Computer-Based Annotation of Putative AraC/XylS-Family Transcription Factors of Known Structure but Unknown Function

Currently, about 20 crystal structures per day are released and deposited in the Protein Data Bank. A significant fraction of these structures is produced by research groups associated with the structural genomics consortium. The biological function of many of these proteins is generally unknown or not validated by experiment. Therefore, a growing need for functional prediction of protein structures has emerged. Here we present an integrated bioinformatics method that combines sequence-based relationships and three-dimensional (3D) structural similarity of transcriptional regulators with computer prediction of their cognate DNA binding sequences. We applied this method to the AraC/XylS family of transcription factors, which is a large family of transcriptional regulators found in many bacteria controlling the expression of genes involved in diverse biological functions. Three putative new members of this family with known 3D structure but unknown function were identified for which a probable functional classification is provided. Our bioinformatics analyses suggest that they could be involved in plant cell wall degradation (Lin2118 protein from Listeria innocua, PDB code 3oou), symbiotic nitrogen fixation (protein from Chromobacterium violaceum, PDB code 3oio), and either metabolism of plant-derived biomass or nitrogen fixation (protein from Rhodopseudomonas palustris, PDB code 3mn2)

UHPLC-MS Phenolic Fingerprinting, Aorta Endothelium Relaxation Effect, Antioxidant, and Enzyme Inhibition Activities of Azara dentata Ruiz & Pav Berries

Azara dentata Ruiz & Pav. is a small Chilean native plant from Patagonia, a producer of small white reddish berries. For the first time, the proximal analysis of the fruits, phenolic fingerprinting, the antioxidant activity, and the enzymatic inhibition and relaxation effects in rat aorta induced by the ethanolic extract of these fruits were investigated. The proximal composition and the mineral (Ca: 2434 ± 40 mg/kg; Mg: 702 ± 13 mg/kg; Fe: 117.1 ± 1.6 mg/kg; Zn: 16.1 ± 0.4 mg/kg) and heavy metal (As: 121 ± 11 µg/kg; Cd: 152 ± 5 µg/kg; Hg: 7.7 ± 1.3 µg/kg; Pb 294 ± 4 µg/kg) contents were analyzed. Anthocyanins, flavonoids, phenolic acids, and coumarins were identified using UHPLC-PDA-QTOF-MS. The ethanolic extracts showed a total phenolic content of 23.50 ± 0.93 mg GAE/g extract. In addition, the antioxidant activity was assessed using both DPPH and TEAC (28.64 ± 1.87 and 34.72 ± 2.33 mg Trolox/g of dry fruit, respectively), FRAP (25.32 ± 0.23 mg Trolox equivalent/g dry fruit), and ORAC (64.95 ± 1.23 mg Trolox equivalents/g dry fruit). The inhibition of enzymatic activities (acetylcholinesterase IC50: 2.87 + 0.23 µg extract/mL, butyrylcholinesterase IC50: 6.73 + 0.07 µg extract/mL, amylase IC50: 5.6 ± 0.0 µg extract/mL, lipase IC50: 30.8 ± 0.0 µg extract/mL, and tyrosinase IC50: 9.25 ± 0.15 µg extract/mL) was also assessed. The extract showed 50–60% relaxation in rat aorta (intact), mediated thorough the release of endothelial nitric oxide. Our results suggest that A. dentata is a good source of compounds with the capacity to inhibit important enzymes, can be hypotensive, and can thus have good potentiality as supplements in the amelioration of neurodegenerative diseases and could also have potential to be used to develop new functional foods. The study highlights the benefits of these neglected small fruits and could boost their consumption.Fil: Cuesta Ramos, Lucia. Universidad de Valencia; EspañaFil: Palacios, Javier. Universidad Arturo Prat (unap);Fil: Barrientos, Ruth E.. Universidad Austral de Chile; ChileFil: Gómez Pelaytay, Jessica Belén. Universidad Nacional de San Juan; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan; ArgentinaFil: Castagnini, Juan Manuel. Universidad de Valencia; EspañaFil: Barba, Francisco J.. Universidad de Valencia; EspañaFil: Tapia, Alejandro. Universidad Nacional de San Juan; ArgentinaFil: Paredes, Adrián. Universidad de Antofagasta (uantof);Fil: Cifuentes, Fredi. Universidad de Antofagasta (uantof);Fil: Simirgiotis, Mario J.. Universidad Austral de Chile; Chil

Molecular dissection of structural variations involved in antithrombin deficiency

Inherited antithrombin deficiency, the most severe form of thrombophilia, is predominantly caused by variants in SERPINC1. Few causal structural variants have been described, usually detected by multiplex ligation-dependent probe amplification or cytogenetic arrays, which only define the gain or loss and the approximate size and location. This study has done a complete dissection of the structural variants affecting SERPINC1 of 39 unrelated patients with antithrombin deficiency using multiplex ligation-dependent probe amplification, comparative genome hybridization array, long-range PCR, and whole genome nanopore sequencing. Structural variants, in all cases only affecting one allele, were deleterious and caused a severe type I deficiency. Most defects were deletions affecting exons of SERPINC1 (82.1%), but the whole cohort was heterogeneous, as tandem duplications, deletion of introns, or retrotransposon insertions were also detected. Their size was also variable, ranging from 193 bp to 8 Mb, and in 54% of the cases involved neighboring genes. All but two structural variants had repetitive elements and/or microhomologies in their breakpoints, suggesting a common mechanism of formation. This study also suggested regions recurrently involved in structural variants causing antithrombin deficiency and found three structural variants with a founder effect: the insertion of a retrotransposon, duplication of exon 6, and a 20-gene deletion. Finally, nanopore sequencing was determined to be the most appropriate method to identify and characterize all structural variants at nucleotide level, independently of their size or type.Supported by the National Institute for Health Research (NIHR) for the NIHR BioResource project (grant numbers RG65966 and RG94028), by the Instituto de Salud Carlos III grant; Fondo Europeo de Desarrollo Regional (FEDER) grant PI18/00598; and Fundación Séneca 19873/GERM/15. M.E.d.l.M.-B. has a postdoctoral contract from University of Murcia, Murcia, Spain. C.B.-P. has a Río Hortega fellowship. B.d.l.M.-B. has a postdoctoral fellowship from Fundación Séneca. J.C.-G. has a predoctoral fellowship from the Ministry of Universities FPU19/03662

Prioridades de investigación en salud en colombia: perspectiva de los investigadores

Colombia tiene una escasa experiencia en identificar prioridades de investigación en salud. En el año 2004 se inició un proyecto para identificar prioridades de investigación en salud, entendiendo por tales las que resultan de un ejercicio ordenado de ponderación basado en una valoración juiciosa de problemáticas sanitarias cuya respuesta y/o solución puede lograrse en gran parte por medio de conocimientos y procesos de investigación. Como referentes del proyecto se tuvieron en cuenta algunos de los métodos de priorización utilizados y recomendados en el ámbito internacional, entre ellos la matriz combinada del Global Forum for Health Resarch. Se pusieron en práctica dos trayectos metodológicos principales: por una parte, diseño y aplicación de un método para ponderar u ordenar, de manera cualitativa y cuantitativa, las problemáticas de investigación en salud; por otra parte, construcción de consensos con investigadores y representantes de comunidades científicas. Para identificar las problemáticas de salud predominantes se realizaron dos reuniones nacionales, dos reuniones regionales y un foro virtual. Una vez dentificadas las problemáticas de salud predominantes, con su respectiva estimación de carga de enfermedad, estas se valoraron por políticos y decisores y se calificaron por investigadores de ciencias básicas, ciencias clínicas y salud pública, en términos del aporte del conocimiento requerido para afrontar, controlar o resolver tales problemáticas. Se obtuvieron unas prioridades de investigación en salud por áreas globales: enfermedades crónicas, enfermedades infecciosas emergentes, Tuberculosis/Lepra, infección nosocomial e infecciones de transmisión sexual/VIH/SIDA

Epidemiological trends of HIV/HCV coinfection in Spain, 2015-2019

Objectives: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. Results: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population.This work was supported in part by the Spanish AIDS Research Network (RD16/0025/0017, RD16/0025/0018), which is included in the Spanish I+D+I Plan and is co-funded by the ISCIII-Subdirección General de Evaluación and European Funding for Regional Development (FEDER). The sponsors had no role in the study design, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the article for publication.S

Human Immunodeficiency Virus/Hepatits C Virus Coinfection in Spain: Elimination Is Feasible, but the Burden of Residual Cirrhosis Will Be Significant

Background: We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. Methods: The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results: The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. Conclusions: Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals.This work was funded by grant Ref. no. GLD14-00279 from the GILEAD Fellowship Programme (Spain) and by the Spanish AIDS Research Network (RD16/0025/0017, RD16/0025/0018) that is included in the Spanish I+D+I Plan and is co-financed by ISCIII-Subdirección General de Evaluacion and European Funding for Regional Development (FEDER).S

Toxicidad hematológica asociada al tratamiento con sulfonamidas y pirimetamina en pacientes VIH positivos y toxoplasmosis cerebral en un hospital de tercer nivel en Colombia

Objective.&nbsp;To determine the frequency of hematologic adverse effects associated with treatment for cerebral toxoplasmosis in HIV / AIDS patients. Design: Retrospective case series. Location: University Hospital Hernando Moncaleano Perdomo (HMP), Neiva, Colombia. Population.&nbsp;Patients with cerebral toxoplasmosis and HIV / AIDS treated at the infection service unit between 2006 and 2009. Población.&nbsp;Pacientes con toxoplasmosis cerebral y VIH/SIDA atendidos en el servicio de infectología entre 2006-2009. Results.&nbsp;51 patients were evaluated during the study period. 40 (78%) were men. The average age was 33 years. 25 patients had cerebral toxoplasmosis as the first marker of HIV infection. 60.7% of cases had hematologic toxicity. 42% of patients had anemia before treatment. The peak onset of bone marrow toxicity was the sixth day of the start of treatment schedule. The anti-toxoplasma scheme that was most commonly associated with myelotoxicity was the combination of pyrimethamine/sulfadoxine, trimethoprim-sulfamethoxazole and clindamycin in 48% of cases.&nbsp;Objetivo.&nbsp;Determinar la frecuencia efectos adversos hematológicos asociados al tratamiento para toxoplasmosis cerebral en pacientes VIH/SIDA. Diseño.&nbsp;Serie de casos retrospectiva. Lugar.&nbsp;Hospital Universitario Hernando Moncaleano Perdomo (HMP), Neiva- Colombia. Población.&nbsp;Pacientes con toxoplasmosis cerebral y VIH/SIDA atendidos en el servicio de Infectología entre 2006-2009. Resultados.&nbsp;51 pacientes fueron evaluados durante el periodo de estudio. 40 (78%) fueron hombres. El promedio de edad fue 33 años. 25 pacientes presentaban toxoplasmosis cerebral como primer marcador de Infección VIH. El 60,7% de los casos presentaron toxicidad hematológica. 42% de los pacientes presentaron anemia previa al tratamiento. El pico de aparición de toxicidad medular fue al sexto día de inicio del esquema de tratamiento. El esquema antitoxoplasma que más comúnmente fue asociado a mielotoxicidad fue la combinación de pirimetamina/sulfadoxina, trimetoprimsulfametoxazol y clindamicina en 48% de los casos

TOI-1801 b: A temperate mini-Neptune around a young M0.5 dwarf

Mallorquín, M., et al.We report the discovery, mass, and radius determination of TOI-1801 b, a temperate mini-Neptune around a young M dwarf. TOI-1801 b was observed in TESS sectors 22 and 49, and the alert that this was a TESS planet candidate with a period of 21.3 days went out in April 2020. However, ground-based follow-up observations, including seeing-limited photometry in and outside transit together with precise radial velocity (RV) measurements with CARMENES and HIRES revealed that the true period of the planet is 10.6 days. These observations also allowed us to retrieve a mass of 5.74 ± 1.46 M⊕, which together with a radius of 2.08 ± 0.12 R⊕, means that TOI-1801 b is most probably composed of water and rock, with an upper limit of 2% by mass of H2 in its atmosphere. The stellar rotation period of 16 days is readily detectable in our RV time series and in the ground-based photometry. We derived a likely age of 600–800 Myr for the parent star TOI-1801, which means that TOI-1801 b is the least massive young mini-Neptune with precise mass and radius determinations. Our results suggest that if TOI-1801 b had a larger atmosphere in the past, it must have been removed by some evolutionary mechanism on timescales shorter than 1 Gyr.This work is partly financed by the Spanish Ministry of Economics and Competitiveness through projects PGC2018-098153-B-C31, PID2019-109522GB-C5[1:4]. E. G. acknowledges the generous support from the Deutsche Forschungsgemeinschaft (DFG) of the grant HA3279/14-1. P.D. acknowledges support from a 51 Pegasi b Postdoctoral Fellowship from the Heising-Simons Foundation. D.H. acknowledges support from the Alfred P. Sloan Foundation, the National Aeronautics and Space Administration (80NSSC21K0652) and the Australian Research Council (FT200100871). This work is partly supported by JSPS KAKENHI Grant Numbers JP18H05439 and JST CREST Grant Number JPMJCR176.Peer reviewe

A Transiting, Temperate Mini-Neptune Orbiting the M Dwarf TOI-1759 Unveiled by TESS

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.-- Full list of authors: Espinoza, Néstor; Pallé, Enric; Kemmer, Jonas; Luque, Rafael; Caballero, José A.; Cifuentes, Carlos; Herrero, Enrique; Sánchez Béjar, Víctor J.; Stock, Stephan; Molaverdikhani, Karan; Morello, Giuseppe; Kossakowski, Diana; Schlecker, Martin; Amado, Pedro J.; Bluhm, Paz; Cortés-Contreras, Miriam; Henning, Thomas; Kreidberg, Laura; Kürster, Martin; Lafarga, Marina; Lodieu, Nicolas; Morales, Juan Carlos; Oshagh, Mahmoudreza; Passegger, Vera M.; Pavlov, Alexey; Quirrenbach, Andreas; Reffert, Sabine; Reiners, Ansgar; Ribas, Ignasi; Rodríguez, Eloy; López, Cristina Rodríguez; Schweitzer, Andreas; Trifonov, Trifon; Chaturvedi, Priyanka; Dreizler, Stefan; Jeffers, Sandra V.; Kaminski, Adrian; López-González, María José; Lillo-Box, Jorge; Montes, David; Nowak, Grzegorz; Pedraz, Santos; Vanaverbeke, Siegfried; Zapatero Osorio, Maria R.; Zechmeister, Mathias; Collins, Karen A.; Girardin, Eric; Guerra, Pere; Naves, Ramon; Crossfield, Ian J. M.; Matthews, Elisabeth C.; Howell, Steve B.; Ciardi, David R.; Gonzales, Erica; Matson, Rachel A.; Beichman, Charles A.; Schlieder, Joshua E.; Barclay, Thomas; Vezie, Michael; Villaseñor, Jesus Noel; Daylan, Tansu; Mireies, Ismael; Dragomir, Diana; Twicken, Joseph D.; Jenkins, Jon; Winn, Joshua N.; Latham, David; Ricker, George; Seager, Sara.We report the discovery and characterization of TOI-1759 b, a temperate (400 K) sub-Neptune-sized exoplanet orbiting the M dwarf TOI-1759 (TIC 408636441). TOI-1759 b was observed by TESS to transit in Sectors 16, 17, and 24, with only one transit observed per sector, creating an ambiguity regarding the orbital period of the planet candidate. Ground-based photometric observations, combined with radial-velocity measurements obtained with the CARMENES spectrograph, confirm an actual period of 18.85019 ± 0.00014 days. A joint analysis of all available photometry and radial velocities reveals a radius of 3.17 ± 0.10 R⊕ and a mass of 10.8 ± 1.5 M⊕. Combining this with the stellar properties derived for TOI-1759 (R⋆ = 0.597 ± 0.015 R⊙; M⋆ = 0.606 ± 0.020 M⊙; Teff = 4065 ± 51 K), we compute a transmission spectroscopic metric (TSM) value of over 80 for the planet, making it a good target for transmission spectroscopy studies. TOI-1759 b is among the top five temperate, small exoplanets (Teq 200 days seem to be present in our radial velocities. While our data suggest both could arise from stellar activity, the later signal's source and periodicity are hard to pinpoint given the ∼200 days baseline of our radial-velocity campaign with CARMENES. Longer baseline radial-velocity campaigns should be performed in order to unveil the true nature of this long-period signal. © 2022. The Author(s). Published by the American Astronomical Society.CARMENES is an instrument at the Centro Astronómico Hispano-Alemán (CAHA) at Calar Alto (Almería, Spain), operated jointly by the Junta de Andalucía and the Instituto de Astrofísica de Andalucía (CSIC). CARMENES was funded by the Max-Planck-Gesellschaft (MPG), the Consejo Superior de Investigaciones Científicas (CSIC), the Ministerio de Economía y Competitividad (MINECO), and the European Regional Development Fund (ERDF) through projects FICTS-2011-02, ICTS-2017-07-CAHA-4, and CAHA16-CE-3978, and the members of the CARMENES Consortium (Max-Planck-Institut für Astronomie, Instituto de Astrofísica de Andalucía, Landessternwarte Königstuhl, Institut de Ciëncies de l'Espai, Institut für Astrophysik Göttingen, Universidad Complutense de Madrid, Thüringer Landessternwarte Tautenburg, Instituto de Astrofísica de Canarias, Hamburger Sternwarte, Centro de Astrobiología, and Centro Astronómico Hispano-Alemán), with additional contributions by the MINECO, the Deutsche Forschungsgemeinschaft through the Major Research Instrumentation Programme and Research Unit FOR2544 "Blue Planets around Red Stars," the Klaus Tschira Stiftung, the states of Baden-Württemberg and Niedersachsen, and by the Junta de Andalucía. This work was based on data from the CARMENES data archive at CAB (CSIC-INTA). We acknowledge financial support from the Agencia Estatal de Investigación of the Ministerio de Ciencia, Innovación y Universidades and the ERDF through projects PID2019-109522GB-C5[1:4], PGC2018-098153-B-C33, AYA2018-84089, PID2019-107061GB-C64, PID2019-110689RB-100, AYA2016-79425-C3-1/2/3-P, and BES-2017-080769, and the Centre of Excellence "Severo Ochoa" and "María de Maeztu" awards to the Instituto de Astrofísica de Canarias (CEX2019-000920-S), Instituto de Astrofísica de Andalucía (SEV-2017-0709), and Centro de Astrobiología (MDM-2017-0737), NASA (NNX17AG24G), and the Generalitat de Catalunya/CERCA program. Data were partly collected with the 90 cm telescope at the Sierra Nevada Observatory (SNO) operated by the Instituto de Astrofí fica de Andalucí a (IAA, CSIC). We acknowledge the telescope operators from the Sierra Nevada Observatory for their support. G.M. has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 895525. This research has made use of the NASA Exoplanet Archive, which is operated by the California Institute of Technology, under contract with the National Aeronautics and Space Administration under the Exoplanet Exploration Program. We acknowledge the use of public TESS data from pipelines at the TESS Science Office and at the TESS Science Processing Operations Center. Resources supporting this work were provided by the NASA High-End Computing (HEC) Program through the NASA Advanced Supercomputing (NAS) Division at Ames Research Center for the production of the SPOC data products.Peer reviewe