Mutational landscape of risk variants in comorbid depression and obesity: a next-generation sequencing approach.

Major depression (MD) and obesity are complex genetic disorders that are frequently comorbid. However, the study of both diseases concurrently remains poorly addressed and therefore the underlying genetic mechanisms involved in this comorbidity remain largely unknown. Here we examine the contribution of common and rare variants to this comorbidity through a next-generation sequencing (NGS) approach. Specific genomic regions of interest in MD and obesity were sequenced in a group of 654 individuals from the PISMA-ep epidemiological study. We obtained variants across the entire frequency spectrum and assessed their association with comorbid MD and obesity, both at variant and gene levels. We identified 55 independent common variants and a burden of rare variants in 4 genes (PARK2, FGF21, HIST1H3D and RSRC1) associated with the comorbid phenotype. Follow-up analyses revealed significantly enriched gene-sets associated with biological processes and pathways involved in metabolic dysregulation, hormone signaling and cell cycle regulation. Our results suggest that, while risk variants specific to the comorbid phenotype have been identified, the genes functionally impacted by the risk variants share cell biological processes and signaling pathways with MD and obesity phenotypes separately. To the best of our knowledge, this is the first study involving a targeted sequencing approach toward the study of the comorbid MD and obesity. The framework presented here allowed a deep characterization of the genetics of the co-occurring MD and obesity, revealing insights into the mutational and functional profile that underlies this comorbidity and contributing to a better understanding of the relationship between these two disabling disorders.

The relationship between BDNF and physical activity on depression.

BACKGROUND/OBJECTIVE: Major depressive disorder (MDD) is one of the leading causes of disease burden and disability worldwide. Brain-derived neurotrophic factor (BDNF) seems to have an important role in the molecular mechanisms underlying MDD aetiology, given its implication in regulating neuronal plasticity. There is evidence that physical activity (PA) improves depressive symptoms, with a key role of BDNF in this effect. We aim to perform a systematic review examining the relationship between the BDNF Val66Met polymorphism and the BDNF protein, PA and MDD. METHODS: Both observational and experimental design original articles or systematic reviews were selected, according to the PRISMA statement. RESULTS: Six studies evaluated the Val66Met polymorphism, suggesting a greater impact of physical activity on depression depending on the Val66Met genotype. More discordant findings were observed among the 13 studies assessing BDNF levels with acute or chronic exercise interventions, mainly due to the high heterogeneity found among intervention designs, limited sample size, and potential bias. CONCLUSIONS: Overall, there is cumulative evidence supporting the potential role of BDNF in the interaction between PA and MDD. However, this review highlights the need for further research with more homogeneous and standardised criteria, and pinpoints important confounding factors that must be considered in future studies to provide robust conclusions.

Delving into the relationship between regular physical exercise and cardiac interoception in two cross-sectional studies.

Cardiac interoception, the ability to sense and process cardiac afferent signals, has been shown to improve after a single session of acute physical exercise. However, it remains unclear whether repetitive engagement in physical exercise over time leads to long-term changes in cardiac interoceptive accuracy. It is also unknown whether those changes affect the neural activity associated with the processing of afferent cardiac signals, assessed by the heart-evoked potential (HEP). In this study, we aimed to investigate this hypothesis through two cross-sectional studies, categorizing participants as active or inactive based on physical fitness (Study I; N = 45) or self-reported physical activity levels (Study II; N = 60). Interoception was assessed at rest using the HEP (Studies I and II), the Heartbeat Counting task (Study II), and the Rubber Hand Illusion (RHI) (Study II). Study I showed strong evidence of better cardiovascular fitness in the active group than in the inactive group as well as robust between-group differences in electrocardiogram (ECG) recordings. Study 2 replicated the clear differences in ECG as a function of regular physical activity. Those results were expected due to clear differences in physical activity habits. In contrast, our analysis revealed no robust differences between groups across cardiac interoception tasks and the RHI, although the direct relevance of these measures to interoception remains under investigation. In sum, our results do not provide convincing evidence to support a strong version of the notion that regular physical exercise is associated with an enhanced in cardiac interoception.

Interaction Effect between Physical Activity and the BDNF Val66Met Polymorphism on Depression in Women from the PISMA-ep Study.

The relationship between depression and the Val66Met polymorphism at the brain-derived neurotrophic factor gene (BDNF), has been largely studied. It has also been related to physical activity, although the results remain inconclusive. The aim of this study is to investigate the relationship between this polymorphism, depression and physical activity in a thoroughly characterised sample of community-based individuals from the PISMA-ep study. A total of 3123 participants from the PISMA-ep study were genotyped for the BDNF Val66Met polymorphism, of which 209 had depression. Our results are in line with previous studies reporting a protective effect of physical activity on depression, specifically in light intensity. Interestingly, we report a gene-environment interaction effect in which Met allele carriers of the BDNF Val66Met polymorphism who reported more hours of physical activity showed a decreased prevalence of depression. This effect was observed in the total sample (OR = 0.95, 95%CI = 0.90-0.99, p = 0.027) and was strengthened in women (OR = 0.93, 95%CI = 0.87-0.98, p = 0.019). These results highlight the potential role of physical activity as a promising therapeutic strategy for preventing and adjuvant treatment of depression and suggest molecular and genetic particularities of depression between sexes.

Body mass index interacts with a genetic-risk score for depression increasing the risk of the disease in high-susceptibility individuals.

Depression is strongly associated with obesity among other chronic physical diseases. The latest mega- and meta-analysis of genome-wide association studies have identified multiple risk loci robustly associated with depression. In this study, we aimed to investigate whether a genetic-risk score (GRS) combining multiple depression risk single nucleotide polymorphisms (SNPs) might have utility in the prediction of this disorder in individuals with obesity. A total of 30 depression-associated SNPs were included in a GRS to predict the risk of depression in a large case-control sample from the Spanish PredictD-CCRT study, a national multicentre, randomized controlled trial, which included 104 cases of depression and 1546 controls. An unweighted GRS was calculated as a summation of the number of risk alleles for depression and incorporated into several logistic regression models with depression status as the main outcome. Constructed models were trained and evaluated in the whole recruited sample. Non-genetic-risk factors were combined with the GRS in several ways across the five predictive models in order to improve predictive ability. An enrichment functional analysis was finally conducted with the aim of providing a general understanding of the biological pathways mapped by analyzed SNPs. We found that an unweighted GRS based on 30 risk loci was significantly associated with a higher risk of depression. Although the GRS itself explained a small amount of variance of depression, we found a significant improvement in the prediction of depression after including some non-genetic-risk factors into the models. The highest predictive ability for depression was achieved when the model included an interaction term between the GRS and the body mass index (BMI), apart from the inclusion of classical demographic information as marginal terms (AUC = 0.71, 95% CI = [0.65, 0.76]). Functional analyses on the 30 SNPs composing the GRS revealed an over-representation of the mapped genes in signaling pathways involved in processes such as extracellular remodeling, proinflammatory regulatory mechanisms, and circadian rhythm alterations. Although the GRS on its own explained a small amount of variance of depression, a significant novel feature of this study is that including non-genetic-risk factors such as BMI together with a GRS came close to the conventional threshold for clinical utility used in ROC analysis and improves the prediction of depression. In this study, the highest predictive ability was achieved by the model combining the GRS and the BMI under an interaction term. Particularly, BMI was identified as a trigger-like risk factor for depression acting in a concerted way with the GRS component. This is an interesting finding since it suggests the existence of a risk overlap between both diseases, and the need for individual depression genetics-risk evaluation in subjects with obesity. This research has therefore potential clinical implications and set the basis for future research directions in exploring the link between depression and obesity-associated disorders. While it is likely that future genome-wide studies with large samples will detect novel genetic variants associated with depression, it seems clear that a combination of genetics and non-genetic information (such is the case of obesity status and other depression comorbidities) will still be needed for the optimization prediction of depression in high-susceptibility individuals.

The role of the FTO gene in the relationship between depression and obesity. A systematic review.

Depression and obesity are major global health problems that frequently co-occur. The FTO gene has one of the strongest links with obesity and high body mass index (BMI) in humans. Besides, this gene is highly expressed in the brain, may play a role in the nervous system, and could confer risk for depression, although scarce literature is available in this respect. We perform a systematic review of the relationship between FTO and both conditions. We selected original articles with observational design or reviews, where depression was assessed with ICD-10, DSM-5 or previous versions, published from 2012 (when the first related paper was published) to November 2020, performed in adults, in English or Spanish and having an optimal methodological quality (evaluated with SIGN checklist). Five original studies were finally included. The results regarding the role of FTO in depression-obesity comorbidity were inconclusive. This leads us to endorse further research covering the role of this gene on both conditions, emphasising a more precise characterization of depression, in order to confirm this role.

Absceso intratonsilar, rara causa de odinofagia / Intratonsillar abscess, a rare cause of odynophagia

No disponible

ESM-1 siRNA Knockdown Decreased Migration and Expression of CXCL3 in Prostate Cancer Cells.

Endothelial cell-specific molecule-1 (ESM-1), also known as endocan, is a soluble proteoglycan expressed by the vascular endothelium, which also circulates in the bloodstream. Inflammatory cytokines and proangiogenic growth factors increase its expression, and increased serum levels have been reported in several cancer types and immunocompetent patients with sepsis. The aim of this study was to analyze the expression profile of CXC-chemokines and the effects of ESM-1 gene knockdown in proliferation, migration and CXC-chemokine expression in highly metastatic human prostate PC-3 cells. Expression profiles of CXC-chemokines were analyzed in metastatic PC-3 and non-tumorigenic PWR-1E cells. siRNA-mediated knockdown of ESM-1 was performed into PC-3 cells, which were subsequently tested for cell migration and proliferation. Effect of siRNA transfection on CXC-chemokine expression was further quantified at the transcript and protein level. RT-qPCR analysis and sandwich ELISA assay revealed higher levels of ESM-1 and several CXC-chemokines in metastatic PC-3 cells compared to non-tumorigenic PWR-1E. Transfection of PC-3 cells with ESM-1-siRNA decreased cell migration with no effect on proliferation, and it was accompanied by decrease in the transcript and protein levels of the angiogenic chemokine CXCL3. We report here for the first time the ESM-1 targeting in PC-3 cells, which resulted in decreased migration, which may be related, at least in part, to decreased expression of the angiogenic CXCL3 chemokine, whose expression was found to be reduced in ESM-1-siRNA transfected cells. Additional studies are required to ascertain the biological role of ESM-1 in prostate cancer cells and the link with the expression of CXCL3.

Emergence and spread of a new community-genotype methicillin-resistant Staphylococcus aureus clone in Colombia.

BACKGROUND: Community-genotype methicillin-resistant Staphylococcus aureus (CG-MRSA) clones are a global concern due to their resistance and increased virulence and their ability to cause infections both hospitalized patients and healthy people in the community. Here, we characterize 32 isolates of a new CG-MRSA clone. These isolates were identified in four cities in Colombia, South America. METHODS: The isolates were recovered from four different epidemiological and prospective studies that were conducted in several regions of Colombia. Molecular characterizations included multilocus sequence typing; pulsed-field gel electrophoresis; SCCmec, agr and spa typing; and whole-genome sequencing. RESULTS: All isolates belonged to ST923 (clonal complex 8), harbouring SCCmec IVa and a spa type t1635 and lacking an arginine catabolism mobile element. The isolates were classified as COL923, were resistant to at least one non-beta-lactam antibiotic, and exhibited high frequencies (>60%) of resistance to macrolides and tetracycline. Using whole-genome sequencing, we found that this new clone harbours novel prophage 3 and beta-island structures and a slightly different pathogenicity island 5. Moreover, isolates belonging to the COL923 clone are grouped in a different clade than USA300 and USA300-LV. CONCLUSION: Our results show the emergence and spread of the COL923 clone in different cities in Colombia. This clone is resistant to several antibiotics and possesses new structures in its mobile genetic elements.

Atypical chemokine receptor CCRL2 is overexpressed in prostate cancer cells.

Atypical chemokine receptors have recently emerged as important molecular players in health and diseases; they affect chemokine availability and function and impact a multitude of pathophysiological events, including the tumorigenesis process. This family of atypical receptors comprises five members: ACKR1/DARC, ACKR2/D6, ACKR3/CXCR7, ACKR4/CCRL1, and ACKR5/CCRL2. This work evaluated the differential expression of these receptors in prostate cancer using quantitative PCR. Further evaluation of CCRL2 at the protein level confirmed its overexpression in a metastatic cell line and in malignant prostatic tissues from patients. CCRL2, a presumed member of the atypical chemokine receptor family, plays a key role in lung dendritic cell trafficking to peripheral lymph nodes. Recent studies have reported the expression of CCRL2 in different human cancer cell lines and tissues. However, its function and expression in prostate cancer has not been previously addressed.

The small leucine rich proteoglycan fibromodulin is overexpressed in human prostate epithelial cancer cell lines in culture and human prostate cancer tissue.

BACKGROUND: Fibromodulin is a small leucine-rich proteoglycan important for extracellular matrix organization and essential for tissue repair in multiple organs. The main function of this proteoglycan is the regulation of collagen fibrillogenesis; however, more recently described roles for fibromodulin have expanded to include regulation of angiogenesis, reprogramming of human fibroblasts into pluripotent cells, modulation of TGF-ß activity, inflammatory processes and association with metastatic phenotypes. Additionally, fibromodulin has been identified as a novel tumor-associated antigen in leukemia, lymphoma, and leiomyoma. Knowledge about its expression in the prostate is limited. METHODS: Fibromodulin expression was analyzed in two different malignant and one non-tumorigenic prostatic cell lines in culture, and in benign and malignant human prostate tissue. Expression was analyzed by real time PCR, immunocytochemistry, and immunohistochemistry. DNA sequencing was performed on a PCR fragment amplified with primers specific for the FMOD gene from cDNA obtained from the cultured cell lines. RESULTS: Both immunostaining and real time PCR analysis of cell lines indicated that fibromodulin was differentially expressed in the cancerous cell lines compared to the non-tumorigenic cell line. Likewise, cancerous tissue expressed significantly higher levels of intracellular fibromodulin compared to matched, benign tissue from the same patients, as well as compared to tissue from patients with only benign disease. CONCLUSIONS: The expression of fibromodulin was higher in prostatic cancer cells (cell-lines and human tissue) than in normal/benign prostatic cells. Additional studies are required to determine the biological and clinical significance and whether this proteoglycan has a role in carcinogenesis of the prostate or in prostate cancer related inflammatory processes.

Tamizaje virtual de compuestosinhibidores de la SA P-2de Candida albicans / Virtual screening of inhibitory compounds SEP-2 Candida albicans

El incremento de la resistencia a antifúngicos en Candida spp. una levadurade carácter oportunista asociada a múltiples infecciones superficiales y sistémicas,plantea la necesidad de buscar diferentes estrategias para hallar nuevas opciones terapéuticas más selectivas y específicas. Una alternativa es el tamizaje basado en el acoplamiento virtual. En el presente trabajo, se analizaron 13418 compuestos con estructuras similares a compuestos reconocidos como inhibidores de la proteína SAP-2,seleccionada como diana antifúngica para el análisis virtual. Materiales y métodos: el estudio se realizó utilizando el programa SYBYL 8, al tiempo que se evaluó la afinidadde estas estructuras con los sitios activos de la enzima seleccionada mediante el programa FlexX integrado en SYBYL 8 y se realizó un consenso comparando los resultados con el programa Autodock Vina. Resultados: los resultados obtenidos mostraron una mayor afinidad por móleculas con estructura similar a los antirretrovirales,inhibidores de proteasas; amprenavir, saquinavir e indinavir. Conclusiones: los resultados obtenidos sugieren que estos lnhibidores de proteasas pueden ser propuestos como modelos para la búsqueda de nuevos antifúngicos que sean más selectivos contra Candida spp...

New agents with potential leishmanicidal activity identified by virtual screening of chemical databases: New agents with potential leishmanicidal activity / Nuevos agentes con potencial actividad leishmanicida identificados mediante tamizaje virtual

Introduction and Objectives: Leishmaniosis, a disease caused by a protozoan parasite, remains a serious public health problem threatening about 350 million people around the world, of which 12 million are believed to be currently infected (WHO 2010). To date, there are no vaccines against the species of parasites and the treatment is based only on chemotherapy with toxic-, expensive- and inefficient- drugs. There is an urgent need for better drugs against Leishmania, the etiological agent of the disease. The main anti-leishmanial drug used in Colombia is meglumineantimoniate [chemical name according to the International Union of Pure and Applied Chemistry (IUPAC): Hydroxy-dioxostiborane; (2R,3R,4R,5S)- 6-methylaminohexane-1,2,3,4,5-pentol, (C7H17NO5)], which is not efficient in the treatment of infections caused by Leishmania braziliensis, the most prevalent specie in the Caribbean coast of Colombia. Methods: We performed an in silico virtual screening of several datasets including ChemBridge and Pubchem. We virtually screened a total of 28.755 compounds against a 3D model of 6-phosphoglucono -lactonase (6-PGL) from Leishmania braziliensis to identify novel inhibitors.Molecular docking of databases was performed using the software Sybyl 8.0 and AutoDockVina. Results: The initial virtual screening using a structure-based method identified 10 compounds, which were later tested with AutodockVina and classified according to their docking scores. Conclusions: These novel and potential inhibitors constitute new drug candidates that must be biologically tested to define their value as an alternative chemotherapeutic agent in the treatment of these protozoan infections. Salud UIS 2013; 45 (1): 33-40.

Introducción y Objetivos: Leishmaniosis, una enfermedad causada por un parásito protozoario, representa un serio problema de salud pública que amenaza a cerca de 350 millones de personas alrededor del mundo, de los cuales se cree que unos 12 millones se encuentran actualmente infectados (WHO 2010). A la fecha no existen vacunas contra las especies del parásito y el tratamiento está basado solo en la quimioterapia con medicamentos tóxicos, costosos, e ineficientes. Existe una necesidad urgente por mejores medicamentos contra Leishmania, el agente etiológico de la enfermedad. El principal medicamento en Colombia usado contra la leishmaniosis es el antimoniato de meglumine [nombre químico según los parámetrosde la International Union of Pure and Applied Chemistry (IUPAC): Hydroxy-dioxostiborane; (2R,3R,4R,5S)-6- methylaminohexane-1,2,3,4,5-pentol, (C7H17NO5)], el cual no es eficiente en el tratamiento de infecciones causadas por Leishmania braziliensis, la especie más prevalente en la costa Caribe de Colombia. Métodos: En este trabajo efectuamos un tamizaje virtual in silico de varias bases de datos incluyendo ChemBridge y Pubchem. Con el objetivo de identificar nuevos inhibidores, un total de 28.755 compuestos fueron tamizados virtualmente contra un modelo 3D de la enzima 6-phosphoglucono -lactonase (6-PGL) de Leishmania braziliensis. El acoplamiento molecular de las bases de datos se efectuó con el programa Sybyl 8.0 y AutoDock Vina. Resultados: mediante tamizaje virtual basado en la estructura se identificaron10 compuestos, los cuales fueron posteriormente evaluados con AutodockVina y clasificados de acuerdo a los puntajes de acoplamiento. Conclusiones: Estos nuevos potenciales inhibidores constituyen candidatos a medicamentos que deben ser evaluados biológicamente para definir su valor como alternativas quimioterapéuticas en el tratamiento de estas infecciones parasíticas. Salud UIS 2013; 45 (1): 33-40.

Molecular identification of the parasites causing cutaneous leishmaniasis on the Caribbean coast of Colombia.

All clinical manifestations of leishmaniasis exist in Colombia, the cutaneous form being the most frequent in the department of Sucre, where the Leishmania species associated with cutaneous leishmaniasis (CL) is unknown. This study was carried out to determine which Leishmania species was responsible for CL in Sucre, based on amplification and sequencing of the Cyt b gene. Isolates of Leishmania were obtained after CL diagnosis of eight patients who received attention in several health care centers of the study area. The nucleotide sequences obtained from patients were compared to Leishmania reference strains and six of the isolates identified as Leishmania (Viannia) braziliensis, the remaining two being identified as Leishmania (Viannia) panamensis and Leishmania (Viannia) guyanensis. This represents the first report of the presence of L. (V.) guyanensis on the Caribbean coast of Colombia.