-pL. Measurable HS-DBS concentrations were correlated with L-pL and WM-DBS, with Bland-Altman analysis indicating agreement between methods. This study provides important insights into the elimination kinetics of NRTI, their intracellular metabolites and DTG. Plasma separation cards are a promising alternative for adherence monitoring, enabling simultaneous quantification of parent and intracellular moieties from a single sample. Differences in TFV-DP levels between TDF and TAF regimens, and DBS sampling method, underscore the need for matrix and regimen-specific interpretation to validate adherence benchmarks. Show less

Polymorphisms in the adenylate cyclase 9 (ADCY9) gene influence the benefits of the cholesteryl ester transfer protein (CETP) modulator dalcetrapib on cardiovascular events after acute coronary syndrome. We hypothesized that Adcy9 inactivation could improve cardiac function and remodelling following myocardial infarction (MI) in absence of CETP activity. Wild-type (WT) and Adcy9-inactivated (Adcy9 All mice developed LV hypertrophy, dilation, and systolic dysfunction, but Adcy9 Adcy9 inactivation reduced infarct size, pathologic remodelling, and cardiac dysfunction. These changes were accompanied by preserved myocardial capillary density and increased adaptive immune response. Most of the benefits of Adcy9 inactivation were only observed in the absence of CETP. Show less

The large HDL particles generated by administration of cholesteryl ester transfer protein inhibitors (CETPi) remain poorly characterized, despite their potential importance in the routing of cholesterol to the liver for excretion, which is the last step of the reverse cholesterol transport. Thus, the effects of the CETPi dalcetrapib and anacetrapib on HDL particle composition were studied in rabbits and humans. The association of rabbit HDL to the LDL receptor (LDLr) in vitro was also evaluated. New Zealand White rabbits receiving atorvastatin were treated with dalcetrapib or anacetrapib. A subset of patients from the dal-PLAQUE-2 study treated with dalcetrapib or placebo were also studied. In rabbits, dalcetrapib and anacetrapib increased HDL-C by more than 58% (P < 0.01) and in turn raised large apo E-containing HDL by 66% (P < 0.001) and 59% (P < 0.01), respectively. Additionally, HDL from CETPi-treated rabbits competed with human LDL for binding to the LDLr on HepG2 cells more than control HDL (P < 0.01). In humans, dalcetrapib increased concentrations of large HDL particles (+69%, P < 0.001) and apo B-depleted plasma apo E (+24%, P < 0.001), leading to the formation of apo E-containing HDL (+47%, P < 0.001) devoid of apo A-I. Overall, in rabbits and humans, CETPi increased large apo E-containing HDL particle concentration, which can interact with hepatic LDLr. The catabolism of these particles may depend on an adequate level of LDLr to contribute to reverse cholesterol transport. Show less

Antigen presentation via major histocompatibility complex (MHC) class I and class II receptors plays a fundamental role in T cell-mediated adaptive immunity. A dysregulation of this fine-tuned recognition might result in the development of autoimmune diseases such as inflammatory bowel diseases that are characterized by chronic relapsing inflammation of the intestinal tract and a damaged intestinal epithelial barrier. While MHCII receptors are usually expressed by professional antigen presenting cells (APC) only, there is increasing evidence that non-immune cells such as intestinal epithelial cells (IEC) might express MHCII upon stimulation with IFN-γ and thus act as non-professional APC. However, little is known about other factors regulating intestinal epithelial MHC expression. Here, we identify IL-27 as an inducer of different MHCI and MHCII receptor subtypes and the invariant chain (CD74/li) in IEC via the STAT1/IRF1/CIITA axis. CIITA, MHCII, and CD74 expression was significantly increased in IEC from Crohn's disease (CD) patients with active disease compared to controls or CD patients in remission. IEC phagocytosed and digested external antigens and apoptotic cells. IL-27 strongly stimulated antigen processing via the immunoproteasome in a IRF1-dependent manner. In co-culture experiments, antigen-primed IEC strongly enhanced lymphocyte proliferation and IL-2 secretion, dependent on direct cell-cell contact. IL-27 pretreatment of IEC significantly increased CD4 Show less

Patients with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) occasionally develop diffuse large B-cell lymphoma (DLBCL). This mostly results from LPL/WM transformation, although clonally unrelated DLBCL can also arise. LPL/WM is characterized by activating Show less

Schizophrenia (SCZ) is a serious mental condition with an unknown cause. According to the reports, Brodmann Area 10 (BA10) is linked to the pathology and cortical dysfunction of SCZ, which demonstrates a number of replicated findings related to research on SCZ and the dysfunction in tasks requiring cognitive control in particular. Genetics' role in the pathophysiology of SCZ is still unclear. Therefore, it may be helpful to understand the effects of these changes on the onset and progression of SCZ to find novel mechanisms involved in the regulation of gene transcription. In order to determine the molecular regulatory mechanisms affecting the SCZ, the long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) axes in the BA10 area were determined using a bioinformatics approach in the present work. A microarray dataset (GSE17612) consisted of brain post-mortem tissues of the BA10 area from SCZ patients and matched healthy subjects was downloaded from the Gene Expression Omnibus (GEO) database. This dataset included probes for both lncRNAs and mRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also discovered using the DIANA-LncBase and miRTarBase databases. In the ceRNA network, positive correlations between DEmRNAs and DElncRNAs were evaluated using the Pearson correlation coefficient. Finally, lncRNA-associated ceRNA axes were built by using the co-expression and DElncRNA-miRNA-DEmRNA connections. We identified the DElncRNA-miRNA-DEmRNA axes, which included two key lncRNAs ( Show less

Zebrafish can achieve scar-free healing of heart injuries, and robustly replace all cardiomyocytes lost to injury via dedifferentiation and proliferation of mature cardiomyocytes. Previous studies suggested that Wnt/β-catenin signaling is active in the injured zebrafish heart, where it induces fibrosis and prevents cardiomyocyte cell cycling. Here, via targeting the destruction complex of the Wnt/β-catenin pathway with pharmacological and genetic tools, we demonstrate that Wnt/β-catenin activity is required for cardiomyocyte proliferation and dedifferentiation, as well as for maturation of the scar during regeneration. Using cardiomyocyte-specific conditional inhibition of the pathway, we show that Wnt/β-catenin signaling acts cell-autonomously to promote cardiomyocyte proliferation. Our results stand in contrast to previous reports and rather support a model in which Wnt/β-catenin signaling plays a positive role during heart regeneration in zebrafish. Show less

Next-generation phenotyping (NGP) is an application of advanced methods of computer vision on medical imaging data such as portrait photos of individuals with rare disorders. NGP on portraits results in gestalt scores that can be used for the selection of appropriate genetic tests, and for the interpretation of the molecular data. Here, we report on an exceptional case of a young girl that was presented at the age of 8 and 15 and enrolled in NGP diagnostics on the latter occasion. The girl had clinical features associated with Koolen-de Vries syndrome (KdVS) and a suggestive facial gestalt. However, chromosomal microarray (CMA), Sanger sequencing, multiplex ligation-dependent probe analysis (MLPA), and trio exome sequencing remained inconclusive. Based on the highly indicative gestalt score for KdVS, the decision was made to perform genome sequencing to also evaluate noncoding variants. This analysis revealed a 4.7 kb de novo deletion partially affecting intron 6 and exon 7 of the KANSL1 gene. This is the smallest reported structural variant to date for this phenotype. The case illustrates how NGP can be integrated into the iterative diagnostic process of test selection and interpretation of sequencing results. Show less

Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population. A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels. Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels. Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients. Show less

Intestinal cells control delivery of lipids to the body by adsorption, storage and secretion. Copper (Cu) is an important trace element and has been shown to modulate lipid metabolism. Mutation of the liver Cu exporter ATP7B is the cause of Wilson disease and is associated with Cu accumulation in different tissues. To determine the relationship of Cu and lipid homeostasis in intestinal cells, a CRISPR/Cas9 knockout of ATP7B (KO) was introduced in Caco-2 cells. KO cells showed increased sensitivity to Cu, elevated intracellular Cu storage, and induction of genes regulating oxidative stress. Chylomicron structural protein ApoB48 was significantly downregulated in KO cells by Cu. Apolipoproteins ApoA1, ApoC3 and ApoE were constitutively induced by loss of ATP7B. Formation of small sized lipid droplets (LDs) was enhanced by Cu, whereas large sized LDs were reduced. Cu reduced triglyceride (TG) storage and secretion. Exposure of KO cells to oleic acid (OA) resulted in enhanced TG storage. The findings suggest that Cu represses intestinal TG lipogenesis, while loss of ATP7B results in OA-induced TG storage. Show less

Pharmacogenomic studies have shown that ADCY9 genotype determines the effects of the CETP (cholesteryl ester transfer protein) inhibitor dalcetrapib on cardiovascular events and atherosclerosis imaging. The underlying mechanisms responsible for the interactions between ADCY9 and CETP activity have not yet been determined. Adcy9-inactivated ( Adcy9 Adcy9 Adcy9 inactivation protects against atherosclerosis, but only in the absence of CETP activity. This atheroprotection may be explained by decreased macrophage accumulation and proliferation in the arterial wall, and improved endothelial function and autonomic tone. Show less

Galectin-3 (Gal-3) is a β-galactoside binding protein that controls cell-cell and cell-extracellular matrix interactions. In lymphoid organs, gal-3 inhibits B cell differentiation by mechanisms poorly understood. The B cell development is dependent on tissue organization and stromal cell signaling, including IL-7 and Notch pathways. Here, we investigate possible mechanisms that gal-3 interferes during B lymphocyte differentiation in the bone marrow (BM) and spleen. The BM of gal-3-deficient mice (Lgals3 Show less

Inhibition of cholesteryl ester transfer protein (CETP) increases HDL cholesterol (HDL-C) levels. However, the circulating CETP level varies and the impact of its inhibition in species with high CETP levels on HDL structure and function remains poorly characterized. This study investigated the effects of dalcetrapib and anacetrapib, the two CETP inhibitors (CETPis) currently being tested in large clinical outcome trials, on HDL particle subclass distribution and cholesterol efflux capacity of serum in rabbits and monkeys. New Zealand White rabbits and vervet monkeys received dalcetrapib and anacetrapib. In rabbits, CETPis increased HDL-C, raised small and large α-migrating HDL, and increased ABCA1-induced cholesterol efflux. In vervet monkeys, although anacetrapib produced similar results, dalcetrapib caused opposite effects because the LDL-C level was increased by 42% and HDL-C decreased by 48% ( Show less

Proteins of the EXT (Exostosin) 1 family are known for their role in human disease. Mutations in EXT1 cause hereditary multiple exostoses (HME), benign outgrowths of the bones, and therefore were classed as tumor suppressors. More recently, their role during embryonic development of Drosophila and mouse was addressed, revealing important functions of EXT1 genes in major signaling pathways. Here, we report the isolation of three zebrafish members of the EXT1 family, which we named ext1a, ext1b, and ext1c, respectively. They are expressed in restricted temporal and spatial domains during development. Both ext1a and ext1b are provided maternally and expressed during gastrulation: ext1a in the neurectoderm and ext1b in the embryonic midline and in the involuting mesendoderm of the germ ring. During somitogenesis stages, transcripts of all three ext genes can be found in the somitic mesoderm. Furthermore, ext1a is expressed in the dorsal neural tube. These expression domains become more pronounced at 24 hr postfertilization (hpf). At 48 hpf, ext1 genes are present in the brain, while somitic expression ceases. Zebrafish have three members of the EXT1 family, in contrast to only one EXT1 gene in mammals or Xenopus, consistent with the occurrence of partial genome duplications in the teleost lineage. Our expression analysis reveals that the three ext genes have distinct expression patterns, reflecting functional divergence after duplication. In addition, expression of ext1a and ext1c responds to elevated and reduced levels of Sonic hedgehog (shh) signaling in the somites, whereas expression of ext1b does not. This suggests a differential relationship between the shh pathway and individual ext gene function in zebrafish. Show less