A New Perspective on Huntington's Disease: How a Neurological Disorder Influences the Peripheral Tissues.

Huntington's disease (HD) is a neurodegenerative disorder caused by a toxic, aggregation-prone expansion of CAG repeats in the HTT gene with an age-dependent progression that leads to behavioral, cognitive and motor symptoms. Principally affecting the frontal cortex and the striatum, mHTT disrupts many cellular functions. In fact, increasing evidence shows that peripheral tissues are affected by neurodegenerative diseases. It establishes an active crosstalk between peripheral tissues and the brain in different neurodegenerative diseases. This review focuses on the current knowledge of peripheral tissue effects in HD animal and cell experimental models and identifies biomarkers and mechanisms involved or affected in the progression of the disease as new therapeutic or early diagnostic options. The particular changes in serum/plasma, blood cells such as lymphocytes, immune blood cells, the pancreas, the heart, the retina, the liver, the kidney and pericytes as a part of the blood-brain barrier are described. It is important to note that several changes in different mouse models of HD present differences between them and between the different ages analyzed. The understanding of the impact of peripheral organ inflammation in HD may open new avenues for the development of novel therapeutic targets.

Unravelling the Inflammatory Processes in the Early Stages of Diabetic Nephropathy and the Potential Effect of (Ss)-DS-ONJ.

Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. The authors demonstrate that the glycolipid mimetic (Ss)-DS-ONJ is able to abolish inflammation via the induction of autophagy flux and provokes the inhibition of inflammasome complex in ex vivo and in vitro models, using adult kidney explants from BB rats. The contribution of (Ss)-DS-ONJ to reducing inflammatory events is mediated by the inhibition of classical stress kinase pathways and the blocking of inflammasome complex activation. The (Ss)-DS-ONJ treatment is able to inhibit the epithelial-to-mesenchymal transition (EMT) progression, but only when the IL18 levels are reduced by the treatment. These findings suggest that (Ss)-DS-ONJ could be a novel, and multifactorial treatment for DN.

Diterpenoids from the Brown Alga Rugulopteryx okamurae and Their Anti-Inflammatory Activity.

Brown algae of the Family Dictyotaceae produce an array of structurally diverse terpenoids, whose biomedical potential in the anti-inflammatory area has been scarcely explored. Herein, the chemical study of the alga Rugulopteryx okamurae has led to the isolation of ten new diterpenoids: rugukadiol A (1), rugukamurals A-C (2-4), and ruguloptones A-F (6-10). The structures of the new compounds were established by spectroscopic means. Compound 1 exhibits an unprecedented diterpenoid skeleton featuring a bridged tricyclic undecane system. Compounds 2-10 belong to the secospatane class of diterpenoids and differ by the oxygenated functions that they contain. In anti-inflammatory assays, the new diterpenoid 1 and the secospatanes 5 and 10 significantly inhibited the production of the inflammatory mediator NO in LPS-stimulated microglial cells Bv.2 and macrophage cells RAW 264.7. Moreover, compounds 1 and 5 were found to strongly inhibit the expression of Nos2 and the pro-inflammatory cytokine Il1b in both immune cell lines.

Inter- and intra-species variation in genome-wide gene expression of Drosophila in response to parasitoid wasp attack.

BACKGROUND: Parasitoid resistance in Drosophila varies considerably, among and within species. An immune response, lamellocyte-mediated encapsulation, evolved in a subclade of Drosophila and was subsequently lost in at least one species within this subclade. While the mechanisms of resistance are fairly well documented in D. melanogaster, much less is known for closely related species. Here, we studied the inter- and intra-species variation in gene expression after parasitoid attack in Drosophila. We used RNA-seq after parasitization of four closely related Drosophila species of the melanogaster subgroup and replicated lines of D. melanogaster experimentally selected for increased resistance to gain insights into short- and long-term evolutionary changes. RESULTS: We found a core set of genes that are consistently up-regulated after parasitoid attack in the species and lines tested, regardless of their level of resistance. Another set of genes showed no up-regulation or expression in D. sechellia, the species unable to raise an immune response against parasitoids. This set consists largely of genes that are lineage-restricted to the melanogaster subgroup. Artificially selected lines did not show significant differences in gene expression with respect to non-selected lines in their responses to parasitoid attack, but several genes showed differential exon usage. CONCLUSIONS: We showed substantial similarities, but also notable differences, in the transcriptional responses to parasitoid attack among four closely related Drosophila species. In contrast, within D. melanogaster, the responses were remarkably similar. We confirmed that in the short-term, selection does not act on a pre-activation of the immune response. Instead it may target alternative mechanisms such as differential exon usage. In the long-term, we found support for the hypothesis that the ability to immunologically resist parasitoid attack is contingent on new genes that are restricted to the melanogaster subgroup.

The yeast rapid tRNA decay pathway competes with elongation factor 1A for substrate tRNAs and acts on tRNAs lacking one or more of several modifications.

The structural and functional integrity of tRNA is crucial for translation. In the yeast Saccharomyces cerevisiae, certain aberrant pre-tRNA species are subject to nuclear surveillance, leading to 3' exonucleolytic degradation, and certain mature tRNA species are subject to rapid tRNA decay (RTD) if they are appropriately hypomodified or bear specific destabilizing mutations, leading to 5'-3' exonucleolytic degradation by Rat1 and Xrn1. Thus, trm8-Δ trm4-Δ strains are temperature sensitive due to lack of m(7)G(46) and m(5)C and the consequent RTD of tRNA(Val(AAC)), and tan1-Δ trm44-Δ strains are temperature sensitive due to lack of ac(4)C(12) and Um(44) and the consequent RTD of tRNA(Ser(CGA)) and tRNA(Ser(UGA)). It is unknown how the RTD pathway interacts with translation and other cellular processes, and how generally this pathway acts on hypomodified tRNAs. We provide evidence here that elongation factor 1A (EF-1A) competes with the RTD pathway for substrate tRNAs, since its overexpression suppresses the tRNA degradation and the growth defect of strains subject to RTD, whereas reduced levels of EF-1A have the opposite effect. We also provide evidence that RTD acts on a variety of tRNAs lacking one or more different modifications, since trm1-Δ trm4-Δ mutants are subject to RTD of tRNA(Ser(CGA)) and tRNA(Ser(UGA)) due to lack of m(2,2)G(26) and m(5)C, and since trm8-Δ, tan1-Δ, and trm1-Δ single mutants are each subject to RTD. These results demonstrate that RTD interacts with the translation machinery and acts widely on hypomodified tRNAs.

Gut microbiome diversity within Clostridia is negatively associated with human obesity.

Clostridia are abundant in the human gut and comprise families associated with host health such as Oscillospiraceae, which has been correlated with leanness. However, culturing bacteria within this family is challenging, leading to their detection primarily through 16S rRNA amplicon sequencing, which has a limited ability to unravel diversity at low taxonomic levels, or by shotgun metagenomics, which is hindered by its high costs and complexity. In this cross-sectional study involving 114 Colombian adults, we used an amplicon-based sequencing strategy with alternative markers-gyrase subunit B (gyrB) and DNA K chaperone heat protein 70 (dnaK)-that evolve faster than the 16S rRNA gene. Comparing the diversity and abundance observed with the three markers in our cohort, we found a reduction in the diversity of Clostridia, particularly within Lachnospiraceae and Oscillospiraceae among obese individuals [as measured by the body mass index (BMI)]. Within Lachnospiraceae, the diversity of Ruminococcus_A negatively correlated with BMI. Within Oscillospiraceae, the genera CAG-170 and Vescimonas also exhibited this negative correlation. In addition, the abundance of Vescimonas was negatively correlated with BMI. Leveraging shotgun metagenomic data, we conducted a phylogenetic and genomic characterization of 120 metagenome-assembled genomes from Vescimonas obtained from a larger sample of the same cohort. We identified 17 of the 72 reported species. The functional annotation of these genomes showed the presence of multiple carbohydrate-active enzymes, particularly glycosyl transferases and glycoside hydrolases, suggesting potential beneficial roles in fiber degradation, carbohydrate metabolism, and butyrate production. IMPORTANCE: The gut microbiota is diverse across various taxonomic levels. At the intra-species level, it comprises multiple strains, some of which may be host-specific. However, our understanding of fine-grained diversity has been hindered by the use of the conserved 16S rRNA gene. While shotgun metagenomics offers higher resolution, it remains costly, may fail to identify specific microbes in complex samples, and requires extensive computational resources and expertise. To address this, we employed a simple and cost-effective analysis of alternative genetic markers to explore diversity within Clostridia, a crucial group within the human gut microbiota whose diversity may be underestimated. We found high intra-species diversity for certain groups and associations with obesity. Notably, we identified Vescimonas, an understudied group. Making use of metagenomic data, we inferred functionality, uncovering potential beneficial roles in dietary fiber and carbohydrate degradation, as well as in short-chain fatty acid production.

Retinal dysfunction in Huntington's disease mouse models concurs with local gliosis and microglia activation.

Huntington's disease (HD) is caused by an aberrant expansion of CAG repeats in the HTT gene that mainly affects basal ganglia. Although striatal dysfunction has been widely studied in HD mouse models, other brain areas can also be relevant to the pathology. In this sense, we have special interest on the retina as this is the most exposed part of the central nervous system that enable health monitoring of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we need to correlate the retinal alterations with those in the inner brain, i.e., striatum. We confirmed the malfunction of the transgenic R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum. Although tissue-enriched genes were downregulated in both areas, a neuroinflammation signature was only clearly induced in the R6/1 retina in which the observed glial activation was reminiscent of the situation in HD patient's brains. The retinal neuroinflammation was confirmed in the slow progressive knock-in zQ175 strain. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD and its associated glial activation.

[Cutaneous leishmaniasis and multidermatomic herpes zoster]. / Leishmaniasis cutánea y herpes zoster multidermatómico.

Standard treatment of leishmaniasis consists of n-metilglucamine, meglumine antimoniate, which can trigger side effects such as general malaise, renal and hepatic impairment, and cardiac arrhythmias. Infrequently, reactivations of varicella-zoster virus infections have been reported. This paper describes a patient with cutaneous leishmaniasis in treatment with meglumine and herpes zoster multiplex. After ruling out other possible causes of immunosuppression, an acyclovir therapy was initiated.

[Atopic dermatitis in adults during the COVID-19 pandemic]. / Dermatitis atópica en adultos durante la pandemia por COVID-19.

OBJECTIVE: To evaluate the clinical course of atopic dermatitis (AD) in adults during the COVID-19 pandemic and to evaluate their comorbidities and cardiovascular risk. METHODS: A cross-sectional study was conducted in adults with AD. Severity and control of AD, quality of life, levels of psychological stress, depression and cardiovascular risk were measured. RESULTS: Forty-two patients were included. A decrease in POEM score (11.83 vs 10.12; p=0.004) and PO-SCORAD (37.77 vs 32.49; p= 0.001) was observed in comparison to the scores at pandemic onset. The quality of life correlated with the severity of AD (p<0.0001) while the levels of stress and depression did not show association. Most patients had a low cardiovascular risk. CONCLUSIONS: The results suggest a decrease in the current severity of AD compared with severity before pandemic. Quality of life is associated with AD severity.

OBJECTIVO: Evaluar el curso clínico de pacientes adultos con dermatitis atópica durante la pandemia por COVID-19, e identificar las comorbilidades y el riesgo cardiovascular. MÉTODOS: Estudio transversal, llevado a cabo en adultos con dermatitis atópica. Se evaluó la gravedad y el control de la dermatitis, la calidad de vida, el grado de estrés psicológico, depresión y riesgo cardiovascular. RESULTADOS: Se seleccionaron 42 pacientes.Se observó una disminución en el puntaje del POEM (11.83 vs 10.12; p=0.004) y del PO-SCORAD (37.77 vs 32.49; p= 0.001) con relación al inicio de la pandemia. La calidad vida se correlacionó con la gravedad de la dermatitis atópica (p<0.0001) a diferencia de los grados de estrés y depresión. La mayoría de los pacientes tuvo riesgo cardiovascular bajo. CONCLUSIONES: Se encontró disminución de la gravedad actual de la dermatitis atópica comparada con la gravedad antes de la pandemia. La calidad de vida se asocia con la gravedad de la dermatitis atópica.

IL-1ß Implications in Type 1 Diabetes Mellitus Progression: Systematic Review and Meta-Analysis.

During Type 1 Diabetes Mellitus (T1DM) progression, there is chronic and low-grade inflammation that could be related to the evolution of the disease. We carried out a systematic review and meta-analysis to evaluate whether peripheral levels of pro-inflammatory markers such as interleukin-1 beta (IL-1ß) is significantly different among patients with or without T1DM, in gender, management of the T1DM, detection in several biological fluids, study design, age range, and glycated hemoglobin. We searched PubMed, Embase, Web of Science, and Scopus databases, and 26 relevant studies (2186 with T1DM, 2047 controls) were included. We evaluated the studies' quality using the Newcastle−Ottawa scale. Meta-analyses were conducted, and heterogeneity and publication bias were examined. Compared with controls, IL-1ß determined by immunoassays (pooled standardized mean difference (SMD): 2.45, 95% CI = 1.73 to 3.17; p < 0.001) was significantly elevated in T1DM. The compared IL-1ß levels in patients <18 years (SMD = 2.81, 95% CI = 1.88−3.74) was significantly elevated. The hemoglobin-glycated (Hbg) levels in patients <18 years were compared (Hbg > 7: SMD = 5.43, 95% CI = 3.31−7.56; p = 0.001). Compared with the study design, IL-1ß evaluated by ELISA (pooled SMD = 3.29, 95% CI = 2.27 to 4.30, p < 0.001) was significantly elevated in T1DM patients. IL-1ß remained significantly higher in patients with a worse management of T1DM and in the early stage of T1DM. IL-1ß levels determine the inflammatory environment during T1DM.

Synthesis and Antioxidant/Anti-Inflammatory Activity of 3-Arylphthalides.

Phthalides are a group of compounds with relevant biological activities in different areas such as cytotoxicity, anti-stroke activity, neuroprotection, and inflammation, among others. In this study we designed and synthesized a series of 3-arylphthalide derivatives in order to identify their antioxidant and anti-inflammatory activities. The synthetic methodology was established in terms of atom and step economy through a dehydrative coupling reaction between 3-hydroxyphthalide and different properly functionalized arene rings. The evaluation of the antioxidant activity was performed by the ABTS assay and for the anti-inflammatory activity the inhibition of LPS-induced nitric oxide (NO) production in microglial cells Bv.2 and macrophage cells RAW 264.7 was measured. The synthesized compound 3-(2,4-dihydroxyphenyl)phthalide (5a) showed better antioxidant activity than the Trolox standard and caused strong inhibition of NO production in LPS-stimulated Bv.2 and RAW 264.7 cells. In addition, compound 5a reduced the expression of the pro-inflammatory cytokines Il1b and Il6 in RAW 264.7 cells. These results, which are the first account of the anti-inflammatory activity of 3-arylphthalides, suggest that compound 5a could be a promising candidate for more advanced anti-inflammatory studies.

Adult kidney explants is a physiologic model for studying diabetic nephropathy.

Inflammatory processes play a central role in the pathogenesis of diabetic nephropathy (DN) in the early stages of the disease. In vitro approach using cell lines help to understand the mechanisms involves and allow the molecular and biochemical processes. Adult kidney (AK) explants remain an essential instrument for advancing our understanding of the molecular and cellular regulation of signalling pathways from an organotipic view with physiological system interaction integrated. AK explants from T1DM animal model (BB rat) are obtained by slicing central kidney area preserving the organ's cytoarchitecture and reproduce the classical events detected during the DN in an in vivo model such as inflammation, epithelial-mesenchymal transition (EMT) processes by the modulation of a-SMA and e-Cadherin among others which have been determined by qRT-PCR, western-blot and immunohistochemistry. In this regard, AK explants reproduce the signalling pathways involve in DN progression (proinflammatory NFkB and inflammasome complex). This work demonstrates AK explants is a physiological experimental approach for studying the development and progression of DN. Furthermore, the inflammatory processes in AK explants under a diabetic environment and/or BB rats could be modulated by potential treatments for DN.

Medical decision support system using weakly-labeled lung CT scans.

Purpose: Determination and development of an effective set of models leveraging Artificial Intelligence techniques to generate a system able to support clinical practitioners working with COVID-19 patients. It involves a pipeline including classification, lung and lesion segmentation, as well as lesion quantification of axial lung CT studies. Approach: A deep neural network architecture based on DenseNet is introduced for the classification of weakly-labeled, variable-sized (and possibly sparse) axial lung CT scans. The models are trained and tested on aggregated, publicly available data sets with over 10 categories. To further assess the models, a data set was collected from multiple medical institutions in Colombia, which includes healthy, COVID-19 and patients with other diseases. It is composed of 1,322 CT studies from a diverse set of CT machines and institutions that make over 550,000 slices. Each CT study was labeled based on a clinical test, and no per-slice annotation took place. This enabled a classification into Normal vs. Abnormal patients, and for those that were considered abnormal, an extra classification step into Abnormal (other diseases) vs. COVID-19. Additionally, the pipeline features a methodology to segment and quantify lesions of COVID-19 patients on the complete CT study, enabling easier localization and progress tracking. Moreover, multiple ablation studies were performed to appropriately assess the elements composing the classification pipeline. Results: The best performing lung CT study classification models achieved 0.83 accuracy, 0.79 sensitivity, 0.87 specificity, 0.82 F1 score and 0.85 precision for the Normal vs. Abnormal task. For the Abnormal vs COVID-19 task, the model obtained 0.86 accuracy, 0.81 sensitivity, 0.91 specificity, 0.84 F1 score and 0.88 precision. The ablation studies showed that using the complete CT study in the pipeline resulted in greater classification performance, restating that relevant COVID-19 patterns cannot be ignored towards the top and bottom of the lung volume. Discussion: The lung CT classification architecture introduced has shown that it can handle weakly-labeled, variable-sized and possibly sparse axial lung studies, reducing the need for expert annotations at a per-slice level. Conclusions: This work presents a working methodology that can guide the development of decision support systems for clinical reasoning in future interventionist or prospective studies.

Dietary antioxidant intake is inversely associated with 2,3-dinor oxylipin metabolites, the major excreted oxylipins in overweight and obese subjects.

Cardiometabolic disease risk factors, including obesity, insulin resistance, high blood pressure, and dyslipidemia, are associated with elevated oxidative stress biomarkers like oxylipins. Increased adiposity by itself induces various isomers of this oxidized lipid family, while dietary polyphenols show benefits in its regulation. Previously, we showed that specific co-abundant microorganisms characterized the gut microbiota of Colombians and associated differentially with diet, lifestyle, obesity, and cardiometabolic health status, which led us to hypothesize that urinary oxylipins would reflect the intensity of oxidative metabolism linked to gut microbiota dysbiosis. Thus, we selected a convenience sample of 105 participants (age: 40.2 ± 11.9 years, 47.6% women), grouped according to microbiota, cardiometabolic health status, and body mass index (BMI); and evaluated 33 urinary oxylipins by HPLC-QqQ-MS/MS (e.g., isoprostanes, prostaglandins, and metabolites), paired with anthropometry and blood chemistry information and dietary antioxidants estimated from a 24-h food recall. In general, oxylipins did not show differences among individuals who differed in gut microbiota. While the unmetabolized oxylipin levels were not associated with BMI, the total content of oxylipin metabolites was highest in obese and cardiometabolically abnormal subjects (e.g., insulin resistant), mainly by prostaglandin-D (2,3-dinor-11ß-PGF2α) and 15-F2t-IsoPs (2,3-dinor-15-F2t-IsoP and 2,3-dinor-15-epi-15-F2t-IsoP) metabolites. The total polyphenol intake in this cohort was 1070 ± 627 mg/day. After adjusting for body weight, the polyphenol intake was significantly higher in lean than overweight and showed an inverse association with dinor-oxylipin levels in principal component analysis. These results suggest that the 2,3-dinor-oxylipins could be more specific biomarkers associated with BMI than their parent oxylipins and that are sensitive to be regulated by dietary antioxidants.

Does Drosophila sechellia escape parasitoid attack by feeding on a toxic resource?

Host shifts can drastically change the selective pressures that animals experience from their environment. Drosophila sechellia is a species restricted to the Seychelles islands, where it specializes on the fruit Morinda citrifolia (noni). This fruit is known to be toxic to closely related Drosophila species, including D. melanogaster and D. simulans, releasing D. sechellia from interspecific competition when breeding on this substrate. Previously, we showed that larvae of D. sechellia are unable to mount an effective immunological response against wasp attack, while larvae of closely-related species can defend themselves from parasitoid attack by melanotic encapsulation. We hypothesized that this inability constitutes a trait loss due to a reduced risk of parasitoid attack in noni. Here we present a lab experiment and field survey aimed to test the hypothesis that specialization on noni has released D. sechellia from the antagonistic interaction with its larval parasitoids. Our results from the lab experiment suggest that noni may be harmful to parasitoid wasps. Our results from the field survey indicate that D. sechellia was found in ripe noni, whereas another Drosophila species, D. malerkotliana, was present in unripe and overripe stages. Parasitic wasps of the species Leptopilina boulardi emerged from overripe noni, where D. malerkotliana was the most abundant host, but not from ripe noni. These results indicate that the specialization of D. sechellia on noni has indeed drastically altered its ecological interactions, leading to a relaxation in the selection pressure to maintain parasitoid resistance.

Anti-Inflammatory (M2) Response Is Induced by a sp2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy.

Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (SS,1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp2-iminosugar glycolipid (sp2-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (SS)-DS-ONJ in microglia. (SS)-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR.

Effects of chlorpyrifos on the crustacean Litopenaeus vannamei.

Shrimps can be used as indicators of the quality of aquatic systems exposed to a variety of pollutants. Chlorpyrifos is one of the most common pesticides found in environmental samples. In order to evaluate the effects of chlorpyrifos, adult organisms of Litopenaeus vannamei were exposed to two sublethal concentrations of the pesticide (0.7 and 1.3 µg/L) for four days. The LC50 (96-hours) value was determined and Lipid oxidation levels (LPO) and the activities of catalase (CAT), glutathion peroxidase (GPx), glutathion-S-transferase (GST) were assessed on the muscle, hepatopancreas and gills from the exposed organisms. In addition, inhibition of acetylcholinesterase (AChE) was determined in the brain. LC50 (96-hours) was 2.10 µg/L of chlorpyrifos. Catalase activity and LPO were elevated in the three tissues, whereas a decrease of AChE activities in the brain and an increase of GST activity in the hepatopancreas were observed.

Differential epigenetic regulation between the alternative promoters, PRDM1α and PRDM1ß, of the tumour suppressor gene PRDM1 in human multiple myeloma cells.

Multiple myeloma (MM) is a B-cell neoplasm that is characterized by the accumulation of malignant plasma cells in the bone marrow. The transcription factor PRDM1 is a master regulator of plasma cell development and is considered to be an oncosuppressor in several lymphoid neoplasms. The PRDM1ß isoform is an alternative promoter of the PRDM1 gene that may interfere with the normal role of the PRDM1α isoform. To explain the induction of the PRDM1ß isoform in MM and to offer potential therapeutic strategies to modulate its expression, we characterized the cis regulatory elements and epigenetic status of its promoter. We observed unexpected patterns of hypermethylation and hypomethylation at the PRDM1α and PRDM1ß promoters, respectively, and prominent H3K4me1 and H3K9me2 enrichment at the PRDM1ß promoter in non-expressing cell lines compared to PRDM1ß-expressing cell lines. After treatment with drugs that inhibit DNA methylation, we were able to modify the activity of the PRDM1ß promoter but not that of the PRDM1α promoter. Epigenetic drugs may offer the ability to control the expression of the PRDM1α/PRDM1ß promoters as components of novel therapeutic approaches.

El síndrome del túnel carpiano y su abordaje terapéutico / Carpal Tunnel Syndrome and its Therapeutic Approach

Introducción: El síndrome del túnel carpiano es una de las causas más frecuentes de dolor crónico, su mayor incidencia está entre la quinta y sexta década de la vida; en Colombia tiene una alta incidencia, llegando al 14 por ciento especialmente en cierto grupo de trabajadores. El abordaje terapéutico incluye tratamiento médico y quirúrgico; en la actualidad ha sido ampliamente discutida la elección entre método endoscópico y cirugía abierta como primera línea de tratamiento. Objetivo: Desarrollar una revisión acerca de los aspectos clínicos y las diferentes opciones de abordaje terapéutico del síndrome del túnel carpiano a través de una exploración de la literatura científica existente. Métodos: Se realizó una búsqueda en las bases de datos SciELO, PubMed, ScienceDirect y Lilacs con las palabras clave indexadas en el DeCS. Conclusión: El síndrome de túnel carpiano es una entidad común con un impacto clínico importante en la vida del paciente, su sintomatología y sus complicaciones afectan las actividades diarias de quien lo padece; el abordaje terapéutico de esta enfermedad se establece comúnmente de forma escalonada, el abordaje quirúrgico es un tema ampliamente discutido; sin embargo, no hay evidencia contundente que establezca una de las opciones quirúrgicas como la definitiva(AU)

Introduction: Carpal tunnel syndrome is one of the most frequent causes of chronic pain, with its highest incidence between the fifth and sixth decades of life; in Colombia, it has a high incidence, reaching 14 percent especially in a certain group of workers. The therapeutic approach includes medical and surgical treatment; currently, the choice between the endoscopic method or open surgery as the first line of treatment has been widely discussed. Objective: To develop a review of the clinical aspects and the different options of therapeutic approach for carpal tunnel syndrome, through an exploration of the existing scientific literature. Methods: A search was carried out in the SciELO, PubMed, ScienceDirect and Lilacs databases, using the keywords indexed in the DeCS. Conclusion: Carpal tunnel syndrome is a common entity with an important clinical impact on the patient's life; its symptomatology and complications affect the daily activities of those who suffer from it. The therapeutic approach to this disease is commonly established in a stepwise manner; the surgical approach is a widely discussed topic. However, there is no conclusive evidence that establishes one of the surgical options as the definitive one/AU)

VAMP2 is implicated in the secretion of antibodies by human plasma cells and can be replaced by other synaptobrevins.

The production and secretion of antibodies by human plasma cells (PCs) are two essential processes of humoral immunity. The secretion process relies on a group of proteins known as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), which are located in the plasma membrane (t-SNAREs) and in the antibody-carrying vesicle membrane (v-SNARE), and mediate the fusion of both membranes. We have previously shown that SNAP23 and STX4 are the t-SNAREs responsible for antibody secretion. Here, using human PCs and antibody-secreting cell lines, we studied and characterized the expression and subcellular distribution of vesicle associated membrane protein (VAMP) isoforms, demonstrating that all isoforms (with the exception of VAMP1) are expressed by the referenced cells. Furthermore, the functional role in antibody secretion of each expressed VAMP isoform was tested using siRNA. Our results show that VAMP2 may be the v-SNARE involved in vesicular antibody release. To further support this conclusion, we used tetanus toxin light chain to cleave VAMP2, conducted experiments to verify co-localization of VAMP2 in antibody-carrying vesicles, and demonstrated the coimmunoprecipitation of VAMP2 with STX4 and SNAP23 and the in situ interaction of VAMP2 with STX4. Taken together, these findings implicate VAMP2 as the main VAMP isoform functionally involved in antibody secretion.