Viral determination and molecular characterization of Aujeszky’s disease virus in slaughter plants and wild boar, as part as the epidemiological surveillance official program in Argentina

La enfermedad de Aujeszky afecta principalmente a la producción porcina y ocasiona pérdidas económicas importantes. En la Argentina, esta enfermedad es considerada endémica, lo que puede resultar en restricciones de comercialización para la región. Las exigencias del mercado externo obligan a avanzar con los planes de control y erradicación de la enfermedad de Aujezsky. Esta enfermedad limita las posibilidades económicas del sector porcino y la comercialización internacional, lo cual influye negativamente en la rentabilidad de las explotaciones y en la calidad de los productos de origen animal. Las técnicas serológicas utilizadas solo detectan la presencia de anticuerpos específicos y no permiten detectar directamente la presencia del patógeno en el organismo ni una infección latente. La utilización de la biología molecular para la confirmación y diagnóstico de la enfermedad de Aujeszky en los planes de vigilancia puede convertirse en una herramienta eficaz para la detección temprana de animales infectados con el virus, así como también para la identificación de las variantes genotípicas que circulan en el país. Este conocimiento aportaría información para establecer políticas sanitarias enfocadas en el control de la enfermedad de Aujeszky, tendientes a la erradicación del virus Herpesvirus porcino tipo 1 (SuHV-1) circulante en la Argentina.Aujezky´s disease principally affects the porcine production, and it generate important economical lost. Currently, In Argentina, Aujeszky is consider an endemic disease and could result in regional commercial restrictions. International requirements for commercialization oblates to develop plans for control and eradication of Aujezsky´s disease. Serological techniques currently used do not allow to identify if the animal is free of pathogen or if it could be a healthy carrier. In surveillance programs, the implementation of Molecular techniques to confirm the diagnostic of this disease is a necessary tool for obtaining early and rapid results. Furthermore, it is also necessary to achieve the molecular characterization of the circulating strains in Argentina in order to establish sanitary politics for eradication of Aujeszky´s disease. This information could allow establishing sanitary politics based on the control of Aujeszky’s diseases and eradication of the circulating Suid Herpesvirus type 1 (SuHV-1).Facultad de Ciencias Veterinaria

Viral determination and molecular characterization of Aujeszky’s disease virus in slaughter plants and wild boar, as part as the epidemiological surveillance official program in Argentina

La enfermedad de Aujeszky afecta principalmente a la producción porcina y ocasiona pérdidas económicas importantes. En la Argentina, esta enfermedad es considerada endémica, lo que puede resultar en restricciones de comercialización para la región. Las exigencias del mercado externo obligan a avanzar con los planes de control y erradicación de la enfermedad de Aujezsky. Esta enfermedad limita las posibilidades económicas del sector porcino y la comercialización internacional, lo cual influye negativamente en la rentabilidad de las explotaciones y en la calidad de los productos de origen animal. Las técnicas serológicas utilizadas solo detectan la presencia de anticuerpos específicos y no permiten detectar directamente la presencia del patógeno en el organismo ni una infección latente. La utilización de la biología molecular para la confirmación y diagnóstico de la enfermedad de Aujeszky en los planes de vigilancia puede convertirse en una herramienta eficaz para la detección temprana de animales infectados con el virus, así como también para la identificación de las variantes genotípicas que circulan en el país. Este conocimiento aportaría información para establecer políticas sanitarias enfocadas en el control de la enfermedad de Aujeszky, tendientes a la erradicación del virus Herpesvirus porcino tipo 1 (SuHV-1) circulante en la Argentina.Aujezky´s disease principally affects the porcine production, and it generate important economical lost. Currently, In Argentina, Aujeszky is consider an endemic disease and could result in regional commercial restrictions. International requirements for commercialization oblates to develop plans for control and eradication of Aujezsky´s disease. Serological techniques currently used do not allow to identify if the animal is free of pathogen or if it could be a healthy carrier. In surveillance programs, the implementation of Molecular techniques to confirm the diagnostic of this disease is a necessary tool for obtaining early and rapid results. Furthermore, it is also necessary to achieve the molecular characterization of the circulating strains in Argentina in order to establish sanitary politics for eradication of Aujeszky´s disease. This information could allow establishing sanitary politics based on the control of Aujeszky’s diseases and eradication of the circulating Suid Herpesvirus type 1 (SuHV-1).Facultad de Ciencias Veterinaria

Viral determination and molecular characterization of Aujeszky’s disease virus in slaughter plants and wild boar, as part as the epidemiological surveillance official program in Argentina

La enfermedad de Aujeszky afecta principalmente a la producción porcina y ocasiona pérdidas económicas importantes. En la Argentina, esta enfermedad es considerada endémica, lo que puede resultar en restricciones de comercialización para la región. Las exigencias del mercado externo obligan a avanzar con los planes de control y erradicación de la enfermedad de Aujezsky. Esta enfermedad limita las posibilidades económicas del sector porcino y la comercialización internacional, lo cual influye negativamente en la rentabilidad de las explotaciones y en la calidad de los productos de origen animal. Las técnicas serológicas utilizadas solo detectan la presencia de anticuerpos específicos y no permiten detectar directamente la presencia del patógeno en el organismo ni una infección latente. La utilización de la biología molecular para la confirmación y diagnóstico de la enfermedad de Aujeszky en los planes de vigilancia puede convertirse en una herramienta eficaz para la detección temprana de animales infectados con el virus, así como también para la identificación de las variantes genotípicas que circulan en el país. Este conocimiento aportaría información para establecer políticas sanitarias enfocadas en el control de la enfermedad de Aujeszky, tendientes a la erradicación del virus Herpesvirus porcino tipo 1 (SuHV-1) circulante en la Argentina.Aujezky´s disease principally affects the porcine production, and it generate important economical lost. Currently, In Argentina, Aujeszky is consider an endemic disease and could result in regional commercial restrictions. International requirements for commercialization oblates to develop plans for control and eradication of Aujezsky´s disease. Serological techniques currently used do not allow to identify if the animal is free of pathogen or if it could be a healthy carrier. In surveillance programs, the implementation of Molecular techniques to confirm the diagnostic of this disease is a necessary tool for obtaining early and rapid results. Furthermore, it is also necessary to achieve the molecular characterization of the circulating strains in Argentina in order to establish sanitary politics for eradication of Aujeszky´s disease. This information could allow establishing sanitary politics based on the control of Aujeszky’s diseases and eradication of the circulating Suid Herpesvirus type 1 (SuHV-1).Facultad de Ciencias Veterinaria

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

Pathogen-sugar interactions revealed by universal saturation transfer analysis

Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an “end-on” manner. uSTA-guided modeling and a high-resolution cryo–electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor