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Pediatric Moyamoya Angiopathy (MMA) is a progressive intracranial occlusive arteriopathy that represents a leading cause of transient ischemic attacks and strokes in childhood. Despite this, up to now no large, exclusively pediatric MMA cohort has been subjected to systematic genetic investigation. In this study, we performed molecular karyotyping, exome sequencing and automated structural assessment of missense variants on a series of 88 pediatric MMA patients and correlated genetic, angiographic and clinical (stroke burden) findings. The two largest subgroups in our cohort consisted of RNF213 and neurofibromatosis type 1 (NF1) patients. While deleterious RNF213 variants were associated with a severe MMA clinical course with early symptom onset, frequent posterior cerebral artery involvement and higher stroke rates in multiple territories, NF1 patients had a similar infarct burden compared to non-NF1 individuals and were often diagnosed incidentally during routine MRIs. Additionally, we found that MMA-associated RNF213 variants have lower predicted functional impact compared to those associated with aortic disease. We also raise the question of MMA as a feature of recurrent as well as rare chromosomal imbalances and further support the possible association of MMA with STAT3 deficiency. In conclusion, we provide a comprehensive characterization at the genetic and clinical level of a large exclusively pediatric MMA population. Due to the clinical differences found across genetic subgroups, we propose genetic testing for risk stratification as part of the routine assessment of pediatric MMA patients., European Journal of Human Genetics, 31 (7), ISSN:1476-5438, ISSN:1018-4813

Resumen Introduccion Se desconocen los factores etiologicos exactos del cancer colorrectal (CCR), aunque se ha intentado relacionar con factores geneticos y ambientales. La posible asociacion con Fusobacterium nucleatum podria abrir posibilidades en el diagnostico precoz. Objetivo Revisar los estudios que analizan la asociacion entre F. nucleatum y el CCR. Metodos Se utilizaron las publicaciones disponibles en la base de datos MEDLINE PubMed hasta el dia 1 de enero de 2020, que incluian los terminos «cancer colorrectal» y «Fusobacterium nucleatum». Se realizo un metaanalisis con el software Stata. Resultados Un total de 57 articulos fueron incluidos en la revision sistematica. El metaanalisis indico una mayor presencia de F. nucleatum en muestras de tejido tumoral de CCR, con respecto a muestras control de tejido sano, con una odds ratio de 4,558 (IC 95%: 3,312-6,272), y cuando se utilizaron muestras control de adenomas colorrectales, con una odds ratio de 3,244 (IC 95%: 2,359-4,462). Conclusion Hay una mayor presencia de F. nucleatum en el CCR. Sin embargo, se necesitan estudios que demuestren esta relacion.

There is growing evidence on the role of legs and bill as ‘thermal windows’ in birds coping with heat stress. However, there is a lack of empirical work examining the relationship between the relative bill and/or leg surface areas and key thermoregulatory traits such as the limits of the thermoneutral zone (TNZ) or the cooling efficiency at high temperatures. Here, we explored this relationship in a Mediterranean population of Great tit (Parus major) facing increasing thermal stress in its environment. The lower and upper critical limits of the TNZ were found to be 17.7 ± 1.6ºC and 34.5 ± 0.7°C, respectively, and the basal metabolic rate was 0.96 ± 0.12 ml O2 min−1 on average. The evaporative water loss (EWL) inflection point was established at 31.85 ± 0.27°C and was not significantly different from the value of the upper critical limit. No significant relationship was observed between the relative bill or tarsi size and TNZ critical limits, breadth, mass‐independent VO2, or mass‐independent EWL at any environmental temperature (from 10 to 40°C). However, Great tit males (but not females) with larger tarsi areas (a proxy of leg surface area) showed higher cooling efficiencies at 40°C. We found no support for the hypothesis that the bill surface area plays a significant role as a thermal window in Great tits, but the leg surface areas may play a role in males’ physiological responses to high temperatures. On the one hand, we argue that the studied population occupies habitats with available microclimates and fresh water for drinking during summer, so active heat dissipation by EWL might be favored instead of dry heat loss through the bill surface. Conversely, male dominance behaviors could imply a greater dependence on cutaneous EWL through the upper leg surfaces as a consequence of higher exposure to harsh environmental conditions than faced by females., Despite recent studies highlighting the role of relative bill and leg sizes on bird thermoregulation, their relationship with thermal physiology has been rarely studied under controlled conditions. We found no support for the hypothesis that bill size plays a significant role as a thermal window in a Mediterranean population of Great tit Parus major , but leg size could have a role on males’ physiological responses to high temperatures. We suggested that sex‐related differences in the role of leg surface in bird thermoregulation could be related to contrasting behavioral patterns.

BackgroundC3 glomerulopathy associated with monoclonal gammopathy (C3G-MIg) is a rare entity. Herein we analysed the clinical and histologic features of a cohort of C3G-MIg patients.MethodsWe conducted a retrospective, multicentre, observational study. Patients diagnosed with C3G-MIg between 1995 and 2021 were enrolled. All had genetic studies of the alternative complement pathway. The degree of disease activity and chronicity were analysed using the C3G histologic index. Descriptive statistics and propensity score matching (PSM) analysis were used to evaluate the main outcome of the study [kidney failure (KF)].ResultsThe study group included 23 patients with a median age 63 of years [interquartile range (IQR) 48–70], and 57% were males. Immunoglobulin G kappa was the most frequent MIg (65%). The diagnosis of C3G-MIg was made in transplanted kidneys in seven patients (30%). Five (22%) patients had C3 nephritic factor and five (22%) had anti-factor H antibodies. One patient carried a pathogenic variant in the CFH gene. During a follow-up of 40 months (IQR 14–69), nine patients (39%) reached KF and these patients had a significantly higher total chronicity score on kidney biopsy. Patients who received clone-targeted therapy had a significantly higher survival compared with other management. Those who achieved haematological response had a significantly higher kidney survival. Outcome was remarkably poor in kidney transplant recipients, with five of them (71%) reaching KF. By PSM (adjusting for age, kidney function, proteinuria and chronicity score), no significant differences were observed in kidney survival between C3G patients with/without MIg.ConclusionsThe C3G histologic index can be used in patients with C3G-MIg to predict kidney prognosis, with higher chronicity scores being associated with worse outcomes. Clone-targeted therapies and the development of a haematological response are associated with better kidney prognosis.

Monogenic forms of obesity are caused by single-gene variants which affect the energy homeostasis by increasing food intake and decreasing energy expenditure. Most of these variants result from disruption of the leptin–melanocortin signaling, which can cause severe early-onset obesity and hyperphagia. These mutation have been identified in genes encoding essential proteins to this pathway, including leptin (LEP), melanocortin 2 receptor accessory proteins 2 (MRAP2) and proopiomelanocortin (POMC). We aimed to investigate the prevalence of LEP, MRAP2 and POMC rare variants in severely obese adults, who developed obesity during childhood. To the best of our knowledge, this is the first study screening rare variants of these genes in patients from Brazil. A total of 122 Brazilian severely obese patients (BMI ≥ 35 kg/m2) were screened for the coding regions of LEP, MRAP2 and POMC by Sanger sequencing. All patients are candidates to the bariatric surgery. Clinical characteristics were described in patients with novel and/or potentially pathogenic variants. Sixteen different variants were identified in these genes, of which two were novel. Among them, one previous variant with potentially deleterious effect in MRAP2 (p.Arg125Cys) was found. In addition, two heterozygous mutations in POMC (p.Phe87Leu and p.Arg90Leu) were predicted to impair protein function. We also observed a POMC homozygous 9 bp insertion (p.Gly99_Ala100insSerSerGly) in three patients. No pathogenic variant was observed in LEP. Our study described for the first time the prevalence of rare potentially pathogenic MRAP2 and POMC variants in a cohort of Brazilian severely obese adults. Level V, cross-sectional descriptive study.

Producción Científica, One of the main challenges in regenerative medicine is the spatiotemporal control of angiogenesis, which is key for the successful repair of many tissues, and determines the proper integration of the implant through the generation of a functional vascular network. To this end, we have designed a three- dimensional (3D) model consisting of a coaxial binary elastin-like recombinamer (ELR) tubular construct. It displays fast and slow proteolytic hydrogels on its inner and outer part, respectively, both sensitive to the urokinase plasminogen activator protease. The ELRs used to build the scaffold included crosslinkable domains to stabilize the structure and a conjugated VEGF-derived peptide (QK) to induce angiogenesis. The mechanical and morphological evaluation of the ELR hydrogels proved their suitability for soft tis- sue regeneration. In addition, in vitro studies evidenced the effect of the QK peptide on endothelial cell spreading and anastomosis. Moreover, immunohistochemical analyses after subcutaneous implantation of the ELR hydrogels in mice showed the induction of a low macrophage response that resolved over time. The implantation of the 3D model constructs evidenced the ability of the fast proteolytic sequence and the QK peptide to guide cell infiltration and capillary formation in the pre-designed arrangement of the constructs. These results set the basis for the application of this type of scaffolds in regenerative medicine, where spatiotemporally controlled vascularization will help in the promotion of an optimal tissue repair., The authors are grateful for the funding from the Span- ish Government (PID2019-110709RB-100, RTI2018–096320-B- C22, RED2018-102417-T, FPU16/04015), Junta de Castilla y León (VA317P18, Infrared2018-UVA06), Interreg V España Portugal POCTEP (0624_2IQBIONEURO_6_E), Centro en Red de Medicina Re- generativa y Terapia Celular de Castilla y León .

Water is the main limiting factor for groundwater-dependent ecosystems (GDEs) in drylands. Predicted climate change (precipitation reductions and temperature increases) and anthropogenic activities such as groundwater drawdown jeopardise the functioning of these ecosystems, presenting new challenges for their management. We developed a trait-based analysis to examine the spatiotemporal variability in the ecophysiology of Ziziphus lotus, a long-lived phreatophyte that dominates one of the few terrestrial GDEs of semiarid regions in Europe. We assessed morpho-functional traits and stem water potential along a naturally occurring gradient of depth-to-groundwater (DTGW, 2–25 m) in a coastal aquifer, and throughout the species-growing season. Increasing DTGW and salinity negatively affected photosynthetic and transpiration rates, increasing plant water stress (lower predawn and midday water potential), and positively affected Huber value (sapwood cross-sectional area per leaf area), reducing leaf area and likely, plant hydraulic demand. However, the species showed greater salt-tolerance at shallow depths. Despite groundwater characteristics, higher atmospheric evaporative demand in the study area, which occurred in summer, fostered higher transpiration rates and water stress, and promoted carbon assimilation and water loss more intensively at shallow water tables. This multiple-trait analysis allowed us to identify plant ecophysiological thresholds related to the increase in salinity, but mostly in DTGW (13 m), and in the evaporative demand during the growing season. These findings highlight the existence of tipping points in the functioning of a long-lived phreatophyte in drylands and can contribute to the sustainable management of GDEs in southern Europe, paving the way for further studies on phreatophytic species. Supplementary Information The online version contains supplementary material available at 10.1007/s00442-021-04993-w.

OBJECTIVE: The objective of this study was to report the identification of antibodies against the glutamate kainate receptor subunit 2 (GluK2-abs) in patients with autoimmune encephalitis, and describe the clinical-immunological features and antibody effects. METHODS: Two sera from 8 patients with similar rat brain immunostaining were used to precipitate the antigen from neuronal cultures. A cell-based assay (CBA) with GluK2-expressing HEK293 cells was used to assess 596 patients with different neurological disorders, and 23 healthy controls. GluK2-ab effects were determined by confocal microscopy in cultured neurons and electrophysiology in GluK2-expressing HEK293 cells. RESULTS: Patients' antibodies precipitated GluK2. GluK2 antibody-specificity was confirmed by CBA, immunoprecipitation, GluK2-immunoabsorption, and GluK2 knockout brain immunohistochemistry. In 2 of 8 samples, antibodies reacted with additional GluK2 epitopes present in GluK1 or GluK3; in both, the reactivity was abrogated after GluK2 immuno-absorption. Six of 8 patients developed acute encephalitis and clinical or magnetic resonance imaging (MRI) features of predominant cerebellar involvement (4 presenting as cerebellitis, which in 2 patients caused obstructive hydrocephalus), and 2 patients had other syndromes (1 with cerebellar symptoms). One of the samples showed mild reactivity with non-kainate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR] and N-methyl-D-aspartate receptors [NMDAR]) leading to identify 6 additional cases with GluK2-abs among patients with anti-AMPAR (5/71) or anti-NMDAR encephalitis (1/73). GluK2-abs internalized GluK2 in HEK293 cells and neurons; these antibody-effects were reversible in neurons. A significant reduction of GluK2-mediated currents was observed in cells treated with patients' GluK2 serum following the time frame of antibody-mediated GluK2 internalization. INTERPRETATION: GluK2-abs associate with an encephalitis with prominent clinicoradiological cerebellar involvement. The antibody effects are predominantly mediated by internalization of GluK2. ANN NEUROL 2021;90:107-123.

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity. We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples. The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each). Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk. Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS.

In this study, an analysis was made of the qualitative and quantitative evolution of the participation and results obtained by the Spanish athletes throughout the Olympic Games, for which their records were compared to those of the men's team fromParis 1900 to Rio 2016. During the study, the growing weight of Spanish women athletes was analysed, resulting in the Women and Sport programme (2007), which seems to have been a determining factor in the improvement of the performance of Spanish women athletes, which surpassed that of the men's team in the last two editions, for the first time in history and in a consecutive manner. The data revealed a growing weight of women, with a historical representation much lower in the Olympic Games (less than 14%until Barcelona 1992) and significantly lower than men from the same (beginning to be more than 30%). This progression has been accompanied by a greater value in the variable weight of the medals, this fact was accentuated in the last editions of London 2012 (65%) and Rio de Janeiro 2016 (60%). It is clear from the results that there is plenty of room for improvement in women's sport. Empowering Spanish female athletes, increasing social and economic recognition, and identifying which are the differential factors that make them more efficient with respect to the male team, can optimize strategies and results in the third sector of sport in Spain.

This study aimed to analyse the effects of invasion by the exotic Ligustrum lucidum on mycorrhizal associations in forests of Celtis tala, and to determine the role that these fungi play in the invasion process. We analyzed colonization and response to mycorrhization of both plant species under greenhouse conditions after inoculation with soil obtained from patches of non-invaded native forests and invaded forests. The spores present in pots at the end of the experiment were counted and identified. Colonization of L. lucidum was greater in plants inoculated with invaded forest soil, whereas colonization of C. tala was greater in plants inoculated with non-invaded native forest soil. Principal component analysis of fungal species abundance showed differences in AMF composition according to host plant and forest type. The results show that L. lucidum establishes symbiosis with native AMF, which triggers changes in community structure. These changes favored the mycorrhization of L. lucidum and interfered with the mycorrhization of C. tala. AMF may have either a direct or indirect role in the invasion process, not only benefiting the invasive species but also preventing the regeneration of native plants.

Background The Black Sea is the largest brackish water body in the world, although it is connected to the Mediterranean Sea and presents an upper water layer similar to some regions of the former, albeit with lower salinity and temperature. Despite its well-known hydrology and physicochemical features, this enormous water mass remains poorly studied at the microbial genomics level. Results We have sampled its different water masses and analyzed the microbiome by shotgun and genome-resolved metagenomics, generating a large number of metagenome-assembled genomes (MAGs) from them. We found various similarities with previously described Black Sea metagenomic datasets, that show remarkable stability in its microbiome. Our datasets are also comparable to other marine anoxic water columns like the Cariaco Basin. The oxic zone resembles to standard marine (e.g. Mediterranean) photic zones, with Cyanobacteria (Synechococcus but a conspicuously absent Prochlorococcus), and photoheterotrophs domination (largely again with marine relatives). The chemocline presents very different characteristics from the oxic surface with many examples of chemolithotrophic metabolism (Thioglobus) and facultatively anaerobic microbes. The euxinic anaerobic zone presents, as expected, features in common with the bottom of meromictic lakes with a massive dominance of sulfate reduction as energy-generating metabolism, a few (but detectable) methanogenesis marker genes, and a large number of “dark matter” streamlined genomes of largely unpredictable ecology. Conclusions The Black Sea oxic zone presents many similarities to the global ocean while the redoxcline and euxinic water masses have similarities to other similar aquatic environments of marine (Cariaco Basin or other Black Sea regions) or freshwater (meromictic monimolimnion strata) origin. The MAG collection represents very well the different types of metabolisms expected in this kind of environment. We are adding critical information about this unique and important ecosystem and its microbiome.

Infantile colic is a prevalent condition characterised by excessive crying with no effective treatment available. We aimed to evaluate the efficacy of Bifidobacterium breve CECT7263 and a combination of this and Lactobacillus fermentum CECT5716 versus simethicone in reducing the daily time spent crying in colicky infants. A multicentre randomised, open-label, parallel, controlled trial of 28 days was performed in 150 infants who were diagnosed with colic according to the Rome III criteria and who randomly received simethicone (80 mg/day; Simethicone group), B. breve CECT7263 (2×108 cfu/day, Bb group), or a combination of L. fermentum CECT5716 and B. breve CECT7263 (1×108 cfu/day per strain, Bb+Lf group). The main outcomes were minutes of crying per day and the percentage of reduction in daily crying from baseline. Data were analysed per intention to treat. All treatments significantly decreased the daily crying time at the end of the intervention (P-time

Enzymes with hydroxymethylpyrimidine/phosphomethylpyrimidine kinase activity (HMPPK) are essential in the vitamin B1 (thiamine pyrophosphate) biosynthesis and recycling pathways. In contrast, enzymes with pyridoxal kinase activity (PLK) produce pyridoxal phosphate (vitamin B6), an essential cofactor for various biochemical reactions. In the ATP-dependent vitamin kinases family, the members of PLK/HMPPK-like subfamily have both enzymatic activities. It has been proposed that the promiscuous PLK activity of ancestral HMPPK enzymes could have been the starting point for this activity. In earlier work, we reconstructed the ancestral sequences of this family and characterized the substrate specificity of the common ancestor between PLK/HMPPK-like and HMPPK enzymes (AncC). From these studies, the Gln45Met mutation was proposed as a critical event for the PLK activity emergence. Here, we crystallize and determine the AncC structure by X-ray crystallography and assess the role of the Gln45Met mutation by site-directed mutagenesis. Kinetic characterization of this mutant shows a significant increase in the PL affinity. Through molecular dynamics simulation and MM/PBSA calculations some residues, important for substrate interactions and catalysis, were identified in the wild type and in the mutated ancestor. Interestingly, a strong epistatic interaction responsible for the evolutionary pathway of the PLK activity in PLK/HMPPK-like enzymes was revealed. Also, other putative mutations relevant to PLK activity in modern PLK/HMPPK-like enzymes were identified.

Vegetation indices can be used to perform quantitative and qualitative assessment of vegetation cover. These indices exploit the reflectance features of leaves to predict their biophysical properties. In general, there are different vegetation indices capable of describing the same biophysical parameter. For instance, vegetation water content can be inferred from at least sixteen vegetation indices, where each one uses the reflectance of leaves in different spectral bands. Therefore, if the leaf moisture content, a vegetation index and the reflectance at the wavelengths to compute the vegetation index are known, then the reflectance in other spectral bands can be computed with a bounded error. The current work proposes a method to predict, by a machine learning regressor, the leaf reflectance (spectral signature) at specific spectral bands using the information of leaf moisture content and a single vegetation index of two tree species (Pinus radiata, and Eucalyptus globulus), which constitute 97.5% of the Valparaiso forests in Chile. Results suggest that the most suitable vegetation index to predict the spectral signature is the Leaf Water Index, which using a Kernel Ridge Regressor achieved the best prediction results, with a RMSE lower than 0.022, and a average R2 greater than 0.95 for Pinus radiata and 0.81 for Eucalyptus globulus, respectively.

Given their predatory characteristics, long life, and high trophic levels, sharks can have a remarkable ability to bioaccumulate and/or biomagnify trace elements (TE). In the present study, 13 TE (Hg, Pb, Cd, Cu, As, Se, Zn, Cr, V, Fe, Ni, Co, and Mn) were analyzed in the muscle tissue of three shark species (Prionace glauca, Carcharhinus falciformis, and Alopias pelagicus) using high-resolution mass spectrometry inductively coupled to a plasma generator (HR-ICP-MS); 30 shark specimens of each specie were obtained during commercial fish landings in the port of Manzanillo, Mexico. The morphometric characteristics and sex of the sharks were recorded. Shark A. pelagicus accumulated higher concentrations of TE, especially for Hg and Cd, than the other species. Significant differences in the TE levels were detected between sexes in P. glauca and A. pelagicus; in all cases, the highest concentrations were found in female muscle tissue. The ability of sharks to bioaccumulate ETs depends of the metals (essentials higher than non-essential) but is explained mainly by feeding habits associated to sexes (population segregation) and size (ontogeny). The association between TE in shark specimens was related to the essentiality, their antagonistic action, and origin. The Se/Hg ratio was significantly higher than 1, evidence of the protective role of dietary Se against Hg uptake and toxicity in all specimens of the three shark species. Also, the elevate inverse correlation of As and Cd versus Se could indicate a protective action of Se against these toxic metals, but the mechanism must be investigated.

This study evaluated the effect of milk supplemented with Lactobacillus rhamnosus SP1 on the occurrence of caries and the salivary concentration of human β-defensin-3 (hβD-3) in preschool children with high caries risk. A sample of 42 children was randomly assigned to two groups; children in the intervention group were given 150 mL of milk supplemented with 107 CFU/mL of Lactobacillus rhamnosus SP1, while children in the control group were given standard milk, for 10 months. The occurrence of dental caries was assessed using the International Caries Detection and Assessment System (ICDAS), and the concentration of hβD-3 was measured in unstimulated saliva using an ELISA test at baseline and after the intervention. There was an increase in the number of teeth with carious lesions (dICDAS2-6 mft) in the control group, and this increase was statistically significant (p = 0.0489). The concentration of hβD-3 in saliva from the intervention group decreased from 597.91 to 126.29 pg/mL (p = 0.0061), unlike in the control group, where no change in hβD-3 salivary concentration was found. These findings showed that regular intake of probiotic-supplemented milk in preschool children with high caries risk decreased the occurrence of caries and the salivary levels of hβD-3. Our results suggest the need for developing and implementing probiotic supplementation, as adjuvants to the conventional treatments for caries and allow to considerate the salivary levels of hβD-3 as markers of oral tissue homeostasis.

Rationale: We recently demonstrated that the Metabesity factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1-CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues. Methods: HMG20A expression profile was assessed by quantitative PCR (QT-PCR), Western blotting and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to either a high-fat diet or a high-fat high-sucrose regimen, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals and 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-Treated astrocytes. The impact of ORY100. An Inhibitor Of The LSD1-CoREST Complex, On Hmg20a Expression, Reactive Astrogliosis And Glucose Metabolism Was Evaluated In Vitro And In Vivo In High-Fat High-Sucrose Fed Mice. Results: We Show That Hmg20a Is Predominantly Expressed In Hypothalamic Astrocytes, The Main Nutrient-Sensing Cell Type Of The Brain. Hmg20a Expression Was Upregulated In Diet-Induced Obesity And Glucose Intolerant Mice, Correlating With Increased Transcript Levels Of Gfap And Il1b Indicative Of Inflammation And Reactive Astrogliosis. Hmg20a Transcript Levels Were Also Increased In Adipose Tissue Of Obese Non-Diabetic Individuals As Compared To Obese Diabetic Patients. Hmg20a Silencing In Astrocytes Resulted In Repression Of Inflammatory, Cholesterol Biogenesis And Epithelial-To-Mesenchymal Transition Pathways Which Are Hallmarks Of Reactive Astrogliosis. Accordingly, Hmg20a Depleted Astrocytes Exhibited Reduced Mitochondrial Bioenergetics And Increased Susceptibility To Apoptosis. Neuron Viability Was Also Hindered In HMG20A-Depleted Astrocyte-Derived Conditioned Media. Ory1001 Treatment Rescued Expression Of Reactive Astrogliosis-Linked Genes In Hmg20a Ablated Astrocytes While Enhancing Cell Surface Area, Gfap Intensity And Stat3 Expression In Healthy Astrocytes, Mimicking The Effect Of Hmg20a. Furthermore, Ory1001 Treatment Protected Against Obesity-Associated Glucose Intolerance In Mice Correlating With A Regression Of Hypothalamic Hmg20a Expression, Indicative Of Reactive Astrogliosis Attenuation With Improved Health Status. Conclusion: Hmg20a Coordinates The Astrocyte Polarization State. Under Physiological Pressure Such As Obesity And Insulin Resistance That Induces Low Grade Inflammation, Hmg20a Expression Is Increased To Induce Reactive Astrogliosis In An Attempt To Preserve The Neuronal Network And Re-Establish Glucose Homeostasis. Nonetheless, A Chronic Metabesity State Or Functional Mutations Will Result In Lower Levels Of Hmg20a, Failure To Promote Reactive Astrogliosis And Increase Susceptibility Of Neurons To Stress-Induced Apoptosis. Such Effects Could Be Reversed By Ory1001 Treatment Both In Vitro And In Vivo, Paving The Way For A New Therapeutic Approach For Type 2 Diabetes Mellitus., The authors are supported by grants from the Consejería de Salud, Fundación Pública Andaluza Progreso y Salud, Junta de Andalucía (PI-0727-2010 and PI-0001-2020 to B.R.G.; PI-0085-2013 to P.I.L.; PI-0006-2016 to E.F.M.; PI-0574-2012 to S.Y.R.Z; PI-0247-2016 to F.J.B.S.), the Consejería de Economía, Innovación y Ciencia (P10.CTS.6359 to B.R.G.; CTS.8081 to E.G.F.), the Ministerio de Economía y Competitividad co-funded by Fondos FEDER (PI10/00871, PI13/00593 and BFU2017-83588-P to B.R.G.; PRE2018-084907 to M.E.M.V.G.; PI13/00309; PI17/01004 to F.J.B.S.; BFU2014-5343-P to J.C.R.; and AGL2017-86927-R to F.M.), Vencer el Cancer (B.R.G), DiabetesCero (B.R.G.) and the Juvenile Diabetes Research Foundation (17-2013-372 and 2-SRA-2019-837-S-B to B.R.G.). E.F.M. was a recipient of a Juan de la Cierva Incorporación Fellowship from the Ministerio de Economía y Competitividad (IJCI-2015-26238). S.Y.R.Z is a recipient of a postdoctoral fellowship from Consejería de Salud, Junta de Andalucía (RH-0070-2013). L.L.N. is supported by a Consejeria de Economia, Conocimiento, Empresas y Universidad postdoctoral fellowship (DOC_00652). F.J.B.S. and E.G.F. are recipients of "Nicolás Monardes" research contracts from Consejería de Salud Junta de Andalucía, (C-0070-2012 and C-0031-2016). A.M.M. is supported by CPII19/00023 and PI18/01590 from the Instituto de Salud Carlos III co-funded by Fondos FEDER. CIBERDEM is an initiative of the Instituto de Salud Carlos III. V.C. is supported by a AECC investigator award.

La presente investigación tiene el objetivo de evaluar el aprendizaje basado en el proyecto de las especies nativas para la fitorremediación de las aguas drenadas en la mina Tangana y la capacidad de bioacumulacion de plomo y cadmio mediante las especies putacca (Familia apiaceae) y totora (Scirpus californicus), en el Distrito de Huachocolpa de la Provincia y Departamento de Huancavelica (Perú). Aplicando la metodología analítica instrumental, se obtuvieron resultados satisfactorios para el medio ambiente, pues ambos metales (cadmio y plomo) fueron absorbidos por estas especies. En este contexto, se obtuvieron las siguientes conclusiones: a) La concentración de cadmio (Cd) y plomo (Pb) en aguas drenadas de la mina Tangana fueron 0,2661 mg Cd/l y 25,7220 mg Pb/l, la cuantificación de concentración de cadmio (Cd) y plomo (Pb) en la especie totora fue 0,0007 mg Cd/Kg y de 0,0037mg Pb/Kg, la cuantificación de concentración de cadmio (Cd) y plomo (Pb) en la especie putacca fue 0,0020 mg Cd/Kg y 0,0948 mg Pb/Kg). De lo mencionado se infiere que la putacca posee mayor absorbancia que la totora. b) El aprendizaje colaborativo con el complemento de las TICs permite que los estudiantes de los diversos niveles educativos reduzcan las brechas de acceso a la información e interacción con los expertos en la materia.

Análisis de las notas de prensa publicadas por García Márquez entre 1980-1984 en diversos diarios de Hispanoamérica. Es fuente importante para el estudio de las ideas del premio Nobel colombiano con respecto a la lengua española, y más concretamente con respecto a los diccionarios y al léxico del español. Se relacionan dichas ideas con aspectos como el significado subjetivo de las palabras, la sumisión a las fuentes normativas, la conservación de la pureza del lenguaje o el panhispanismo, todo ello desde un acercamiento glotopolítico

Actinomycosis remains an underdiagnosed disease, especially in situations such as those specifically caused by Actinomyces neuii, a pathogen that naturally inhabits normal flora but has become implicated as a cause of sepsis and has been observed over a wide age range, and we continue discovering unusual places that can have this pathogen as an infectious origin or as mixed infections.

International audience; Gibberellic acid (GA) is a major plant hormone involved in several biological processes from the flowering to the symbiosis with microorganisms. Thus, the GA regulation is crucial for plant biology. This regulation occurs via the DELLA proteins that belong to the GRAS transcription factor family. DELLA proteins are characterised by a DELLA N-terminal and a GRAS C-terminal domains. It is well known that DELLA activity appears after the bryophytes divergence and then evolved in the vascular plant lineages. Here we present the phylogeny of DELLA across 75 species belonging to various lineages from algae, liverworts and angiosperms. Our study confirmed two main duplication events, the first occurring before the angiosperms divergence and the other specific to the eudicots lineage. Comparative analysis of DELLA subclades in angiosperms revealed the loss in Poaceae and strong alteration in other species of the DELLA functional domain in the DELLA2 clade. In addition, molecular evolution analysis suggests that each of the clades (named DELLA1.1, DELLA1.2 and DELLA2) evolved differently but copies of each subclade are under strong purifying selection. This also suggests that, although the DELLA functional domain is altered in DELLA2, DELLA2 orthologs are still functional and operate in a different way compared to DELLA1 copies. In angiosperms, additional duplication events occurred and led to duplicate copies in species, genus or family such as in the Fabaceae subfamily Papilionoideae. This duplication led to the formation of additional paralogs in the DELLA1.2 subclade (DELLA1.2.1 and DELLA1.2.2). Interestingly, both copies appeared to be under relaxing selection revealing different evolutionary fate of the DELLA duplicated copies.

Due to the effects of Hurricane Patricia (2015), the bulk freighter "El Llanitos" ran aground in the rocky intertidal zone of Colima, Mexico. We assessed the impact of this ship's stranding on a population of the gastropod Plicopurpura pansa. Toxic elements, hydrocarbons, shell deformities, presence of tumors, imposex, and morphological relationships were analyzed. Two years after the stranding occurred, high cyanide concentrations (0.0363 mg/l) and Ni concentrations above permissible limits (3.35 mg/l) were found in surface seawater. Hydrocarbon concentrations were high in the aft zone of the ship and decreased towards the bow area of the freighter. The P. pansa specimens collected closest to the ship structure presented a high prevalence of tumorations in the structure of the foot and morphological anomalies in the shell structure; imposex was 32% and there was evidence of effects on the growth indicator. The evidence presented here supports the existence of a significant impact from the grounding of the ship on a protected gastropod species associated with the rocky intertidal zone on the coast of Colima. The potential of P. pansa as a bioindicator species of pollution caused by toxic elements and hydrocarbons associated with stranding events in the tropical Pacific is documented.

All metazoans depend on the consumption of O2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O2 to produce reactive oxygen species that can drive cell adaptations1,2,3,4, a phenomenon that occurs in hypoxia4,5,6,7,8 and whose precise mechanism remains unknown. Ca2+ is the best known ion that acts as a second messenger9, yet the role ascribed to Na+ is to serve as a mere mediator of membrane potential10. Here we show that Na+ acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia11 drives acidification of the matrix and the release of free Ca2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na+/Ca2+ exchanger promotes the import of Na+ into the matrix. Na+ interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na+ import through the Na+/Ca2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na+ controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism., This research has been financed by Spanish Government grants (ISCIII and AEI agencies, partially funded by the European Union FEDER/ERDF) CSD2007-00020 (RosasNet, Consolider-Ingenio 2010 programme to A.M.-R. and J.A.E.); CP07/00143, PS09/00101, PI12/00875, PI15/00107 and RTI2018-094203-B-I00 (to A.M.-R.); CP12/03304 and PI15/01100 (to L.M.); CP14/00008, CPII19/00005 and PI16/00735 (to J.E.); SAF2016-77222-R (to A. Cogolludo); PI17/01286 (to P.N.); SAF2015-65633-R, RTI2018-099357-B-I00 and CB16/10/00282 (to J.A.E.); RTI2018-095793-B-I00 (to M.G.L.); and SAF2017-84494-2-R (to J.R.-C.), by the European Union (ITN GA317433 to J.A.E. and MC-CIG GA304217 to R.A.-P.), by grants from the Comunidad de Madrid B2017/BMD-3727 (to A. Cogolludo) and B2017/BMD-3827 (to M.G.L.), by a grant from the Fundación Domingo Martínez (to M.G.L. and A.M.-R.), by the Human Frontier Science Program grant HFSP-RGP0016/2018 (to J.A.E.), by grants from the Fundación BBVA (to R.A.-P. and J.R.-C.), by the UCM-Banco Santander grant PR75/18-21561 (to A.M.-d.-P.), by the Programa Red Guipuzcoana de Ciencia, Tecnología e Información 2018-CIEN-000058-01 (to J.R.-C.) and from the Basque Government under the ELKARTEK Program (grant no. KK-2019/bmG19 to J.R.-C.), by the Swiss National Science Foundation (SNF) grant 310030_124970/1 (to A.B.), by a travel grant from the IIS-IP (to P.H.-A.) and by the COST actions TD0901 (HypoxiaNet) and BM1203 (EU-ROS). The CNIC is supported by the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (Spanish Government award SEV-2015-0505). CIC biomaGUNE is supported by the María de Maeztu Units of Excellence Program from the Spanish Government (MDM-2017-0720). P.H.-A. was a recipient of a predoctoral FPU fellowship from the Spanish Government. E.N. is a recipient of a predoctoral FPI fellowship from the Universidad Autónoma de Madrid (UAM). A.M.-R., L.M. and J.E. are supported by the I3SNS or ‘Miguel Servet’ programmes (ISCIII, Spanish Government; partially funded by the FEDER/ERDF).

El trabajo de investigación se realizó con el objetivo de conocer el efecto y rendimiento del biol y súper biol en la producción agroecológica de lechuga (lactuca sativa) variedad: “seda”. Se realizó en una parcela del C.P. Chinchopampa del Distrito de Chaglla-Huánuco. Las concentraciones estudiadas de biol y súper biol fueron 5%, 7.5% y 10%, y se aplicaron a 200 plantas de lechuga por tratamiento, cuya duración de la investigación fue 100 días. El diseño experimental fue el Diseño Completamente Azar, se evaluó: altura, diámetro, peso, análisis fisicoquímico, análisis organoléptico y microbiológico. Los tratamientos estudiados fueron la concentración de biol y súper biol al 5% (T1), 7.5% (T2), 10% (T3) y testigo (T0), se colocó 10 plantas de lechugas por tratamiento. Se realizó la prueba de significación de Duncan al 5%. Los resultados mostraron, que el tratamiento T3 de súper biol con 10% obtuvieron mayor diámetro 19.65 cm, peso 557.5 g y altura de 10.83 cm y el T2 con biol con 7.5 % el diámetro fue de 16.50 cm, peso 428.2 g y altura 9.48 cm. Así mismo las características isicoquímicas de la lechuga, el pH y acidez resultaron por encima de los valores permitidos, por ser cultivadas en suelos ácidos. Con relación a las características microbiológicas de Escherichia coli y Salmonella resultó que todos los tratamientos estaban bajo los límites permisibles. En el análisis organoléptico la mejor aceptación en textura y apariencia fue el T2 con súper biol con 7.5%. La relación beneficio costo: biol resultó siendo de 3.37 y por cada sol invertido se gana 2.37 soles, en súper biol se obtuvo 3.09 y por cada sol invertido se gana 2.09 soles. La aplicación del biol y súper biol es una alternativa ecológica para fertilizar cultivos, reduciendo el uso de fertilizantes químicos y los costos de producción.

The HIV reservoir is the main barrier to eradicating HIV infection, and resting memory CD4 T (Trm) cells are one of the most relevant cellular component harboring latent proviruses. This is the first study analyzing the transcriptional profile of Trm cells, in two well-characterized groups of HIV patients with distinct mechanisms of viral replication control (spontaneous versus treatment-induced). We use a systems biology approach to unravel subtle but important differences in the molecular mechanisms operating at the cellular level that could be associated with the host's ability to control virus replication and persistence. Despite the absence of significant differences in the transcriptome of Trm cells between Elite Controllers (ECs) and cART-treated (TX) patients at the single gene level, we found 353 gene ontology (GO) categories upregulated in EC compared with TX. Our results suggest the existence of mechanisms at two different levels: first boosting both adaptive and innate immune responses, and second promoting active viral replication and halting HIV latency in the Trm cell compartment of ECs as compared with TX patients. These differences in the transcriptional profile of Trm cells could be involved in the lower HIV reservoir observed in ECs compared with TX individuals, although mechanistic studies are needed to confirm this hypothesis. Combining transcriptome analysis and systems biology methods is likely to provide important findings to help us in the design of therapeutic strategies aimed at purging the HIV reservoir. KEY MESSAGES: HIV-elite controllers have the lowest HIV-DNA content in resting memory CD4 T cells. HIV-ECs show a particular transcriptional profile in resting memory CD4 T cells. Molecular mechanisms of enhanced adaptative and innate immune response in HIV-ECs. High viral replication and low viral latency establishment associate to the EC status.

Background: Psychosis is common in bipolar disorder (BD) and is related to more severe cognitive impairments. Since the molecular mechanism of BD psychosis is elusive, we conducted this study to explore the proteomic differences associated with BD psychosis in the dorsolateral prefrontal cortex (DLPFC; BA9). Methods: Postmortem DLPFC gray matter tissues from five pairs of age-matched male BD subjects with and without psychosis history were used. Tissue proteomes were identified and quantified by label-free liquid chromatography tandem mass spectrometry and then compared between groups. Statistical significance was set at q < 0.40 and Log2 fold change (Log2FC) ≥ |1|. Protein groups with differential expression between groups at p < 0.05 were subjected to pathway analysis. Results: Eleven protein groups differed significantly between groups, including the reduction of tenascin C (q = 0.005, Log2FC = −1.78), the elevations of synaptoporin (q = 0.235, Log2FC = 1.17) and brain-specific angiogenesis inhibitor 1-associated protein 3 (q = 0.241, Log2FC = 2.10) in BD with psychosis. The between-group differences of these proteins were confirmed by Western blots. The top enriched pathways (p < 0.05 with ≥ 3 hits) were the outgrowth of neurons, neuronal cell proliferation, growth of neurites, and outgrowth of neurites, which were all predicted to be upregulated in BD with psychosis. Limitations: Small sample size and uncertain relationships of the observed proteomic differences with illness stage and acute psychosis. Conclusions: These results suggested BD with psychosis history may be associated with abnormalities in neurodevelopment, neuroplasticity, neurotransmission, and neuromodulation in the DLPFC.

The golden twin-spot moth or tomato looper, Chrysodeixis chalcites (Esper), is a polyphagous and worldwide pest that causes important aesthetic damages to banana fruits in the Canary Islands. The life history parameters of C. chalcites were determined under laboratory conditions in base on the age-stage, two-sex life table at 15, 20, 25, 30, and 35°C, 65% relative humidity (RH), and a photoperiod of 16:8 (L:D) h, when it was reared on a semi-synthetic diet. The results show that C. chalcites was able to develop and survive from 15 to 30°C, but no development occurred at 35°C. Developmental threshold temperatures of the egg, larval, pupal, and total preoviposition stages were 10.42, 11.73, 11.22, and 9.42°C, respectively, and their effective accumulated temperatures were 58.31, 265.96, 118.57, and 562.39 degree-days, respectively. The adult longevity was reduced with increasing temperature, which ranged between 16.27 and 34.85 d for females and between 14.27 and 35.21 d for males. The highest values of net reproductive rate (R0) and fecundity were observed at 25°C, with 232.70 offspring and 1,224.74 eggs, respectively. Both the intrinsic rate of increase (r) and finite rate of increase (λ) increased significantly and mean generation time (T) decreased significantly with increasing temperature. These results provide useful information that will allow predicting the impact of climate change on the distribution and population dynamics of C. chalcites and developing successful integrated management programs.

Objectives To describe the kinetics of circulating cytokines and chemokines in humans with ZIKAV infection. Methods Serum levels of different immune mediators in patients with ZIKAV infection were measured at distinct stages of the disease, as well as in culture supernatants from human monocytes infected with a clinical ZIKAV isolate. We also looked for clinical features associated with specific immune signatures among symptomatic patients. Results We evaluated 23 ZIKAV-infected patients. Their mean age was 32 ± 8.3 years and 65% were female. ZIKAV patients showed elevated IL-9, IL-17A, and CXCL10 levels at acute stages of the disease. At day 28, levels of CCL4 and CCL5 were increased, whereas IL-1RA, CXCL8 and CCL2 were decreased. At baseline, IL-7 was increased among patients with headache, whereas CCL2, and CCL3 were decreased in patients with bleeding and rash, respectively. Our clinical ZIKAV isolate induced a broad immune response in monocytes that did not resemble the signature observed in ZIKAV patients. Conclusions We showed a unique immune signature in our cohort of ZIKAV-infected patients. Our study may provide valuable evidence helpful to identify immune correlates of protection against ZIKAV.

hScrib and hDlg belong to the PDZ family of proteins. Since the identification of these highly phylogenetically conserved scaffolds, an increasing amount of experiments has elucidated the roles of hScrib and hDlg in a variety of cell functions. Remarkably, their participation during the establishment of polarity in epithelial cells is well documented. Although the role of both proteins in the immune system is scantly known, it has become a growing field of investigation. Here, we summarize the interactions and functions of hScrib and hDlg1, which participate in diverse functions involving cell polarization in immune cells, and discuss their relevance in the immune cell biology. The fundamental role of hScrib and hDlg1 during the establishment of the immunological synapse, hence T cell activation, and the recently described role of hScrib in reactive oxygen species production in macrophages and of hDlg1 in cytokine production by dendritic cells highlight the importance of both proteins in immune cell biology. The expression of these proteins in other leukocytes can be anticipated and needs to be confirmed. Due to their multiple interaction domains, there is a wide range of possible interactions of hScrib and hDlg1 that remains to be explored in the immune system.

Balamuthia mandrillaris are free-living amoebae (FLA) which are parasites within both humans and animals causing a wide range of sicknesses and acting as vehicles for many microorganisms such as mycobacterium. We present two young male patients, who died with highly unusual mixed infections involving Balamuthia or Balamuthia-like amoebae in the brain tissues plus Mycobacteria, one tuberculous encephalitis and the other cutaneous. Case 1 was a 21-year-old Hispanic male with 1 month of global headache, nausea, vomiting, fever (39 °C), confusion, and garbled speech, as well as pulmonary tuberculosis 1 year ago with possible meningeal TB at the time of admission to the hospital. The patient never developed skin injuries, and he died after 65 days of hospitalization, in August 2006. Case 2 was a 28-year-old male patient with mild parietal headache of 3-week evolution, associated at the beginning with light dizziness, with neurological examination at his normal admission. Twenty-five days later, he presented mental confusion and psychomotor agitation, and in the next 3 h, he suffered from cardiorespiratory arrest, being referred to intensive care; brain death was verified, and he died on January 8, 2005. To the best of our knowledge, these two cases are the first case reports of Balamuthia-like and Mycobacterium tuberculosis/Balamuthia mandrillaris and Mycobacterium sp. from Peru and are presented for academic interest.

We present comments on an article recently published in Ecology and Evolution (“High‐resolution melting of the cytochrome B gene in fecal DNA: A powerful approach for fox species identification of the Lycalopex genus in Chile”) by Anabalon et al. that reported the presence of Darwin's fox (Lycalopex fulvipes), a temperate forest specialist, in the hyperarid Atacama Desert of northern Chile. We argue that this putative record lacks ecological support in light of ongoing research on this endangered species, and contains numerous methodological flaws and omissions related to the molecular identification of the species. Based on these issues, we suggest the scientific community and conservation decision‐makers disregard the alleged presence of the Darwin's fox in the Atacama Desert.

To investigate the effects of a badminton competition with 2 matches in a day on hip strength and range of motion (ROM) and exercise-induced muscle damage in elite junior badminton players. Twenty players (age: 17±0.8 years; body mass: 62.9±6.5 kg, height: 173.8±8.9 cm) participated in this study. Passive hip internal (IR) and external rotation (ER), abduction (ABD) and adduction (ADD) hip ROM, isometric hip ADD and ABD muscle strength, countermovement vertical jump (CMJ) height and blood creatine kinase concentration (CK) were measured before and after a badminton competition during an international tournament. Blood samples were collected 24 h after the end of the last match. Compared to baseline values, hip IR and ER ROM were significantly decreased at post-competition in the dominant (IR=-9.0%; p=0.007 and ER=-15.2%; p=0.002) and non-dominant limbs (IR=-9.08%; p=0.004 and ER=-19.4%; p, Funding received from Badminton World Federation (BWF), Kuala Lumpur (Malaysia).

Depositional episodes are readily identified along representative localities of the Lower Cretaceous Cupido platform in northeastern Mexico. The basal part of the Cupido Formation exhibits a progradational reef platform that, at the upper limit, is truncated by a sequence boundary defined by a breccia. This breccia marks the development of a peculiar sedimentary facies informally known as the Cupidito unit, a distinctive stratigraphical unit in northeastern Mexico that remained uninterpreted for decades. Through the analysis of facies, microfacies and stable isotope comparisons from representative localities (Potrero Chico, Potrero de García, La Huasteca, La Muralla and Puerto Mexico) and from other previously reported outcrops, this work describes six diagnostic features for Cupidito and an improved stratigraphic model is proposed. The depositional sequence suggests a broad flat-topped platform with a general low organic productivity and restricted conditions followed by recurrent inundations of lagoon waters. Before drowning, this carbonate platform remained under equilibrium conditions interrupted by short pulses of relative higher-temperatures (48.3 °C and 39.2 °C). Coral-rudist-stromatoporoid patch-reefs with inferred inter-tropical temperatures between 31.5 °C and 32.2 °C originated as a progradational response to the instauration of a new Sequence Boundary at the base of Cupidito.

Predictive staging models of Alzheimer’s disease broadly fall into one of two categories: cortical origin versus subcortical origin. Using multimodal biomarkers and longitudinal structural imaging in two large independent datasets, Fernández-Cabello et al. find robust evidence in favour of the latter., Alzheimer’s disease neurodegeneration is thought to spread across anatomically and functionally connected brain regions. However, the precise sequence of spread remains ambiguous. The prevailing model used to guide in vivo human neuroimaging and non-human animal research assumes that Alzheimer’s degeneration starts in the entorhinal cortices, before spreading to the temporoparietal cortex. Challenging this model, we previously provided evidence that in vivo markers of neurodegeneration within the nucleus basalis of Meynert (NbM), a subregion of the basal forebrain heavily populated by cortically projecting cholinergic neurons, precedes and predicts entorhinal degeneration. There have been few systematic attempts at directly comparing staging models using in vivo longitudinal biomarker data, and none to our knowledge testing if comparative evidence generalizes across independent samples. Here we addressed the sequence of pathological staging in Alzheimer’s disease using two independent samples of the Alzheimer’s Disease Neuroimaging Initiative (n1 = 284; n2 = 553) with harmonized CSF assays of amyloid-β and hyperphosphorylated tau (pTau), and longitudinal structural MRI data over 2 years. We derived measures of grey matter degeneration in a priori NbM and the entorhinal cortical regions of interest. To examine the spreading of degeneration, we used a predictive modelling strategy that tests whether baseline grey matter volume in a seed region accounts for longitudinal change in a target region. We demonstrated that predictive spread favoured the NbM→entorhinal over the entorhinal→NbM model. This evidence generalized across the independent samples. We also showed that CSF concentrations of pTau/amyloid-β moderated the observed predictive relationship, consistent with evidence in rodent models of an underlying trans-synaptic mechanism of pathophysiological spread. The moderating effect of CSF was robust to additional factors, including clinical diagnosis. We then applied our predictive modelling strategy to an exploratory whole-brain voxel-wise analysis to examine the spatial specificity of the NbM→entorhinal model. We found that smaller baseline NbM volumes predicted greater degeneration in localized regions of the entorhinal and perirhinal cortices. By contrast, smaller baseline entorhinal volumes predicted degeneration in the medial temporal cortex, recapitulating a prior influential staging model. Our findings suggest that degeneration of the basal forebrain cholinergic projection system is a robust and reliable upstream event of entorhinal and neocortical degeneration, calling into question a prevailing view of Alzheimer’s disease pathogenesis.

Introduction: Mutations in the ESR1 gene (ESR1m) are important mechanisms of resistance to endocrine therapy (ET) in estrogen receptor-positive (ER+) advanced breast cancer and have been recognized as a prognostic and predictive biomarker as well as a potential therapeutic target. ESR1m prevalence has been described as 9-45% in cohorts of ET-resistant metastatic tumors in a variety of publications. We recently reported a prevalence of 25% in a cohort of ER+ breast cancer patients with visceral metastasis. However, the role of ESR1m as a mechanism of resistance to ET used in early-stage disease is not well studied. Neoadjuvant endocrine therapy (NET) is being increasingly explored, not only to allow less extensive surgery but also as a scientific tool, exploring biomarkers to predict outcomes. The preoperative endocrine prognostic index (PEPI) combining Ki67 score, ER Allred score, tumor size, and nodal status after NET is a surrogate of endocrine sensitivity and can identify a subgroup of patients with primary resistance to ET. In this study, we evaluated the prevalence of ESR1m in tumor samples from patients with ER+ breast cancer that were primarily resistant to neoadjuvant aromatase inhibitor (AI) therapy. Methods: We followed a prospective cohort of postmenopausal patients with ER+ HER2- stages II-III breast cancer treated with neoadjuvant endocrine therapy (NET). Patients were treated with anastrozole for a recommended period of at least three months. Tumor samples from patients with a pattern of primary endocrine-resistant tumors (defined as a PEPI Score higher than 3) were selected and analyzed for the presence of ESR1m. ESR1m were evaluated in formalin-fixed paraffin-embedded (FFPE) breast cancer tissue using real-time quantitative polymerase chain reaction (RT-qPCR). Mutations in codons 380, 537, and 538 of the ESR1 gene were analyzed. Results: 127 patients were included in the cohort, of which 100 (79%) had completed NET and had surgery. Among these patients, the PEPI Score ranged from 0 to 3 in 70% (70/100), and 30% (30/100) had a PEPI Score of 4 or more and were selected. 23 patients were included in the analysis (6 did not consent or were lost to follow-up, and one was HER2-positive). Patients characteristics are summarized in Table 1. The median duration of NET was 22 weeks. All samples of tumor tissue from the surgical specimens after NET were evaluable. Quantification of DNA extraction and reference gene cycle threshold values confirmed that the material was adequate for the analysis. We compared these findings with a study from our group using the same methodology in patients with advanced disease where ESR1 mutations were detected in 25% (n=32) of patients with visceral metastasis of ER+ breast cancer resistant to endocrine therapy. ESR1 mutations were not identified in any of the 23 patients with early-stage ER+ breast cancer resistant to NET (p 0.01, Fisher´s exact test) Discussion: Growing evidence supports the notion that there are different mechanisms of primary and secondary endocrine resistance. Our study suggests that ESR1 mutations do not evolve rapidly and do not represent a common mechanism of primary endocrine resistance in the neoadjuvant setting. Therefore, ESR1m should be considered a mechanism of acquired endocrine resistance in the context of advanced disease. Further research should be conducted to identify factors associated with intrinsic resistance to ET. Citation Format: Tomas Reinert, Susana Ramalho, Vivian CA Vasconcelos, Leonardo R Silva, Ana Elisa R Silva, Camila A Andrade, Maria Beatriz PL Kraft, Guilherme P Coelho, Jovana Mandelli, Monique Binotto, Cesar Cabello, Geisilene RP Silva, Jose Bines, Carlos H Barrios, Matthew J Ellis, Marcia S Graudenz. ESR1 mutations are not a mechanism of primary resistance to aromatase inhibitors in ER-positive breast cancer treated with neoadjuvant endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-08.

The aim of this research was to evaluate the redox system of Noc­ardia corallina B-276 in the biotransformation of 1-phenyl-1-propanone ( 1a ), 2-hydro­xy-1-phenylethanone ( 2a ) and methyl (2-chlorophenyl)(oxo)acetate ( 3a ) into 1-phenylpropan-1-ol ( 1b ), 1-phenyl-1,2-ethanediol ( 2b ) and methyl (2-chloro­phenyl)(hydroxy)acetate ( 3b ). The biomass of N. corallina was obtained in a liquid medium with an initial pH of 8.50, but the pH changed during the 96 h of the culture media, the final pH was between 4.74 and 7.62. The N. corallina biomass biocatalyzed the enantioselective reduction of 1a – 3a to the corresponding alcohols. Whereas, during the process of oxidation of the rac -alcohols 1b–3b, 1b was oxidized in enantioselective way, the oxidation of 2b was not selective, but 3b was biotransformed mainly to ( R )- 3b . These results are indicative that N. corallina produced reductases and oxidases, whereby the biocatalytic activity was influenced by the final pH of the culture media, the reaction time and structure of the substrate.

We thank R Romero-Calcerrada and J M Requena-Mullor for helpful discussions, and three anonymous reviewers for their constructive suggestions to improve this paper. We also thank the Spanish Ministry of Economy and Business (Project CGL2014-61610-EXP) for the financial support, as well as the Spanish Ministry of Education for the FPU Predoctoral Fellowship of MPR (FPU14/06782) and MTTG (16/02214). MPR gratefully acknowledges funding from Universidad de Almeria for a research stay at the Laboratory of Regional Analysis and Remote Sensing (LART) of University of Buenos Aires to develop this study. This research was done within the LTSER Platforms of the Arid Iberian South East-Spain (LTER_EU_ES_027) and Sierra Nevada/Granada (ES- SNE)-Spain (LTER_EU_ES_010), and contributes to the Global Land Programme., The spatial mapping of social-ecological system (SES) archetypes constitutes a fundamental tool to operationalize the SES concept in empirical research. Approaches to detect, map, and characterize SES archetypes have evolved over the last decade towards more integrative and comparable perspectives guided by SES conceptual frameworks and reference lists of variables. However, hardly any studies have investigated how to empirically identify the most relevant set of indicators to map the diversity of SESs. In this study, we propose a data-driven methodological routine based on multivariate statistical analysis to identify the most relevant indicators for mapping and characterizing SES archetypes in a particular region. Taking Andalusia (Spain) as a case study, we applied this methodological routine to 86 indicators representing multiple variables and dimensions of the SES. Additionally, we assessed how the empirical relevance of these indicators contributes to previous expert and empirical knowledge on key variables for characterizing SESs. We identified 29 key indicators that allowed us to map 15 SES archetypes encompassing natural, mosaic, agricultural, and urban systems, which uncovered contrasting land sharing and land sparing patterns throughout the territory. We found synergies but also disagreements between empirical and expert knowledge on the relevance of variables: agreement on their widespread relevance (32.7% of the variables, e.g. crop and livestock production, net primary productivity, population density); relevance conditioned by the context or the scale (16.3%, e.g. land protection, educational level); lack of agreement (20.4%, e.g. economic level, land tenure); need of further assessments due to the lack of expert or empirical knowledge (30.6%). Overall, our data-driven approach can contribute to more objective selection of relevant indicators for SES mapping, which may help to produce comparable and generalizable empirical knowledge on key variables for characterizing SESs, as well as to derive more representative descriptions and causal factor configurations in SES archetype analysis., Spanish Government CGL2014-61610-EXP FPU14/06782 16/02214, Universidad de Almeria, LTSER Platforms of the Arid Iberian South East-Spain LTER_EU_ES_027, Sierra Nevada/Granada (ES- SNE)-Spain LTER_EU_ES_010

26 páginas, 2 tablas, 10 figuras., Bluetongue, caused by bluetongue virus (BTV), is a widespread arthropod-borne disease of ruminants that entails a recurrent threat to the primary sector of developed and developing countries. In this work, we report modified vaccinia virus Ankara (MVA) and ChAdOx1-vectored vaccines designed to simultaneously express the immunogenic NS1 protein and/or NS2-Nt, the N-terminal half of protein NS2 (NS21-180). A single dose of MVA or ChAdOx1 expressing NS1-NS2-Nt improved the protection conferred by NS1 alone in IFNAR(-/-) mice. Moreover, mice immunized with ChAdOx1/MVA-NS1, ChAdOx1/MVA-NS2-Nt, or ChAdOx1/MVA-NS1-NS2-Nt developed strong cytotoxic CD81 T-cell responses against NS1, NS2-Nt, or both proteins and were fully protected against a lethal infection with BTV serotypes 1, 4, and 8. Furthermore, although a single immunization with ChAdOx1-NS1-NS2-Nt partially protected sheep against BTV-4, the administration of a booster dose of MVA-NS1- NS2-Nt promoted a faster viral clearance, reduction of the period and level of viremia and also protected from the pathology produced by BTV infection. IMPORTANCE Current BTV vaccines are effective but they do not allow to distinguish between vaccinated and infected animals (DIVA strategy) and are serotype specific. In this work we have develop a DIVA multiserotype vaccination strategy based on adenoviral (ChAdOx1) and MVA vaccine vectors, the most widely used in current phase I and II clinical trials, and the conserved nonstructural BTV proteins NS1 and NS2. This immunization strategy solves the major drawbacks of the current marketed vaccines., This work was supported by grants AGL2017-82570-R and PID2020-112992RR-I00 from the Spanish Ministry of Science and by the EU Horizon 2020 Program (European Commission grant agreement no. 727393-PALE-Blu). S.U.T. was a recipient of a predoctoral fellowship from the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Centro de Investigación en Sanidad Animal (program FPI-SGIT2018). We declare no competing interests. J.O. conceived the study. S.U.T. and L.J.C. wrote the manuscript with contributions from J.O. and inputs from all other authors. S.U.T., L.J.C., S.G., and A.M.L. designed and developed all the vaccines used in this work. S.U.T., L.J.C., E.C.P., G.L., and S.M. conducted mice experiments and cytometric analysis. J.B. and P.S.C. conducted sheep immunizations, postmortem studies, and histopathological analysis. S.U.T. and L.J.C. analyzed antibodies, viremias, and hematological parameters. A.N. helped revising the article

8 Pág. Centro de Investigación en Sanidad Animal (CISA), Hemotropic mycoplasmas cause hemolytic anemia in a variety of wild and domestic mammals. Despite growing evidence about their widespread presence and genetic diversity in wildlife, their presence has never been investigated in Chilean artiodactyls. We aimed to describe the presence and diversity of hemoplasmas in pudus (Pudu puda), a small cervid native to Chile. Hemoplasma infection was assessed in blood samples from 43 wild and 33 captive pudus from central and southern Chile by direct sequencing of the 16S rRNA gene. We detected hemoplasmas in 13%, with no statistical differences between wild (19%) and captive animals (6%). A sequence closely related to Mycoplasma ovis was present both in wild (14%) and captive (6%) pudus. Two previously undescribed sequences, classified in a clade including hemoplasmas from carnivores, were found in one wild pudu each. This study presents the first evidence of the presence of M. ovislike organisms in Chile and of the susceptibility of pudus to infection with hemoplasmas. Further research is needed to understand the pathologic consequences of this pathogen for pudus, its effects at the population level, and their potential impact on the health small ruminants and other wildlife species in Chile.

Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%). Supported by Generalitat de Catalunya through Departament de Salut (SLT002/16/00174 to URD-Cat consortium) and Departament d’Empresa i Coneixement and the CERCA Program; FP7 and H2020 EU projects RD-Connect, Solve-RD, and EJP-RD grants FP7 305444, H2020 779257, and H2020 825575 for CNAG-CRG; Spanish Ministry of Science and Innovation to the EMBL partnership and through the Instituto de Salud Carlos III grants PT13/0001/0044 and PT17/0009/0019 for CNAG-CRG and grants PI16/01048, PI19/01310, PI18/00451, PI18/00498, and PI21/00935 for IDIBAPS (Instituto Nacional de Bioinformática); ELIXIR Implementation Studies (CNAG-CRG); Centro de Investigaciones Biomédicas en Red de Enfermedades Raras; Centro de Excelencia Severo Ochoa grant SEV-2016-0571 (CNAG-CRG) and grant CEX 2018-000806-S (ISGLOBAL); and cofinancing with funds from the European Regional Development Fund by the Spanish Ministry of Science and Innovation corresponding to the Programa Operativo FEDER Plurirregional de España (POPE) 2014 to 2020 and by the Secretaria d’Universitats i Recerca, Departament d’Empresa i Coneixement of the Generalitat de Catalunya corresponding to the Programa Operatiu FEDER de Catalunya 2014 to 2020.

Cyttaria Berkeley (Cyttariaceae, Cyttariales, Class Discomycetes), is a genus of eleven species, seven from South America and four from Australasia (Australia, Tasmania, and New Zealand). Cyttaria is a monophyletic genus defined by the following synapomorphies: fleshy to gelatinous stromata with endostromatic apothecia; and complete lack of fungal chitin in the cell walls, having instead β-1-3-glucan. All Cyttaria are exclusive parasites of Nothofagus species. A cladistic analysis of the genus was performed using 18 characters from macromorphology, micro-morphology, and phenology. Polarity of characters is based on the outgroup comparison method (using the Class Discomycetes as a whole) and on the ontogenetic criterion. A hypothetical outgroup was constructed using all plesiomorphic states. Two equally parsimonious cladograms were produced, each with 40 steps and a consistency index of 0.70. These differed in the position of the South American species C. hookeri and C. johowii. In one cladogram, C. hookeri is the sister group to the rest of the genus, and in the other, both species form a monophyletic group (ascospores ovoid) that is the sister group of the rest of the genus. Our analysis of the two characters causing this difference (position of apothecia on stroma, and shape of ascospores) supports the latter hypothesis. In both cladograms, all of the Australasian species form a monophyletic group (thick ectostroma), and, within that, two subgroups are defined: C. gunnii-C. pallida (papillae present), and C. nigra-C. septentrionalis (ectostroma with black incrustations). The Australasian species form a monophyletic group (spermatangia absent) with C. berteroi, and this last group forms a monophyletic group (conidia absent) with C. espinosae. Cytlaria darwimi and C. exigua form another monophyletic group (very thick ectostroma). Excluding C. hookeri and C. johowii, C. hariotii is the sister group to the remaining eight species.

The coating composition of nanomedicines is one of the main features in determining the medicines' fate, clearance, and immunoresponse in the body. To highlight the coatings' impact in pulmonary administration, two micellar superparamagnetic iron oxide nanoparticles (SPION) were compared. These nanoparticles are similar in size and charge but have different coatings: either phosphatidylcholine (PC-SPION) or bovine serum albumin (BSA-SPION). The aim of the study was to increase the understanding of the nano-bio interaction with the cellular and non-cellular components of the lung and underline valuable coatings either for local lung-targeted drug delivery in theranostic application or patient-friendly route systemic administration. PC-SPION and BSA-SPION were deposited in the alveoli by in vivo instillation and, despite the complexity of imaging the lung, SPION were macroscopically visualized by MRI. Impressively, PC-SPION were retained within the lungs for at least a week, while BSA-SPION were cleared more rapidly. The different lung residence times were confirmed by histological analysis and supported by a flow cytometry analysis of the SPION interactions with different myeloid cell populations. To further comprehend the way in which these nanoformulations interact with lung components at the molecular level, we used fluorescence spectroscopy, turbidity measurements, and dynamic light scattering to evaluate the interactions of the two SPION with surfactant protein A (SP-A), a key protein in setting up the NP behavior in the alveolar fluid. We found that SP-A induced aggregation of PC-SPION, but not BSA-SPION, which likely caused PC-SPION retention in the lung without inducing inflammation. In conclusion, the two SPION show different outcomes from interaction with SP-A leading to distinctive fate in the lung. PC-SPION hold great promise as imaging and theranostic agents when prolonged pulmonary drug delivery is required.

3-Cyanoalanine and cyanohydrins are intermediate nitriles produced in cyanide degradation pathways in plants and bacteria. 3-Cyanoalanine is generated from cyanide by the 3-cyanoalanine synthase, an enzyme mainly characterized in cyanogenic plants. NIT4-type nitrilases use 3-cyanoalanine as a substrate, forming ammonium and aspartate. In some organisms, this enzyme also generates asparagine through an additional nitrile hydratase activity. The alkaliphilic bacterium Pseudomonas pseudoalcaligenes CECT5344 assimilates cyanide through an intermediate cyanohydrin, which is further converted into ammonium by the nitrilase NitC. This bacterium also contains three additional nitrilases, including Nit4. In this work, a proteomic analysis of P. pseudoalcaligenes CECT5344 cells grown with 3-cyanoalanine as the sole nitrogen source has revealed the overproduction of different proteins involved in nitrogen metabolism, including the nitrilase NitC. In contrast, the nitrilase Nit4 was not induced by 3-cyanoalanine, and it was only overproduced in cells grown with a cyanide-containing jewelry-manufacturing residue. Phenotypes of single and double mutant strains defective in nit4 or/and nitC revealed the implication of the nitrilase NitC in the assimilation of 3-cyanoalanine and suggest that the 3-cyanoalanine assimilation pathway in P. pseudoalcaligenes CECT5344 depends on the presence or absence of cyanide. When cyanide is present, 3-cyanoalanine is assimilated via Nit4, but in the absence of cyanide, a novel pathway for 3-cyanoalanine assimilation, in which the nitrilase NitC uses the nitrile generated after deamination of the α-amino group from 3-cyanoalanine, is proposed. IMPORTANCE Nitriles are organic cyanides with important industrial applications, but they are also found in nature. 3-Cyanoalanine is synthesized by plants and some bacteria to detoxify cyanide from endogenous or exogenous sources, but this nitrile may be also involved in other processes such as stress tolerance, nitrogen and sulfur metabolism, and signaling. The cyanide-degrading bacterium Pseudomonas pseudoalcaligenes CECT5344 grows with 3-cyanoalanine as the sole nitrogen source, but it does not use this nitrile as an intermediate in the cyanide assimilation pathway. In this work, a quantitative proteomic analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to study, for the first time, the response to 3-cyanoalanine at the proteomic level. Proteomic data, together with phenotypes of different nitrilase-defective mutants of P. pseudoalcaligenes CECT5344, provide evidence that in the absence of cyanide, the nitrilase Nit4 is not involved in 3-cyanoalanine assimilation, and instead, the nitrilase NitC participates in a novel alternative 3-cyanoalanine assimilation pathway.