Development of a Structure-Based, pH-Dependent Lipophilicity Scale of Amino Acids from Continuum Solvation Calculations

Lipophilicity is a fundamental property to characterize the structure and function of proteins, motivating the development of lipophilicity scales. Here we report a versatile strategy to derive a pH-adapted scale that relies on theoretical estimates of distribution coefficients from conformational ensembles of amino acids. This is accomplished by using an accurately parametrized version of the IEFPCM/MST continuum solvation model, as an effective way to describe the partitioning between n-octanol and water, in conjunction with a formalism that combines partition coefficients of neutral and ionic species of residues, and the corresponding pKa of ionizable groups. Two weighting schemes are considered to derive solvent-like and protein-like scales, which have been calibrated by comparison with other experimental scales developed in different chemical/biological environments and pH conditions, as well as by examining properties such as the retention time of small peptides and the recognition of antigenic peptides. A straightforward extension to nonstandard residues is enabled by this efficient methodological strategy

Inequality in mortality in pre-industrial Southern Europe during an epidemic episode : socio-economic determinants (eighteenth - nineteenth centuries Spain)

The objective of this study is to gain more comprehensive knowledge about social inequality in mortality in pre-industrial periods. With this aim, we have reconstructed the life courses of the inhabitants of the town of Vera in south-east Spain for the period 1797-1812 in order to estimate the influence of socio-economic status on ordinary and extraordinary mortality, given that, during this period, the town suffered from several epidemic outbreaks of yellow fever. As a result of these outbreaks, around a quarter of the town's population died. The results obtained indicate social inequality in mortality at least from the end of the eighteenth century. Although the differences are higher in mortality caused by non-infectious diseases or ill-defined causes, the coefficients also show a certain social gradient in mortality derived from infectious diseases. However, with respect to this latter type of mortality, the place of residence - seems to have a greater influence on the chances of survival than socio-economic status

Density-Dependent Prevalence of Francisella tularensis in Fluctuating Vole Populations, Northwestern Spain

Self Archiving; https://wwwnc.cdc.gov/eid/page/copyright-and-disclaimers J.J.L.L., F.M., and R.R.P. held official licenses for trapping wildlife in Spain. Capture permits were provided by the Dirección General del Medio Natural, Junta de Castilla y León. This study was supported by projects ECOVOLE (grant CGL2012-35348), ECOTULA (grant CGL2015-66962-C2-1-R), and RESERTULA (grant CLG2015-66962-C2-2-R), which were funded by the Ministerio de Economía y Competitividad MINECO/FEDER, Spain. R.R.P. was supported by a PhD studentship from the University of Valladolid (co-funded by Banco Santander).Peer reviewedPublisher PD

Possible contribution of X-ray binary jets to the Galactic cosmic ray and neutrino flux

For over a century, the identification of high-energy cosmic ray (CR) sources remains an open question. For Galactic CRs with energy up to $10^{15}$ eV, supernova remnants (SNRs) have traditionally been thought the main candidate source. However, recent TeV gamma-ray observations have questioned the SNR paradigm. Propagating CRs are deflected by the Galactic magnetic field, hence, gamma-rays and neutrinos produced via inelastic hadronic interactions are the only means for unveiling the CR sources. In this work, we study the gamma-ray and neutrino emission produced by CRs accelerated inside Galactic jets of stellar-mass black holes in X-ray binaries (BHXBs). We calculate the intrinsic neutrino emission of two prototypical BHXBs, Cygnus X-1 and GX 339-4, for which we have high-quality, quasi-simultaneous multiwavelength spectra. Based on these prototypical sources, we discuss the likelihood of the 35 known Galactic BHXBs to be efficient CR accelerators. Moreover, we estimate the potential contribution to the CR spectrum of a viable population of BHXBs that reside in the Galactic plane. When these BHXBs go into outburst, they may accelerate particles up to 100s of TeV that contribute to the diffuse gamma-ray and neutrino spectra while propagating in the Galactic medium. Using HERMES, an open-source code that calculates the hadronic processes along the line of sight, we discuss the contribution of BHXBs to the diffuse gamma-ray and neutrino fluxes, and compare these to their intrinsic gamma-ray and neutrino emissions. Finally, we discuss the contribution of BHXBs to the observed spectrum of Galactic CRs.Comment: 17 pages, 10+6 figures, accepted for publication on MNRA

Infectiousness of patients with smear-negative pulmonary tuberculosis, assessed by Real-time Polymerase Chain Reaction, Xpert®MTB/RIF

Currently, pulmonary tuberculosis (TB) isolation recommendations are based on serial sputum smear microscopy. To assess infectiousness of smear-negative/GeneXpert-positive (Sm-/GXpert+) pulmonary TB, we evaluated 511 contacts of pulmonary TB patients attended at a teaching hospital in Spain (2010-2018). There were no statistically significant differences in rates of Mycobacterium tuberculosis infection (46.2% contacts of smear-positive and 34.6% contacts of Sm-/GXpert+ pulmonary TB patients, p=0.112). Sm-/GXpert+ pulmonary TB poses a substantial risk of transmission of M. tuberculosis infection. Our results add evidence to support including Real-time Polymerase Chain Reaction (Xpert®MTB/RIF) in the work-up diagnosis of suspected pulmonary TB cases to make decisions on air-borne isolation

Development and RF-Performance of AlGaN/GaN and InAlN/GaN HEMTs on Large-Diameter High-Resistivity Silicon Substrates

A CMOS-compatible industrial processing and RF analysis of 150 mm GaN-on-HR-Si substrates with AlGaN and InAlN barrier is presented. Process development along with transfer to large-wafer scale is shown and some HEMT calibration devices produced on AlGaN/GaN following the aforementioned procedure are characterized in terms of RF-performance by using a set of measured multi-bias S-parameters. An automatic small-signal equivalent circuit extraction strategy for these AlGaN/GaN DUTs is validated and some de-embedded figures of merit are drawn out in order to initially evaluate this promising technology.This work is supported by the I Plan Propio de la Univ. de Málaga (PhD Grant-401), and the European Microwave Association™ by the EuMA Internship Award 2021 edition. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

MRP4-mediated cAMP efflux is essential for mouse spermatozoa capacitation

Mammalian spermatozoa must undergo biochemical and structural changes to acquire the capacity for fertilization, in a process known as capacitation. Activation of PKA enzymes is essential for capacitation, and thus cAMP levels are tightly regulated during this process. Previously, we demonstrated that during capacitation, bovine spermatozoa extrude cAMP through multidrug resistance-associated protein 4 (MRP4, also known as ABCC4), which regulates intracellular levels of the nucleotide and provides cAMP to the extracellular space. Here, we report the presence of functional MRP4 in murine spermatozoa, since its pharmacological inhibition with MK571 decreased levels of extracellular cAMP. This also produced a sudden increase in PKA activity, with decreased tyrosine phosphorylation at the end of capacitation. Blockade of MRP4 inhibited induction of acrosome reaction, hyperactivation and in vitro fertilization. Moreover, MRP4 inhibition generated an increase in Ca2+ levels mediated by PKA, and depletion of Ca2+ salts from the medium prevented the loss of motility and phosphotyrosine inhibition produced by MK571. These results were supported using spermatozoa from CatSper Ca2+ channel knockout mice. Taken together, these results suggest that cAMP efflux via MRP4 plays an essential role in mouse sperm capacitation.This article has an associated First Person interview with the first author of the paper.Fil: Alonso, Carlos Agustín Isidro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Lottero Leconte, Raquel María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Vernaz, Z. J. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Di Siervi, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Gervasi, Maria Gracia. University of Massachussets; Estados UnidosFil: Buffone, Mariano Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Davio, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Perez Martinez, Silvina Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Central Dopamine D2 Receptors Regulate Growth-HormoneDependent Body Growth and Pheromone Signaling to Conspecific Males

Competition between adult males for limited resources such as food and receptive females is shaped by the male pattern of pituitary growth hormone (GH) secretion that determines body size and the production of urinary pheromones involved in male-to-male aggression. In the brain, dopamine (DA) provides incentive salience to stimuli that predict the availability of food and sexual partners. Although the importance of the GH axis and central DA neurotransmission in social dominance and fitness is clearly appreciated, the two systems have always been studied unconnectedly. Here we conducted a cell-specific genetic dissection study in conditional mutant mice that selectively lack DA D2 receptors (D2R) from pituitary lactotropes (lacDrd2KO) or neurons (neuroDrd2KO). Whereas lacDrd2KO mice developed a normal GH axis, neuroDrd2KO mice displayed fewer somatotropes; reduced hypothalamic Ghrh expression, pituitary GH content, and serum IGF-I levels; and exhibited reduced body size and weight. As a consequence of a GH axis deficit, neuroDrd2KO adult males excreted low levels of major urinary proteins and their urine failed to promote aggression and territorial behavior in control male challengers, in contrast to the urine taken from control adult males. These findings reveal that central D2Rs mediate a euroendocrineexocrine cascade that controls the maturation of the GH axis and downstream signals that are critical for fitness, social dominance, and competition between adult males.Fil: Noain, Daniela Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Pérez Millán, María Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Bello Gay, Estefania Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Casas Cordero, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Gelman, Diego Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Peper, Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; ArgentinaFil: Isabel Garcia-tornadu. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Malcolm J Low. Michigan State University; Estados Unidos;Fil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones En Ingeniería Genética y Biología Molecular; Argentin

World Health Organization (WHO) antibiotic regimen against other regimens for the treatment of leprosy : a systematic review and meta-analysis

Altres ajuts: Maria Lazo-Porras is funded by the Swiss Goverment Excellence Scholarship (2018.0698).To evaluate the effectiveness and safety of the World Health Organization antibiotic regimen for the treatment of paucibacillary (PB) and multibacillary (MB) leprosy compared to other available regimens. We performed a search from 1982 to July 2018 without language restriction. We included randomized controlled trials, quasi-randomized trials, and comparative observational studies (cohorts and case-control studies) that enrolled patients of any age with PB or MB leprosy that were treated with any of the leprosy antibiotic regimens established by the WHO in 1982 and used any other antimicrobial regimen as a controller. Primary efficacy outcomes included: complete clinical cure, clinical improvement of the lesions, relapse rate, treatment failure. Data were pooled using a random effects model to estimate the treatment effects reported as relative risk (RR) with 95% confidence intervals (CI). We found 25 eligible studies, 11 evaluated patients with paucibacillary leprosy, while 13 evaluated patients with MB leprosy and 1 evaluated patients of both groups. Diverse regimen treatments and outcomes were studied. Complete cure at 6 months of multidrug therapy (MDT) in comparison to rifampin-ofloxacin-minocycline (ROM) found RR of 1.06 (95% CI 0.88-1.27) in five studies. Whereas six studies compare the same outcome at different follow up periods between 6 months and 5 years, according to the analysis ROM was not better than MDT (RR of 1.01 (95% CI 0.78-1.31)) in PB leprosy. Not better treatment than the implemented by the WHO was found. Diverse outcome and treatment regimens were studied, more statements to standardized the measurements of outcomes are needed

New concepts and objectives for protein-amino acid nutrition in rabbits: a review

In the European context, the new legislation to avoid mineral contamination and the ban on antibiotics as growth promoters has led to the definition of new objectives in respect of nitrogen supply. The present study summarizes the state of nitrogen nutrition in rabbits and reviews the role of protein and amino acids in rabbit health and the new nitrogen value of protein sources based on true ileal digestibility (TID) for future recommendations. The main sources of nitrogen for microbial growth are ammonia, urea and protein (endogenous and dietary). The surplus of nitrogen flow to the caecum increases mortality rates during fattening by favouring the growth of potential pathogenic bacteria. Accordingly, feeding strategies to reduce ileal nitrogen flow have been reviewed. A large reduction of dietary protein level might have negative consequences on growth performances and mortality. In order to formulate balanced low protein diets, data on ileal and faecal amino acid digestibility of 14 raw materials is summarized. The use of this different unit for amino acid digestibility is also discussed