Estudios de impacto de observaciones satelitales con el algoritmo de asimilación HIRLAM-4DVar

Ponencia presentada en: 6º Simposio de Meteorologia e Geofisica da APMG celebrado del 16 al 18 de marzo de 2009 en Costa Caparica, Portugal.We have carried out a number of observation impact studies with the aim to determine the individual and joint contributions of different space-based observing systems on the skill of short-range forecasts (up to 48 hours) over the Northern Atlantic and European regions. These studies are an essential part of the current HIRLAM data assimilation plan to include in the near future a bigger set of satellite observations than currently used in the operational runs of the different meteorological services within the HIRLAM consortium. In our experiments with data from up to 8 different satellites and the HIRLAM 4D-Var scheme running with a 6-hours long assimilation window, we have detected a significant positive impact on the forecast skill. The satellite observations not only help to better characterize the initial state, they reduce the mean size of increments and so contribute to filter numerical noise generated by the advection scheme in the assimilation algorithm. Analysing the geographical distribution of this impact, we have found some dependency on the type of observation in line with expectations, but we have ascertained too a good level of synergism among them. We recognise the need to consider more experiments with longer periods before more sound conclusions can be drawn and we are working on them

Nanoparticles engineered to bind cellular motors for efficient delivery

Background: Dynein is a cytoskeletal molecular motor protein that transports cellular cargoes along microtubules. Biomimetic synthetic peptides designed to bind dynein have been shown to acquire dynamic properties such as cell accumulation and active intra- and inter-cellular motion through cell-to-cell contacts and projections to distant cells. On the basis of these properties dynein-binding peptides could be used to functionalize nanoparticles for drug delivery applications. Results: Here, we show that gold nanoparticles modified with dynein-binding delivery sequences become mobile, powered by molecular motor proteins. Modified nanoparticles showed dynamic properties, such as travelling the cytosol, crossing intracellular barriers and shuttling the nuclear membrane. Furthermore, nanoparticles were transported from one cell to another through cell-to-cell contacts and quickly spread to distant cells through cell projections. Conclusions: The capacity of these motor-bound nanoparticles to spread to many cells and increasing cellular retention, thus avoiding losses and allowing lower dosage, could make them candidate carriers for drug delivery

Identification of potential inhibitors of protein-protein interaction useful to fight against Ebola and other highly pathogenic viruses

16 p.-1 fig.-1 tab.Despite the efforts to develop new treatments against Ebola virus (EBOV) there is currently no antiviral drug licensed to treat patients with Ebola virus disease (EVD). Therefore, there is still an urgent need to find new drugs to fight against EBOV. In order to do this, a virtual screening was done on the druggable interaction between the EBOV glycoprotein (GP) and the host receptor NPC1 with a subsequent selection of compounds for further validation. This screening led to the identification of new small organic molecules with potent inhibitory action against EBOV infection using lentiviral EBOV-GP-pseudotype viruses. Moreover, some of these compounds have shown their ability to interfere with the intracellular cholesterol transport receptor NPC1 using an ELISA-based assay. These preliminary results pave the way to hit to lead optimization programs that lead to successful candidates.Funding from “la Caixa” Banking Foundation under the project code HR18-00469 is acknowledged. This research was partially supported through Instituto de Salud Carlos III (FIS PI 181007 and ISCIII-COV20/01007), CSIC (201980E024 and 202020E079), Spanish Ministry of Science and Innovation (RTI2018-097305-R-I00) and the European Commission Horizon 2020 Framework Programme (Project VIRUSCAN FETPROACT-2016 and VACDIVA-SFS-12-2019-1-862874).Peer reviewe

Human immunodeficiency virus/hepatits C virus coinfection in Spain: Elimination is feasible, but the burden of residual cirrhosis will be significant

Background We assessed the prevalence of antibodies against hepatitis C virus (HCV-Abs) and active HCV infection in patients infected with human immunodeficiency virus (HIV) in Spain in 2016 and compared the results with those of similar studies performed in 2002, 2009, and 2015. Methods The study was performed in 43 centers during October-November 2016. The sample was estimated for an accuracy of 2% and selected by proportional allocation and simple random sampling. During 2016, criteria for therapy based on direct-acting antiviral agents (DAA) were at least significant liver fibrosis, severe extrahepatic manifestations of HCV, and high risk of HCV transmissibility. Results The reference population and the sample size were 38904 and 1588 patients, respectively. The prevalence of HCV-Abs in 2002, 2009, 2015, and 2016 was 60.8%, 50.2%, 37.7%, and 34.6%, respectively (P trend <.001, from 2002 to 2015). The prevalence of active HCV in 2002, 2009, 2015, and 2016 was 54.0%, 34.0%, 22.1%, and 11.7%, respectively (P trend <.001). The anti-HCV treatment uptake in 2002, 2009, 2015, and 2016 was 23.0%, 48.0%, 59.3%, and 74.7%, respectively (P trend <.001). In 2016, HCV-related cirrhosis was present in 7.6% of all HIV-infected individuals, 15.0% of patients with active HCV, and 31.5% of patients who cleared HCV after anti-HCV therapy. Conclusions Our findings suggest that with universal access to DAA-based therapy and continued efforts in prevention and screening, it will be possible to eliminate active HCV among HIV-infected individuals in Spain in the short term. However, the burden of HCV-related cirrhosis will continue to be significant among HIV-infected individuals

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms

Protection against Tuberculosis in Eurasian Wild Boar Vaccinated with Heat-Inactivated Mycobacterium bovis

Tuberculosis (TB) caused by Mycobacterium bovis and closely related members of the Mycobacterium tuberculosis complex continues to affect humans and animals worldwide and its control requires vaccination of wildlife reservoir species such as Eurasian wild boar (Sus scrofa). Vaccination efforts for TB control in wildlife have been based primarily on oral live BCG formulations. However, this is the first report of the use of oral inactivated vaccines for controlling TB in wildlife. In this study, four groups of 5 wild boar each were vaccinated with inactivated M. bovis by the oral and intramuscular routes, vaccinated with oral BCG or left unvaccinated as controls. All groups were later challenged with a field strain of M. bovis. The results of the IFN-gamma response, serum antibody levels, M. bovis culture, TB lesion scores, and the expression of C3 and MUT genes were compared between these four groups. The results suggested that vaccination with heat-inactivated M. bovis or BCG protect wild boar from TB. These results also encouraged testing combinations of BCG and inactivated M. bovis to vaccinate wild boar against TB. Vaccine formulations using heat-inactivated M. bovis for TB control in wildlife would have the advantage of being environmentally safe and more stable under field conditions when compared to live BCG vaccines. The antibody response and MUT expression levels can help differentiating between vaccinated and infected wild boar and as correlates of protective response in vaccinated animals. These results suggest that vaccine studies in free-living wild boar are now possible to reveal the full potential of protecting against TB using oral M. bovis inactivated and BCG vaccines

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

Altres ajuts: Spanish AIDS Research Network; European Funding for Regional Development (FEDER).Objectives: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. Results: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population

Blocking miRNA biogenesis in adult forebrain neurons enhances seizure susceptibility, fear memory, and food intake by increasing neuronal responsiveness

The RNase Dicer is essential for the maturation of most microRNAs, a molecular system that plays an essential role in fine-tuning gene expression. To gain molecular insight into the role of Dicer and the microRNA system in brain function, we conducted 2 complementary RNA-seq screens in the hippocampus of inducible forebrain-restricted Dicer1 mutants aimed at identifying the microRNAs primarily affected by Dicer loss and their targets, respectively. Functional genomics analyses predicted the main biological processes and phenotypes associated with impaired microRNA maturation, including categories related to microRNA biology, signal transduction, seizures, and synaptic transmission and plasticity. Consistent with these predictions, we found that, soon after recombination, Dicer-deficient mice exhibited an exaggerated seizure response, enhanced induction of immediate early genes in response to different stimuli, stronger and more stable fear memory, hyperphagia, and increased excitability of CA1 pyramidal neurons. In the long term, we also observed slow and progressive excitotoxic neurodegeneration. Overall, our results indicate that interfering with microRNA biogenesis causes an increase in neuronal responsiveness and disrupts homeostatic mechanisms that protect the neuron against overactivation, which may explain both the initial and late phenotypes associated with the loss of Dicer in excitatory neurons.A.F. held a doctoral fellowship funded by the Consolider programme (grant number CSD2007-00023). Research at A.B.'s laboratory is supported by a grant from the Spanish MINECO (SAF2011-22855), Prometeo/2012/005 from the Generalitat Valenciana and a NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation. Research at E.G.B.'s laboratory is supported by a MINECO grant (BFU2011-27326). The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa.”Peer reviewe

Properties of the epileptiform activity in the cingulate cortex of a mouse model of LIS1 dysfunction

Dysfunction of the LIS1 gene causes lissencephaly, a drastic neurological disorder characterized by a deep disruption of the cortical structure. We aim to uncover alterations of the cortical neuronal networks related with the propagation of epileptiform activity in the Lis1/sLis1 mouse, a model lacking the LisH domain in heterozygosis. We did extracellular field-potential and intracellular recordings in brain slices of the anterior cingulate cortex (ACC) or the retrosplenial cortex (RSC) to study epileptiform activity evoked in the presence of bicuculline (10 µM), a blocker of GABAA receptors. The sensitivity to bicuculline of the generation of epileptiform discharges was similar in wild type (WT) and Lis1/sLis1 cortex (EC50 1.99 and 2.24 µM, respectively). In the Lis1/sLis1 cortex, we observed a decreased frequency of the oscillatory post-discharges of the epileptiform events; also, the propagation of epileptiform events along layer 2/3 was slower in the Lis1/sLis1 cortex (WT 47.69 ± 2.16 mm/s, n = 25; Lis1/sLis1 37.34 ± 2.43 mm/s, n = 15; p = 0.004). The intrinsic electrophysiological properties of layer 2/3 pyramidal neurons were similar in WT and Lis1/sLis1 cortex, but the frequency of the spontaneous EPSCs was lower and their peak amplitude higher in Lis1/sLis1 pyramidal neurons. Finally, the propagation of epileptiform activity was differently affected by AMPA receptor blockers: CNQX had a larger effect in both ACC and RSC while GYKI53655 had a larger effect only in the ACC in the WT and Lis1/sLis1 cortex. All these changes indicate that the dysfunction of the LIS1 gene causes abnormalities in the properties of epileptiform discharges and in their propagation along the layer 2/3 in the anterior cingulate cortex and in the restrosplenial cortex.Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.This work was supported by the Spanish Ministerio de Economía y Competitividad (MINECO/AEI/FEDER, UE; grant numbers SAF2017-83702-R, PID2020-118171RB-I00), Spanish State Research Agency, through the “Programa Severo Ochoa” for Centers of Excellence in R&D (grant number SEV-2017-0723), and Generalitat Valenciana (program Prometeo II, grant number 2018/041).Peer reviewe