Air quality forecasts on a kilometer-scale grid over complex Spanish terrains

The CALIOPE Air Quality Forecast System (CALIOPE-AQFS) represents the current state of the art in air quality forecasting systems of high-resolution running on high-performance computing platforms. It provides a 48 h forecast of NO2, O3, SO2, PM10, PM2.5, CO, and C6H6at a 4 km horizontal resolution over all of Spain, and at a 1 km horizontal resolution over the most populated areas in Spain with complex terrains (the Barcelona (BCN), Madrid (MAD) and Andalusia (AND) domains). Increased horizontal resolution from 4 to 1 km over the aforementioned domains leads to finer textures and more realistic concentration maps, which is justified by the increase in NO2/O3spatial correlation coefficients from 0.79/0.69 (4 km) to 0.81/0.73 (1 km). High-resolution emissions using the bottom-up HERMESv2.0 model are essential for improving model performance when increasing resolution on an urban scale, but it is still insufficient. Decreasing grid spacing does not reveal the expected improvement in hourly statistics, i.e., decreasing NO2bias by only ~ 2 µg m-3and increasing O3 bias by ~ 1 µg m-3. The grid effect is less pronounced for PM10, because part of its mass consists of secondary aerosols, which are less affected than the locally emitted primary components by a decreasing grid size. The resolution increase has the highest impact over Barcelona, where air flow is controlled mainly by mesoscale phenomena and a lower planetary boundary layer (PBL). Despite the merits and potential uses of the 1-km simulation, the limitations of current model formulations do not allow confirmation of their expected superiority close to highly urbanized areas and large emissions sources. Future work should combine high grid resolutions with techniques that decrease subgrid variability (e.g., stochastic field methods), and also include models that consider urban morphology and thermal parameters.Postprint (published version

Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich's ataxia

Frataxin (FXN) deficiency causes Friedreich's ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.This work was supported by grants from Ministerio de Economía y Competitividad (Spanish Ministry of Economy and Competitiveness) [grant no. PI11/00678] within the framework of the National R+D+I Plan and co-funded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y Fomento de la Investigación and FEDER funds; the European Community's Seventh Framework Programme FP7/2007-2013 [grant agreement no. 242193 EFACTS]; the Generalitat Valenciana (Prometeo programme); the Fundació la Marató de TV3; the Fundación Alicia Koplowitz. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative developed by the Instituto de Salud Carlos III in cooperative and translational research on rare diseases.Peer Reviewe

Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich's ataxia

Frataxin (FXN) deficiency causes Friedreich's ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the beta-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence

Ancient origin of the CAG expansion causing Huntington disease in a Spanish population

25 p. Figuras, tablas, bibliografíaHuntington disease (HD, MIM# 143100) is an autosomal dominant neurodegenerative disorder characterized clinically by progressive motor impairment, cognitive decline, and emotional deterioration. The disease is caused by the abnormal expansion of a CAG trinucleotide repeat in the first exon of the huntingtin gene in chromosome 4p16.3. HD is spread worldwide and it is generally accepted that few mutational events account for the origin of the pathogenic CAG expansion in most populations. We have investigated the genetic history of HD mutation in 83 family probands from the Land of Valencia, Eastern Spain. An analysis of the HD/CCG repeat in informative families suggested that at least two main chromosomes were associated in the Valencian population, one associated with allele 7 (77 mutant chromosomes) and one associated with allele 10 (2 mutant chromosomes). Haplotype A-7-A (H1) was observed in 47 out of 48 phase-known mutant chromosomes, obtained by segregation analysis, through the haplotype analysis of rs1313770-HD/CCGrs82334, as it also was in 120 out of 166 chromosomes constructed by means of the PHASE program. The genetic history and geographical distribution of the main haplotype H1 were both studied by constructing extended haplotypes with flanking STRs D4S106 and D4S3034. We found that we were able to determine the age of the CAG expansion associated with the haplotype H1 as being between 4,700 and 10,000 years ago. Furthermore, we observed a nonhomogenous distribution in the different regions associated with the different extended haplotypes of the ancestral haplotype H1, suggesting that local founder effects have occurred.This work was supported by the Fondo de investigación Sanitaria (FIS grant 01/1159), the Instituto de Salud Carlos III (grant G03/56) for the Spanish Network on Cerebellar Ataxias, and the Generalitat Valenciana (grant GRUPOS03/015).Peer reviewe

Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway

[EN] Mutations in SH3TC2 (KIAA1985) cause Charcot-Marie-Tooth disease (CMT) type 4C, a demyelinating inherited neuropathy characterized by early-onset and scoliosis. Here we demonstrate that the SH3TC2 protein is present in several components of the endocytic pathway including early endosomes, late endosomes and clathrin-coated vesicles close to the trans-Golgi network and in the plasma membrane. Myristoylation of SH3TC2 in glycine 2 is necessary but not sufficient for the proper location of the protein in the cell membranes. In addition to myristoylation, correct anchoring also needs the presence of SH3 and TPR domains. Mutations that cause a stop codon and produce premature truncations that remove most of the TPR domains are expressed as the wild-type protein. In contrast, missense mutations in or around the region of the first-TPR domain are absent from early endosomes, reduced in plasma membrane and late endosomes and are variably present in clathrin-coated vesicles. Our findings suggest that the endocytic and membrane trafficking pathway is involved in the pathogenesis of CMT4C disease. We postulate that missense mutations of SH3TC2 could impair communication between the Schwann cell and the axon causing an abnormal myelin formation.This work was supported by the Fondo de Investigacion Sanitaria [grant numbers PI08/90857, PI08/0889, CP08/00053] and the Spanish Ministry Science and Innovation [grant number SAF2006-01047]. V. L. is a recipient of JAE predoctoral fellowship from the Spanish Scientific Research Council (CSIC). M. I. G. has a `Ramon y Cajal' contract funded by the Ministry of Science and Innovation. C. E. has a `Miguel Servet' contract funded by the Fondo de Investigacion Sanitaria. Both CIBERER and CIBERNED are initiatives from the Instituto de Salud Carlos III. We are grateful to patients and their families for their kind collaboration. We thank B. Alarcón for his technical assistance and also anonymous reviewers for their invaluable insight and suggestionsLupo, V.; Galindo, MI.; Martínez-Rubio, D.; Sevilla, T.; Vílchez, JJ.; Palau, F.; Espinós-Armero, CÁ. (2009). Missense mutations in the SH3TC2 protein causing Charcot-Marie-Tooth disease type 4C affect its localization in the plasma membrane and endocytic pathway. Human Molecular Genetics. 18(23):4603-4614. https://doi.org/10.1093/hmg/ddp42746034614182

Multilevel simulation-based co-design of next generation HPC microprocessors

This paper demonstrates the combined use of three simulation tools in support of a co-design methodology for an HPC-focused System-on-a-Chip (SoC) design. The simulation tools make different trade-offs between simulation speed, accuracy and model abstraction level, and are shown to be complementary. We apply the MUSA trace-based simulator for the initial sizing of vector register length, system-level cache (SLC) size and memory bandwidth. It has proven to be very efficient at pruning the design space, as its models enable sufficient accuracy without having to resort to highly detailed simulations. Then we apply gem5, a cycle-accurate micro-architecture simulator, for a more refined analysis of the performance potential of our reference SoC architecture, with models able to capture detailed hardware behavior at the cost of simulation speed. Furthermore, we study the network-on-chip (NoC) topology and IP placements using both gem5 for representative small- to medium-scale configurations and SESAM/VPSim, a transaction-level emulator for larger scale systems with good simulation speed and sufficient architectural details. Overall, we consider several system design concerns, such as processor subsystem sizing and NoC settings. We apply the selected simulation tools, focusing on different levels of abstraction, to study several configurations with various design concerns and evaluate them to guide architectural design and optimization decisions. Performance analysis is carried out with a number of representative benchmarks. The obtained numerical results provide guidance and hints to designers regarding SIMD instruction width, SLC sizing, memory bandwidth as well as the best placement of memory controllers and NoC form factor. Thus, we provide critical insights for efficient design of future HPC microprocessors.This work has been performed in the context of the European Processor Initiative (EPI) project, which has received funding from the European Union’s Horizon 2020 research and innovation program under Grant Agreement № 826647. A special thanks to Amir Charif and Arief Wicaksana for their invaluable contributions to the SESAM/VPSim tool in the initial phases of the EPI project.Peer ReviewedPostprint (author's final draft

Mutations in the urocanase gene UROC1 are associated with urocanic aciduria

[EN] Urocanase is an enzyme in the histidine pathway encoded by the UROC1 gene. This report describes the first putative mutations, p. L70P and p.R450C, in the coding region of the UROC1 gene in a girl with urocanic aciduria presenting with mental retardation and intermittent ataxia. Computed (in silico) predictions, protein expression studies and enzyme activity assays suggest that none of the mutations can produce a fully functional enzyme. The p. L70P substitution, which probably implies the disruption of an alpha-helix in the N-terminus, would alter its properties and therefore, its function. The p.R450C change would render impossible any interaction between urocanase and its substrate and would loss its enzyme activity. Consequently, these studies suggest that both mutations could alter the correct activity of urocanase, which would explain the clinical and biochemical findings described in this patient.We are grateful to the patient for her kind collaboration. We are indebted to Dr C Marco-Marín for the in silico structural studies. CIBERER is an initiative of the Instituto de Salud Carlos III. This work was supported by grants from the Fondo de Investigación Sanitaria (PI051318 and PI070548).Espinós-Armero, CÁ.; Pineda, M.; Martínez-Rubio, D.; Aída Ormazabal; María Antonia Vilaseca; Leo J. M. Spaapen; Palau, F.... (2009). Mutations in the urocanase gene UROC1 are associated with urocanic aciduria. Journal of Medical Genetics. 46(6):407-411. https://doi.org/10.1136/jmg.2008.06063240741146

Targeted next generation sequencing in patients with inborn errors of metabolism

BACKGROUND: Next-generation sequencing (NGS) technology has allowed the promotion of genetic diagnosis and are becoming increasingly inexpensive and faster. To evaluate the utility of NGS in the clinical field, a targeted genetic panel approach was designed for the diagnosis of a set of inborn errors of metabolism (IEM). The final aim of the study was to compare the findings for the diagnostic yield of NGS in patients who presented with consistent clinical and biochemical suspicion of IEM with those obtained for patients who did not have specific biomarkers. METHODS: The subjects studied (n = 146) were classified into two categories: Group 1 (n = 81), which consisted of patients with clinical and biochemical suspicion of IEM, and Group 2 (n = 65), which consisted of IEM cases with clinical suspicion and unspecific biomarkers. A total of 171 genes were analyzed using a custom targeted panel of genes followed by Sanger validation. RESULTS: Genetic diagnosis was achieved in 50% of patients (73/146). In addition, the diagnostic yield obtained for Group 1 was 78% (63/81), and this rate decreased to 15.4% (10/65) in Group 2 (X2 = 76.171; p < 0.0001). CONCLUSIONS: A rapid and effective genetic diagnosis was achieved in our cohort, particularly the group that had both clinical and biochemical indications for the diagnosis

Enfermedades neurológicas hereditarias: genes, mutaciones, clínica y epidemiologia genética (premio Reina Sofía 2004, de prevención de deficiencias)

Esta memoria quiere ser un resumen de los estudios y hallazgos de laboratorio y de las contribuciones científicas de la Unidad de Genética Molecular en el campo de la genética molecular de las enfermedades neurológicas, trastornos que se encuadran en el término de enfermedades raras, así como las aplicaciones en medicina clínica a las que han dado lugar, concretamente por lo que respecta al diagnóstico molecular y al consejo genético. La memoria está dividida en cuatro capítulos que hacen referencia a las ataxias hereditarias, las neuropatías periféricas hereditarias, los trastornos del movimiento y las distrofias musculares. En todos ellos se mencionan explícitamente los aspectos clínicos del diagnóstico molecular, incluidos los diagnósticos prenatal y presintomático, así como el consejo genético

Sterilization Procedure for Temperature-Sensitive Hydrogels Loaded with Silver Nanoparticles for Clinical Applications

Anti-bacterial agents; Post-operative infections; Silver nanoparticlesAgents antibacterians; Infeccions postoperatòries; Nanopartícules de plataAgentes antibacterianos; Infecciones postoperatorias; Nanopartículas de plataHydrogels (HG) have recognized benefits as drug delivery platforms for biomedical applications. Their high sensitivity to sterilization processes is however one of the greatest challenges regarding their clinical translation. Concerning infection diseases, prevention of post-operatory related infections is crucial to ensure appropriate patient recovery and good clinical outcomes. Silver nanoparticles (AgNPs) have shown good antimicrobial properties but sustained release at the right place is required. Thus, we produced and characterized thermo-sensitive HG based on Pluronic® F127 loaded with AgNPs (HG-AgNPs) and their integrity and functionality after sterilization by dry-heat and autoclave methods were carefully assessed. The quality attributes of HG-AgNPs were seriously affected by dry-heat methods but not by autoclaving methods, which allowed to ensure the required sterility. Also, direct sterilization of the final HG-AgNPs product proved more effective than of the raw material, allowing simpler production procedures in non-sterile conditions. The mechanical properties were assessed in post mortem rat models and the HG-AgNPs were tested for its antimicrobial properties in vitro using extremely drug-resistant (XDR) clinical strains. The produced HG-AgNPs prove to be versatile, easy produced and cost-effective products, with activity against XDR strains and an adequate gelation time and spreadability features and optimal for in situ biomedical applications