PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders.

Prohormone convertase 1/3, encoded by the PCSK1 gene, is a serine endoprotease that is involved in the processing of a variety of proneuropeptides and prohormones. Humans who are homozygous or compound heterozygous for loss-of-function mutations in PCSK1 exhibit a variable and pleiotropic syndrome consisting of some or all of the following: obesity, malabsorptive diarrhea, hypogonadotropic hypogonadism, altered thyroid and adrenal function, and impaired regulation of plasma glucose levels in association with elevated circulating proinsulin-to-insulin ratio. Recently, more common variants in the PCSK1 gene have been found to be associated with alterations in body mass index, increased circulating proinsulin levels, and defects in glucose homeostasis. This review provides an overview of the endocrinopathies and other disorders observed in prohormone convertase 1/3-deficient patients, discusses the possible biochemical basis for these manifestations of the disease, and proposes a model whereby certain missense mutations in PCSK1 may result in proteins with a dominant negative action.FWO VlaanderenThis is the author accepted manuscript. The final version is available from the Endocrine Society via http://dx.doi.org/10.1210/er.2015-111

A generalized framework to expand incomplete phylogenies using non-molecular phylogenetic information

Aim: The increasing availability of molecular information has lifted our understanding of species evolutionary relationships to unprecedent levels. However, current estimates of the world's biodiversity suggest that about a fifth of all extant species are yet to be described, and we still lack molecular information for many of the known species. Hence, evolutionary biologists will have to tackle phylogenetic uncertainty for a long time to come. This prospect has urged the development of software to expand phylogenies based on non-molecular phylogenetic information, and while the available tools provide some valuable features, major drawbacks persist and some of the proposed solutions are hardly generalizable to any group of organisms. Innovation: Here, we present a completely generalized and flexible framework to expand incomplete phylogenies. The framework is implemented in the R package “randtip”, a toolkit of functions that was designed to randomly bind phylogenetically uncertain taxa in backbone phylogenies through a fully customizable and automatic procedure that uses taxonomic ranks as a major source of phylogenetic information. Although randtip can generate fully operative phylogenies for any group of organisms using just a list of species and a backbone tree, we stress that the “blind” expansion of phylogenies using “quick-and-dirty” approaches often leads to suboptimal solutions. Thus, we discuss a variety of circumstances that may require customizing simulation parameters beyond default settings to optimally expand the trees, including a detailed step-by-step tutorial that was designed to provide guidelines to non-specialist users. Main Conclusions: Phylogenetic uncertainty should be tackled with caution, assessing potential pitfalls and opportunities to optimize parameter space prior to launch any simulation. Used judiciously, our framework will help evolutionary biologists to efficiently expand incomplete phylogenies and thereby account for phylogenetic uncertainty in quantitative analysesMinistry of Science and Innovation of Spain, Grant/Award Number: CGL2017- 86926-P; Regional Government of Madrid, Spain, Grant/Award Number: CM/ JIN/2019-00

Dietary and Gut Microbiota Polyamines in Obesity- and Age-Related Diseases

The polyamines putrescine, spermidine, and spermine are widely distributed polycationic compounds essential for cellular functions. Intracellular polyamine pools are tightly regulated by a complex regulatory mechanism involving de novo biosynthesis, catabolism, and transport across the plasma membrane. In mammals, both the production of polyamines and their uptake from the extracellular space are controlled by a set of proteins named antizymes and antizyme inhibitors. Dysregulation of polyamine levels has been implicated in a variety of human pathologies, especially cancer. Additionally, decreases in the intracellular and circulating polyamine levels during aging have been reported. The differences in the polyamine content existing among tissues are mainly due to the endogenous polyamine metabolism. In addition, a part of the tissue polyamines has its origin in the diet or their production by the intestinal microbiome. Emerging evidence has suggested that exogenous polyamines (either orally administrated or synthetized by the gut microbiota) are able to induce longevity in mice, and that spermidine supplementation exerts cardioprotective effects in animal models. Furthermore, the administration of either spermidine or spermine has been shown to be effective for improving glucose homeostasis and insulin sensitivity and reducing adiposity and hepatic fat accumulation in diet-induced obesity mouse models. The exogenous addition of agmatine, a cationic molecule produced through arginine decarboxylation by bacteria and plants, also exerts significant effects on glucose metabolism in obese models, as well as cardioprotective effects. In this review, we will discuss some aspects of polyamine metabolism and transport, how diet can affect circulating and local polyamine levels, and how the modulation of either polyamine intake or polyamine production by gut microbiota can be used for potential therapeutic purposes

Metabotypes of response to bariatric surgery independent of the magnitude of weight loss

Objective Bariatric surgery is considered the most efficient treatment for morbid obesity and its related diseases. However, its role as a metabolic modifier is not well understood. We aimed to determine biosignatures of response to bariatric surgery and elucidate short-term metabolic adaptations. Methods We used a LC- and FIA-ESI-MS/MS approach to quantify acylcarnitines, (lyso)phosphatidylcholines, sphingomyelins, amino acids, biogenic amines and hexoses in serum samples of subjects with morbid obesity (n = 39) before and 1, 3 and 6 months after bariatric surgery. K-means cluster analysis allowed to distinguish metabotypes of response to bariatric surgery. Results For the first time, global metabolic changes following bariatric surgery independent of the baseline health status of the subjects have been revealed. We identify two metabolic phenotypes (metabotypes) at the interval 6 months-baseline after surgery, which presented differences in the levels of compounds of urea metabolism, gluconeogenic precursors and (lyso)phospholipid particles. Clinically, metabotypes were different in terms of the degree of improvement in insulin resistance, cholesterol, low-density lipoproteins and uric acid independent of the magnitude of weight loss. Conclusions This study opens new perspectives and new hypotheses on the metabolic benefits of bariatric surgery and understanding of the biology of obesity and its associated diseases

Characterization of metabolomic profile associated with metabolic improvement after bariatric surgery in subjects with morbid obesity

The exact impact of bariatric surgery in metabolically 'healthy' (MH) or 'unhealthy' (MU) phenotypes for the study of the metabolic improvement is still unknown. We applied an untargeted LC-ESI-TripleTOF-MS-driven metabolomics approach in serum samples from 39 patients with morbid obesity (MH and MU) 1, 3, and 6 months after bariatric surgery. Multiple factor analysis, along with correlation and enrichment analyses, was carried out to distinguish those metabolites associated with metabolic improvement. Hydroxypropionic acids, medium-/long-chain hydroxy fatty acids, and bile acid glucuronides were the most discriminative biomarkers of response between MH and MU phenotypes. Hydroxypropionic (hydroxyphenyllactic-related) acids, amino acids, and glycerolipids were the most significant clusters of metabolites altered after bariatric surgery in MU ( p < 0.001). After surgery, MU and MH changed toward a common metabolic state 3 months after surgery. We observed a negative correlation with changes in waist circumference and cholesterol levels with metabolites of lipid metabolism. Glycemic variables were correlated with hexoses, which, in turn, correlated with gluconic acid and amino acid metabolism. Finally, we noted that hydroxyphenyllactic acid was associated with amino acid and lipid metabolism. Microbial metabolism of amino acid and BA glucuronidation pathways may be the key points of metabolic rearrangement after surgery

The Brazilian Tunable Filter Imager for the SOAR telescope

This paper presents a new Tunable Filter Instrument for the SOAR telescope. The Brazilian Tunable Filter Imager (BTFI) is a versatile, new technology, tunable optical imager to be used in seeing-limited mode and at higher spatial fidelity using the SAM Ground-Layer Adaptive Optics facility at the SOAR telescope. The instrument opens important new science capabilities for the SOAR community, from studies of the centers of nearby galaxies and the insterstellar medium to statistical cosmological investigations. The BTFI takes advantage of three new technologies. The imaging Bragg Tunable Filter concept utilizes Volume Phase Holographic Gratings in a double-pass configuration, as a tunable filter, while a new Fabry-Perot (FP) concept involves technologies which allow a single FP etalon to act over a large range of interference orders and spectral resolutions. Both technologies will be in the same instrument. Spectral resolutions spanning the range between 25 and 30,000 can be achieved through the use of iBTF at low resolution and scanning FPs beyond R ~2,000. The third new technologies in BTFI is the use of EMCCDs for rapid and cyclically wavelength scanning thus mitigating the damaging effect of atmospheric variability through data acquisition. An additional important feature of the instrument is that it has two optical channels which allow for the simultaneous recording of the narrow-band, filtered image with the remaining (complementary) broad-band light. This avoids the uncertainties inherent in tunable filter imaging using a single detector. The system was designed to supply tunable filter imaging with a field-of-view of 3 arcmin on a side, sampled at 0.12" for direct Nasmyth seeing-limited area spectroscopy and for SAM's visitor instrument port for GLAO-fed area spectroscopy. The instrument has seen first light, as a SOAR visitor instrument. It is now in comissioning phase.Comment: accepted in PAS

Hepatic and serum branched-chain fatty acid profile in patients with nonalcoholic fatty liver disease: A case–control study

Objective Alterations in the hepatic lipidome are a crucial factor involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to evaluate the serum and hepatic profile of branched-chain fatty acids (BCFAs) in patients with different stages of NAFLD. Methods This was a case–control study performed in 27 patients without NAFLD, 49 patients with nonalcoholic fatty liver, and 17 patients with nonalcoholic steatohepatitis, defined by liver biopsies. Serum and hepatic levels of BCFAs were analyzed by gas chromatography–mass spectrometry. The hepatic expression of genes involved in the endogenous synthesis of BCFAs was analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). Results A significant increase in hepatic BCFAs was found in subjects with NAFLD compared with those without NAFLD; no differences were observed in serum BCFAs between study groups. Trimethyl BCFAs, iso-BCFAs, and anteiso-BCFAs were increased in subjects with NAFLD (either nonalcoholic fatty liver or nonalcoholic steatohepatitis) compared with those without NAFLD. Correlation analysis showed a relationship between hepatic BCFAs and the histopathological diagnosis of NAFLD, as well as other histological and biochemical parameters related to this disease. Gene expression analysis in liver showed that the mRNA levels of BCAT1, BCAT2, and BCKDHA were upregulated in patients with NAFLD. Conclusions These results suggest that the increased production of liver BCFAs might be related to NAFLD development and progression.This work was funded by the Institute of Health “Carlos III” (ISCIII) and cofunded by the Fondo Europeo de Desarrollo Regional-FEDER (grant number PI20/00505). J.C.F-G was supported by an intensification research program (INT21/00078, ISCIII, Spain; cofunded by the Fondo Europeo de Desarrollo Regional-FEDER), M.A.M-S was supported by a PFIS predoctoral fellowship from the ISCIII (FI21/00003, ISCIII, Spain; cofunded by the Fondo Europeo de Desarrollo Regional-FEDER), and B.R-M was supported by the “Miguel Servet Type I” program (CP19/00098, ISCIII, Spain; cofunded by the Fondo Europeo de Desarrollo Regional-FEDER). The funding organizations played no role in the design of the study, review and interpretation of the data, or final approval of the manuscript. Funding for open access charge: Universidad de Málaga / CBU

An update on the observational facilities at CASLEO

Presentamos una puesta al día sobre los diferentes telescopios e instrumentos disponibles en el Complejo Astronómico El Leoncito (CASLEO), Argentina. Todos los telescopios y sus instrumentos están completamente automatizados, y se operan rutinariamente en modo remoto. Los observadores pueden utilizar el telescopio Jorge Sahade (JS) de 2.15 m para im´agenes, polarimetr´ıa CCD, y espectroscop´ıa (tanto en baja como alta resoluci´on), mientras que se encuentran en estudio nuevos desarrollos instrumentales. Actualmente, cerca del 70 % de los astr´onomos optan por observar en forma remota. El telescopio Helen Sawyer Hogg (HSH) de 0.6 m tambi´en se encuentra disponible para observaci´on remota, y puede usarse para obtener im´agenes con un campo de 9.26×9.26 arcmin2 . Tambi´en operan en el CASLEO dos telescopios menores, a trav´es de sendos convenios con el Nicolaus Copernicus Astronomical Centre (NCAC, Polonia) y el Instituto de Astrof´ısica de Andalucía (IAA, España). La comunidad argentina tiene acceso al 20 % del tiempo disponible en cada uno de estos instrumentos (solo en modo servicio).We present an update on the different telescopes and instruments available at the Complejo Astron´omico El Leoncito (CASLEO), Argentina. All the telescopes and their instruments are fully automated, and are routinely operated in remote mode. Observers can use the 2.15 m Jorge Sahade (JS) telescope for imaging, CCD polarimetry, and spectroscopy (both low and high resolution), future instrumental developments are also in progress. Presently, about 70 % of the astronomers opt to observe remotely. The Helen Sawyer Hogg (HSH) 0.6 m telescope is now also available for remote observing, and it can be used to obtain images with a 9.26 × 9.26 arcmin2 field of view. Two smaller telescopes, operated under agreements with NCAC (Poland) and IAA (Spain), respectively, are also operational at CASLEO. The Argentine community has access to 20 % of the available time at each of these instruments (only in service mode).Fil: Aballay, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Cellone, Sergio Aldo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; ArgentinaFil: Fernández, G. E. L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Giménez, M. A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Giuliani Ramos, Bruno Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Giuliani, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Godoy, Rodolfo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Mammana, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas; ArgentinaFil: Molina, Hector Rolando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; Argentina. Universidad Nacional de San Juan; ArgentinaFil: Ostrov, Pablo Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Pereyra, Pablo Florencio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Pinto, Juan Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; Argentin

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis.

Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS-/-) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS-/- mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS-/- livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease