Management and analysis of high-throughput sequence data for infectious animal diseases.

Advances in technology and decreasing costs have accelerated the use of high-throughput sequencing (HTS) for both diagnosis and characterisation of infectious animal diseases. High-throughput sequencing offers several advantages over previous techniques, including rapid turnaround times and the ability to resolve single nucleotide changes among samples, both of which are important for epidemiological investigations of outbreaks. However, due to the plethora of genetic data being routinely generated, the storage and analysis of these data are proving challenging in their own right. In this article, the authors provide insight into the aspects of data management and analysis that should be considered before adopting HTS for routine animal health diagnostics. These elements fall largely into three interrelated categories: data storage, data analysis and quality assurance. Each has numerous complexities and may need to be adapted as HTS evolves. Making appropriate strategic decisions about bioinformatic sequence analysis early on in project development will help to avert major issues in the long term.

Les avancées technologiques dans le domaine du séquençage à haut débit (SHD) et la diminution des coûts liés à cette technique en ont accéléré l'utilisation à des fins de diagnostic et de caractérisation des maladies animales infectieuses. Le séquençage à haut débit offre plusieurs avantages par rapport aux techniques antérieures, en particulier la rapidité de son exécution et une résolution de l'ordre d'un seul changement de nucléotide parmi plusieurs échantillons, ce qui présente un grand intérêt lors des enquêtes épidémiologiques sur les foyers. Néanmoins, la pléthore de données génétiques générées en routine par le SHD devient un véritable problème en termes de stockage et d'analyse de ces données. Les auteurs apportent un éclairage sur les aspects de la gestion et de l'analyse des données qu'il convient de prendre en compte avant d'adopter le SHD pour le diagnostic de routine en santé animale. Ces éléments relèvent de trois catégories étroitement reliées : le stockage de données, l'analyse de données et l'assurance qualité. Chacun de ces aspects présente de nombreuses complexités et nécessitera sans doute d'être adapté à mesure que le SHD évolue. Lorsqu'elles sont prises dès la phase initiale d'un projet, des décisions stratégiques appropriées en matière d'analyse bio-informatique de séquences peuvent contribuer à éviter des problèmes majeurs sur le long terme.

Los avances tecnológicos y la reducción de los costos han acelerado el uso de la secuenciación de alto rendimiento (SAR) con fines de diagnóstico y caracterización de enfermedades animales infecciosas. La secuenciación de alto rendimiento presenta varias ventajas en comparación con otras técnicas anteriores, en particular ciclos más rápidos y una resolución que permite detectar diferencias de un solo nucleótido entre las muestras, aspectos ambos de gran importancia para el estudio epidemiológico de brotes infecciosos. Sin embargo, debido al sinnúmero de datos genéticos que constantemente se generan, no es de extrañar que esté resultando problemático almacenar y analizar los datos obtenidos. Los autores arrojan luz sobre los aspectos de la gestión y el análisis de datos que conviene tener en cuenta antes de aplicar la SAR a las labores sistemáticas de diagnóstico en sanidad animal. Estos elementos corresponden a grandes líneas a tres categorías relacionadas entre sí: el almacenamiento de datos; el análisis de datos; y la garantía de calidad. Cada una de ellas presenta multitud de complicaciones y exige un proceso permanente de adaptación a medida que la técnica de secuenciación va evolucionando. El hecho de adoptar las buenas decisiones estratégicas sobre el análisis bioinformático de secuencias en los primeros momentos de la concepción de un proyecto ayudará a evitar importantes problemas a largo plazo.

Disease outbreak response: why epidemiology plays a central role.

The need to control transboundary animal disease outbreaks is widely recognised, as is the need for evidence-based decisions regarding which control measures to implement. Key data and information are required to inform this evidence base. To ensure effective communication of the evidence, a rapid process of collation, interpretation and translation is required. This paper describes how epidemiology can provide the framework through which relevant specialists can be engaged to this end, and highlights the central role of epidemiologists, with their unique combination of skills, in this process. It provides an example of an evidence team led by epidemiologists, namely the United Kingdom National Emergency Epidemiology Group, which was established to address this need. It then goes on to consider the different strands of epidemiology, the need for a wide multidisciplinary approach, and the importance of training and preparedness activities to facilitate rapid response.

La nécessité de contrôler les foyers de maladies animales transfrontalières est largement reconnue, tout comme celle de fonder la prise de décisions sur des données probantes pour la mise en oeuvre des mesures de contrôle. Afin de documenter cette base d'éléments probants, il est nécessaire d'obtenir un certain nombre de données et d'informations clés. Un processus rapide de collecte, d'interprétation et de traduction des données doit être mis en place afin de communiquer ces éléments probants de manière efficace. Les auteurs décrivent le cadre que l'épidémiologie peut apporter aux chercheurs pour s'engager sur cette voie ; ils soulignent le rôle central des épidémiologistes dans ce processus, grâce au faisceau unique de compétences dont ils disposent. Ils donnent l'exemple d'une équipe animée par des épidémiologistes travaillant sur les données probantes qui a été mise en place spécifiquement pour répondre à ce besoin : le Groupe national d'épidémiologie d'urgence du Royaume-Uni (National Emergency Epidemiology Group). Les auteurs concluent en menant une réflexion sur les différentes branches de l'épidémiologie, le besoin d'une approche pluridisciplinaire large et l'importance des activités de formation et de préparation pour une réponse rapide.

Hay coincidencia general en que hoy resulta imperativo combatir los brotes transfronterizos de enfermedades animales, al igual que es necesario contar con un sólido fundamento de datos factuales para tomar decisiones sobre las medidas de lucha que conviene implantar. Para generar esta base empírica hay que disponer de un conjunto esencial de datos e información y para comunicarla eficazmente se requiere un rápido proceso de recogida, interpretación y traducción. Los autores explican cómo puede la epidemiología constituir el marco de referencia desde el que trabajen para tal fin los distintos especialistas y destacan la función central que cumplen en este proceso los epidemiólogos, gracias a la singular combinación de competencias que presentan. A modo de ejemplo, describen un equipo dedicado al estudio de datos factuales que fue establecido, bajo la dirección de epidemiólogos, justamente para responder a esta necesidad: el Grupo nacional de respuesta epidemiológica a situaciones de emergencia del Reino Unido (National Emergency Epidemiology Group). Por último, tras detenerse en las distintas vertientes de la epidemiología, inciden en la necesidad de abordar la cuestión desde un planteamiento ampliamente pluridisciplinar y en la importancia que revisten las actividades de formación y preparación para facilitar una respuesta rápida.

The World Animal Health Information System as a tool to support decision-making and research in animal health.

The World Animal Health Information System (WAHIS) collects and publishes a wealth of information gathered by individual countries' Veterinary Services, including detailed country-specific information on outbreaks of diseases listed by the World Organisation for Animal Health (WOAH, founded as OIE), including emerging diseases, in domestic animals and wildlife, and non-listed diseases in wildlife. The data set is one of the most comprehensive in the world, with 182 Members obliged to report this information to WOAH in a timely manner. As such, the data provide invaluable input for Veterinary Services, animal health researchers and stakeholders to gain insight into risk from infectious diseases, for example through the development of predictive models and risk assessments to address the risk from trade of animal products, globalisation, or movement of wildlife or vectors across country borders. This paper reviews previous analyses that have been conducted using WAHIS data and outlines ways in which these data can be used for preparedness and risk assessment.

Le Système mondial d'information zoosanitaire (WAHIS) collecte et publie une grande quantité d'informations recueillies auprès des Services vétérinaires nationaux, parmi lesquelles des données détaillées spécifiques aux pays sur les foyers de maladies listées par l'Organisation mondiale de la santé animale (OMSA, fondée en tant qu'OIE), dont les maladies émergentes, chez les animaux domestiques et dans la faune sauvage, ainsi que de maladies non listées affectant la faune sauvage. Cet ensemble de données est l'un des plus exhaustifs du monde puisque les 182 Membres de l'OMSA ont l'obligation de lui faire remonter ces informations dans WAHIS dans des délais spécifiés. Ces données sont précieuses pour les Services vétérinaires, les chercheurs travaillant dans le domaine de la santé animale et les parties prenantes car elles permettent de mieux comprendre les risques relatifs aux maladies infectieuses, notamment grâce aux modèles prédictifs et aux évaluations de risques pour traiter le risque lié au commerce de produits d'origine animale, à la mondialisation, aux mouvements de la faune sauvage ou aux vecteurs entre les pays. Les auteurs font le point sur des analyses antérieures qui ont été menées en utilisant les données de WAHIS et soulignent comment ces données peuvent être utilisées dans le cadre d'un travail de préparation et d'évaluation des risques.

El Sistema Mundial de Información Zoosanitaria (WAHIS) colecta y publica una gran cantidad de datos recogidos por los Servicios Veterinarios de cada país, en particular detallada información sobre brotes de enfermedades listadas por la Organización Mundial de Sanidad Animal (OMSA, fundada como OIE), incluidas las enfermedades emergentes, que hayan afectado a los animales domésticos o la fauna silvestre, así como enfermedades no listadas que afectan a la fauna silvestre. Se trata de uno de los conjuntos de datos más completos del mundo, ya que los 182 Miembros tienen la obligación de comunicar esta información a la OMSA dentro de plazos determinados. Estos datos son una fuente de información de gran utilidad para los Servicios Veterinarios, los investigadores que trabajan en sanidad animal y demás partes interesadas porque permiten mejorar la comprensión de los riesgos derivados de las enfermedades infecciosas, por ejemplo elaborando modelos predictivos y evaluaciones de riesgo que ayuden a manejar los riesgos ligados al comercio de productos de origen animal, la globalización o al movimiento transfronterizo de animales salvajes o vectores de enfermedad. Los autores repasan una serie de análisis previamente realizados con datos de WAHIS y explican en síntesis cómo pueden utilizarse estos datos con fines de preparación y evaluación de riesgos.

A New Opportunity for "Old" Molecules: Targeting PARP1 Activity through a Non-Enzymatic Mechanism.

In recent years, new therapies have been developed based on molecules that target molecular mechanisms involved in both the initiation and maintenance of the oncogenic process. Among these molecules are the poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. PARP1 has emerged as a target with great therapeutic potential for some tumor types, drawing attention to this enzyme and resulting in many small molecule inhibitors of its enzymatic activity. Therefore, many PARP inhibitors are currently in clinical trials for the treatment of homologous recombination (HR)-deficient tumors, BRCA-related cancers, taking advantage of synthetic lethality. In addition, several novel cellular functions unrelated to its role in DNA repair have been described, including post-translational modification of transcription factors, or acting through protein-protein interactions as a co-activator or co-repressor of transcription. Previously, we reported that this enzyme may play a key role as a transcriptional co-activator of an important component of cell cycle regulation, the transcription factor E2F1. Here, we show that PARP inhibitors, which interfere with its activity in cell cycle regulation, perform this without affecting its enzymatic function.

Neurogenic Fever after Subarachnoid Hemorrhage in Animal Models: A Systematic Review.

The observation of neurogenic fever resulting from subarachnoid hemorrhage (SAH) in animal models is a useful tool for the interpretation of its pathophysiology in humans, which is still a major challenge in the management of neurocritical patients. This systematic review aims to identify the prognostic factors and pathophysiological elements that determine the onset of neurogenic fever and its severity in animal models. In addition, our study aims to analyze which pharmacological treatments are most effective. All the articles available in Pubmed, Embase, and the Biological Science Collection until August 2021 concerning in vivo experimental studies on SAH animal models, including full texts and abstracts written in English and Italian, were considered. The risk of bias was assessed with SYRCLE's Risk of Bias tool. In total, 81 records were retrieved; after excluding duplicates, 76 records were potentially relevant. A total of 64 articles was excluded after title and abstract screening. The remaining 12 studies were evaluated as full texts, and 6 other studies were excluded (SAH-induced animal studies without a body temperature assessment). In one study, body temperature was measured after SAH induction, but the authors did not report temperature recording. Therefore, only five studies met the search criteria. The high methodological heterogeneity (different animal species, different temperature measurement methods, and different methods of the induction of bleeding) prevented meta-analysis. Synthesis methodology without meta-analysis (SWiM) was used for data analysis. The total number of animals used as controls was 87 (23 rabbits, 32 mice, and 32 rats), while there were 130 animals used as interventions (54 rabbits, 44 mice, and 32 rats). The presence of blood in the subarachnoid space, particularly red blood cells, is responsible for neurogenic fever; the role of hemoglobin is unclear. The mechanism is apparently not mediated by prostaglandins. The autonomic nervous system innervating brown adipose tissue is undoubtedly implicated in the onset of neurogenic fever. The activation of the central adenosine-1 receptor is effective in controlling the temperature of animals with neurogenic fever (by inhibiting thermogenesis of brown adipose tissue).

An animal model for mitochondrial tyrosyl-tRNA synthetase deficiency reveals links between oxidative phosphorylation and retinal function.

Mitochondria maintain a distinct pool of ribosomal machinery, including tRNAs and tRNAs activating enzymes, such as mitochondrial tyrosyl-tRNA synthetase (YARS2). Mutations in YARS2, which typically lead to the impairment of mitochondrial protein synthesis, have been linked to an array of human diseases including optic neuropathy. However, the lack of YARS2 mutation animal model makes us difficult to elucidate the pathophysiology underlying YARS2 deficiency. To explore this system, we generated YARS2 knockout (KO) HeLa cells and zebrafish using CRISPR/Cas9 technology. We observed the aberrant tRNATyr aminoacylation overall and reductions in the levels in mitochondrion- and nucleus-encoding subunits of oxidative phosphorylation system (OXPHOS), which were especially pronounced effects in the subunits of complex I and complex IV. These deficiencies manifested the decreased levels of intact supercomplexes overall. Immunoprecipitation assays showed that YARS2 bound to specific subunits of complex I and complex IV, suggesting the posttranslational stabilization of OXPHOS. Furthermore, YARS2 ablation caused defects in the stability and activities of OXPHOS complexes. These biochemical defects could be rescued by the overexpression of YARS2 cDNA in the YARS2KO cells. In zebrafish, the yars2KO larva conferred deficient COX activities in the retina, abnormal mitochondrial morphology, and numbers in the photoreceptor and retinal ganglion cells. The zebrafish further exhibited the retinal defects affecting both rods and cones. Vision defects in yars2KO zebrafish recapitulated the clinical phenotypes in the optic neuropathy patients carrying the YARS2 mutations. Our findings highlighted the critical role of YARS2 in the stability and activity of OXPHOS and its pathological consequence in vision impairments.

Serial systemic candidiasis alters Candida albicans macromorphology associated with enhancement of virulence attributes.

Candida albicans is one of the major pathogens found in superficial and invasive infections. This fungus expresses several virulence factors and fitness attributes that are essential to the pathogenesis. In our previous study using a murine model of serial systemic candidiasis, virulence of the recovered C. albicans was enhanced and several virulence factors were also modified after five successive passages through mice (P1-P5). In this study, we aimed to correlate the different fungal morphologies, as well as the filamentation, invasion, and stress resistance abilities, of the cells recovered after passing through this model of infection with our previous findings regarding virulence. We obtained two colony morphology types from the recovered cells, differing in their peripheral filamentation. The morphotype 1, which presented zero to five filaments in the colony edge, was higher in P2, while morphotype 2, which presented more than five filaments in the colony edge, was predominant from P3 to P5. In general, morphotype 1 showed similar levels regarding filamentation in serum, invasion of agar and cells, and resistance to osmotic, oxidative, and thermal stress in all passages analyzed. The morphotype 2, however, exhibited an enhancement in these abilities over the passages. We observed an accordance with the increased virulence over the passages obtained in our previous study and the increased adaptability profile of morphotype 2. Therefore, we suggest that the behavior observed previously in the pathogenesis and virulence could be attributed, at least in part, to the greater presence and ability of morphotype 2.

A novel animal model of colonic stenosis to aid the development of new stents for colon strictures.

BACKGROUND: The incidence of colonic stenosis, primarily caused by colon cancer and Crohn's disease, is increasing each year. The development of safer stents for colonic stenosis is required because perforation associated with cancer stent placement worsens the prognosis and stent placement for anastomotic stenosis due to Crohn's disease or colectomy is not first choice due to the high migration rate. The wall of the large intestine where the stent is inserted receives the complex forces from the peristaltic movement of the large intestine and stool in addition to the reaction tension of the stent, causing perforation and migration. Animal models may help develop new and safe stents, but no animal model closely reproduces the condition of human colonic stenosis. Herein, we present a novel animal model of colonic stenosis, which closely replicates the human colonic size. METHODS: The artificial colonic stenosis model was developed by wrapping the porcine colon with a silicone sheet after laparotomy. The usefulness of the model was evaluated by investigating the availability of endoscopic stent placement, morphological maintenance of colonic stenosis, adverse effects on pigs, and modeling time. The first three and the last three modeling times were analyzed using Student's t-test. RESULTS: Endoscopic stent placement was performed in all cases without intraoperative complications. There were no postoperative model complications or deaths. Adhesions to the surrounding tissue in the abdominal cavity of the artificial colon stenosis were slight. The morphology of the isolated artificial stenoses was completely maintained, and no necrosis or perforation was observed. CONCLUSIONS: We developed a novel and feasible animal model of colonic stenosis using pigs. We believe that this animal model will be useful for developing a safer stent for obstruction caused by benign diseases and colon cancer.

Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis.

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human ß2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.

Abattoir-based serological surveillance for transboundary and zoonotic diseases in cattle and swine in Cambodia: a pilot study in Phnom Penh province during 2019 and 2020.

A pilot animal disease surveillance program was implemented at four abattoirs in Phnom Penh, Cambodia, between October 2019 and January 2020. A total of 1141 samples were collected from 477 cattle and 664 swine. Serological testing was performed using commercial antibody ELISA kits for zoonotic and high-impact animal diseases, namely brucellosis, Q fever, classical swine fever (CSF), porcine reproductive and respiratory syndrome (PRRS) and African swine fever (ASF). Only two samples tested positive for Brucella antibodies (0.2%, 95% CI 0.4-0.6, n = 1141). The seroprevalence of Q fever was 0.8% (95% CI 0.3-2.1, n = 477) in the cattle samples, while CSF, PRRS and ASF in pigs were 55.4% (95% CI 51.6-59.2, n = 655), 81.2% (95% CI 78.1-84.0, n = 655) and 2.6% (95% CI 1.6-4.1, n = 664), respectively. All 38 doubtful and 17 positive ASF antibody ELISA samples were negative when tested by real-time PCR. Univariate analyses demonstrated that the factor significantly associated with positive results of ASF was the abattoir location (p-value = 0.002). Based on logistic regression models, significant risk factors for CSF were province of origin (p-value = 1.7 × 10-6), abattoir (p-value = 3.6 × 10-11) and PRRS positivity (p-value = 0.004), and for PRRS were province of origin (p-value = 0.0004) and CSF positivity (p-value = 0.001). In conclusion, the seroprevalences of zoonotic diseases in this study were very low. The high prevalence of CSF and PRRS antibodies were most likely the result of vaccination. All ASF seropositive pigs, including those that gave equivocal results, originated from large-scale Cambodian-based commercial farms, as well as Thailand, which raises questions about possible illegal vaccination or low-pathogenicity ASF variants. The pilot abattoir serological surveillance program described here has the potential to provide a sentinel for incursions of novel and endemic pathogens, although further work is required to demonstrate its capacity to provide information on the longitudinal disease trends.

MODELS OF PARASPINAL MUSCLE DEGENERATION IN RATS: HIGH-FAT DIET AND PROLONGED COMPRESSION.

OBJECTIVE: The aim: To study the structural features of the lumbar m. multifidus and the m. psoas after keeping rats on a high-fat diet (obesity) or compressing their lumbar paraspinal muscles by binding the muscles using non-absorbable sutures. PATIENTS AND METHODS: Materials and methods: The study was performed on 2-month-old male rats (n=15) into three groups of 5: control group (normal diet without any surgical interventions), high-fat diet (model I: 40-45% kcal fat), and paraspinal muscles compression (model II: paraspinal muscles were tied from L2 to S1 with non-absorbable sutures Nurolon® 3). The experiment lasted for 90 days, after those fragments of the lumbar m. multifidus and m. psoas removed and histomorphometry analysis performed. RESULTS: Results: 12 weeks from the beginning of the experiment, the high-fat diet rats weighed, on average, 22% (p=0.001) more than the control group rats. Similar degenerative changes such as uneven muscle fibre width and sarcoplasm colouring, 'wavy' and swollen fibres, loss of striation, karyopyknosis were observed in the lumbar paraspinal muscles in both models. In high-fat diet group the fat area (%) in the m. multifidus was 1.8 times larger (р<0.001) and in the m. psoas was greater by 2.2 times (р<0.001) than in the control. Fibrous tissue replaced muscle fibres in m. multifidus in model II and was 12.66%. CONCLUSION: Conclusions: The relevance of the models is proven: after 3 months, it is possible to obtain degenerative changes in the muscle tissue that are extremely similar to those observed in the muscles of patients with degenerative spine diseases.

Heparin-based blood purification attenuates organ injury in baboons with Streptococcus pneumoniae pneumonia.

Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to 1) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction and 2) test the safety and efficacy of a novel extracorporeal blood filter to remove proinflammatory molecules and improve organ function. After a dose-finding pilot study, 12 animals were inoculated with Streptococcus pneumoniae [5 × 109 colony-forming units (CFU)], given ceftriaxone at 24 h after inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate (n = 6) or sham treatment (n = 6) for 4 h at 30 h after inoculation. For safety analysis, four uninfected animals also underwent purification. At 48 h, necropsy was performed. Inoculated animals developed severe pneumonia and septic shock. Compared with sham-treated animals, septic animals treated with purification displayed significantly less kidney injury, metabolic acidosis, hypoglycemia, and shock (P < 0.05). Purification blocked the rise in peripheral blood S. pneumoniae DNA, attenuated bronchoalveolar lavage (BAL) CCL4, CCL2, and IL-18 levels, and reduced renal oxidative injury and classical NLRP3 inflammasome activation. Purification was safe in both uninfected and infected animals and produced no adverse effects. We demonstrate that heparin-based blood purification significantly attenuates levels of circulating S. pneumoniae DNA and BAL cytokines and is renal protective in baboons with severe pneumococcal pneumonia and septic shock. Purification was associated with less severe acute kidney injury, metabolic derangements, and shock. These results support future clinical studies in critically ill septic patients.

Developmental endothelial locus-1 as a potential biomarker for the incidence of acute exacerbation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Despite the high disease burden of chronic obstructive pulmonary disease (COPD) and risk of acute COPD exacerbation, few COPD biomarkers are available. As developmental endothelial locus-1 (DEL-1) has been proposed to possess beneficial effects, including anti-inflammatory effects, we hypothesized that DEL-1 could be a blood biomarker for COPD. OBJECTIVE: To elucidate the role of plasma DEL-1 as a biomarker of COPD in terms of pathogenesis and for predicting acute exacerbation. METHODS: Cigarette smoke extract (CSE) or saline was intratracheally administered to wild-type (WT) and DEL-1 knockout (KO) C57BL/6 mice. Subsequently, lung sections were obtained to quantify the degree of emphysema using the mean linear intercept (MLI). Additionally, plasma DEL-1 levels were compared between COPD and non-COPD participants recruited in ongoing prospective cohorts. Using negative binomial regression analysis, the association between the plasma DEL-1 level and subsequent acute exacerbation risk was evaluated in patients with COPD. RESULTS: In the in vivo study, DEL-1 KO induced emphysema (KO saline vs. WT saline; P = 0.003) and augmented CSE-induced emphysema (KO CSE vs. WT CSE; P < 0.001) in 29 mice. Among 537 participants, patients with COPD presented plasma log (DEL-1) levels lower than non-COPD participants (P = 0.04), especially non-COPD never smokers (P = 0.019). During 1.2 ± 0.3 years, patients with COPD in the lowest quartile of Log(DEL-1) demonstrated an increased risk of subsequent acute exacerbation, compared with those in the highest quartile of Log(DEL-1) (adjusted incidence rate ratio, 3.64; 95% confidence interval, 1.03-12.9). CONCLUSION: Low DEL-1 levels are associated with COPD development and increased risk of subsequent COPD acute exacerbation. DEL-1 can be a useful biomarker in patients with COPD.

Research perspectives on animal health in the era of artificial intelligence.

Leveraging artificial intelligence (AI) approaches in animal health (AH) makes it possible to address highly complex issues such as those encountered in quantitative and predictive epidemiology, animal/human precision-based medicine, or to study host × pathogen interactions. AI may contribute (i) to diagnosis and disease case detection, (ii) to more reliable predictions and reduced errors, (iii) to representing more realistically complex biological systems and rendering computing codes more readable to non-computer scientists, (iv) to speeding-up decisions and improving accuracy in risk analyses, and (v) to better targeted interventions and anticipated negative effects. In turn, challenges in AH may stimulate AI research due to specificity of AH systems, data, constraints, and analytical objectives. Based on a literature review of scientific papers at the interface between AI and AH covering the period 2009-2019, and interviews with French researchers positioned at this interface, the present study explains the main AH areas where various AI approaches are currently mobilised, how it may contribute to renew AH research issues and remove methodological or conceptual barriers. After presenting the possible obstacles and levers, we propose several recommendations to better grasp the challenge represented by the AH/AI interface. With the development of several recent concepts promoting a global and multisectoral perspective in the field of health, AI should contribute to defract the different disciplines in AH towards more transversal and integrative research.

Animal disease surveillance: Its importance & present status in India.

Animal disease surveillance encompasses systematic collection of long-term data on disease events, risk factors and other relevant parameters followed by analyzing the same with reference to temporal and spatial characteristics to arrive at a conclusion so that necessary preventive measures can be taken. In India, the animal disease surveillance is done through National Animal Disease Reporting System, which is a web-based information technology system for disease reporting from States and Union Territories with the aim to record, monitor livestock disease situation and to initiate the preventive and curative action in a swift manner during disease emergencies. National Animal Disease Referral Expert System is a dynamic geographic information system and remote sensing-enabled expert system that captures an incidence of 13 economically important livestock diseases from all over the country and also provides livestock disease forecasting. The laboratories under State and Central governments, several research institutes under the Indian Council of Agricultural Research and veterinary colleges are involved in livestock disease diagnosis including zoonotic diseases. An integrated surveillance system is necessary for early detection of emerging/zoonotic diseases in humans. This review provides information on disease reporting and surveillance systems in animal health sector and the need for One Health approach to improve and strengthen the zoonotic disease surveillance system in India.

Late intervention in the remnant kidney model attenuates proteinuria but not glomerular filtration rate decline.

AIM: The use of animal models to predict the response to new therapies in humans is a vexing issue in nephrology. Unlike patients with chronic kidney disease (CKD), few rodent models develop a progressive decline in glomerular filtration rate (GFR) so that experimental studies frequently report a reduction in proteinuria as the primary efficacy outcome. Moreover, while humans present with established kidney disease that continues to progress, many experimental studies investigate therapies in the prevention rather than in a therapeutic setting. METHODS: We used the remnant kidney (subtotal nephrectomy [SNX]) rat model that develops a decline in GFR in conjunction with heavy proteinuria and hypertension along with the histological hallmarks of CKD in humans, glomerulosclerosis and tubulointerstitial fibrosis. Using agents that had been shown to improve GFR as well as proteinuria in the prevention setting, angiotensin-converting enzyme (ACE) inhibition with enalapril and SIRT1 activation with SRT3025, treatment was initiated 6 weeks after SNX. RESULTS: While enalapril reduced blood pressure, proteinuria and histological injury, it did not improve GFR, as measured by inulin clearance. SRT3025 improved neither GFR nor structural damage despite a reduction in proteinuria. CONCLUSION: These findings demonstrate that neither a reduction in proteinuria nor a reversal of structural damage in the kidney will necessarily translate to a restoration of kidney function.

An Engineered sgsh Mutant Zebrafish Recapitulates Molecular and Behavioural Pathobiology of Sanfilippo Syndrome A/MPS IIIA.

Mucopolysaccharidosis IIIA (MPS IIIA, Sanfilippo syndrome type A), a paediatric neurological lysosomal storage disease, is caused by impaired function of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH) resulting in impaired catabolism of heparan sulfate glycosaminoglycan (HS GAG) and its accumulation in tissues. MPS IIIA represents a significant proportion of childhood dementias. This condition generally leads to patient death in the teenage years, yet no effective therapy exists for MPS IIIA and a complete understanding of the mechanisms of MPS IIIA pathogenesis is lacking. Here, we employ targeted CRISPR/Cas9 mutagenesis to generate a model of MPS IIIA in the zebrafish, a model organism with strong genetic tractability and amenity for high-throughput screening. The sgshΔex5-6 zebrafish mutant exhibits a complete absence of Sgsh enzymatic activity, leading to progressive accumulation of HS degradation products with age. sgshΔex5-6 zebrafish faithfully recapitulate diverse CNS-specific features of MPS IIIA, including neuronal lysosomal overabundance, complex behavioural phenotypes, and profound, lifelong neuroinflammation. We further demonstrate that neuroinflammation in sgshΔex5-6 zebrafish is largely dependent on interleukin-1ß and can be attenuated via the pharmacological inhibition of Caspase-1, which partially rescues behavioural abnormalities in sgshΔex5-6 mutant larvae in a context-dependent manner. We expect the sgshΔex5-6 zebrafish mutant to be a valuable resource in gaining a better understanding of MPS IIIA pathobiology towards the development of timely and effective therapeutic interventions.

Bench to Shop™: An Interdisciplinary Training Program for Transitioning of Transboundary Animal Disease Research to Commercialization.

Transboundary animal diseases (TADs) are livestock diseases characterized as highly contagious, fast-spreading, and capable of producing high morbidity and mortality. Accidental or intentional introduction of these diseases into the United States could devastate the economy, food security, and public health. Training of researchers, scientists and animal health workers is often limited to prevention and diagnosis with little emphasis on the importance of translating knowledge to the development of new products for the prevention, detection and control of outbreaks. The Bench to Shop™ training program was developed to fill this gap and applied an innovative blended-learning method through the use of an online platform, a 3-week experiential training, and a 1-month follow-up project. The program specifically targeted next-generation researchers, including PhD students, post-doctoral researchers, and early-career faculty. A total of 17 trainees, in two cohorts, were selected through a national and international recruitment process. Program evaluation consisted of focus groups, follow-up interviews, and pre- and post-tests of didactic material, revealing statistically significant gains in knowledge. Participants expanded their professional networks with leaders in industry and regulatory agencies related to production and/or commercialization of TAD products and deepened their commitment toward keeping our country safe from TADs. Post-program impacts on trainees included advancing products toward commercialization, partnering with connections made through the program, and demonstrating dedication to homeland security by pursuing product development related educational and career opportunities. Overall, results suggest this program provides an added value and should be readily available to the current and future workforce.

Review: Other Helicobacter species.

This review covers the most important, accessible, and relevant literature published between April 2019 and April 2020 in the field of non-Helicobacter pylori Helicobacter species (NHPH). The initial part of the review covers new insights regarding the presence of gastric and enterohepatic NHPH in humans and animals, while the subsequent section focuses on the progress in our understanding of animal models, the pathogenicity and omics of these species. Over the last year, the clinical relevance of gastric NHPH infections in humans was highlighted. With regard to NHPH in animals, the ancestral source of Helicobacter suis was further established showing that Cynomolgus macaques are the common ancestor of the pig-associated H. suis population, and 3 novel Helicobacter species isolated from the gastric mucosa of red foxes were described. "Helicobacter burdigaliensis" sp nov. and "Helicobacter labetoulli" sp nov. were proposed as novel enterohepatic Helicobacter species associated with human digestive diseases. An analysis of Helicobacter cinaedi recurrent infections in humans proposed long-term antibiotic therapies. Several studies using rodent models further elucidated the mechanisms underlying the development of NHPH-related disease, as well as intestinal immunity in inflammatory bowel disease models. Omics approaches supported Helicobacteraceae taxonomy and unraveled the transcriptomic signatures of H. suis and Helicobacter heilmannii upon adherence to the human gastric epithelium. With regard to virulence, data showed that the nuclear remodeling promoted by cytolethal distending toxin of Helicobacters involves the MAFB oncoprotein and is associated with nucleoplasmic reticulum formation in surviving cells.

The gulf between emergency plans and the resources needed: a global review.

Preparedness for an animal emergency event reduces a country's economic and production losses and decreases animal disease threats to neighbouring countries. Investing in animal disease preparedness reduces economic expenditures during an emergency as well as in recovery. An essential component of animal disease preparedness is a national contingency plan that is fit for purpose. This useful document should be frequently updated and can be modified with new information from self-assessments and after-action reports, which should identify resource needs and improvements to be made. National contingency plans are recommended in global international guidance and by animal health and veterinary organisations. Despite this, some countries lack national contingency plans that are fit for purpose, or the resources to implement them. This review concentrates on trends in national contingency planning around the world. In 2018 and 2019, the authors surveyed existing global animal disease contingency plans. Of the 181 Members of the World Organisation for Animal Health (OIE), 163 were reported to have some form of national contingency plan. (Over the course of the review from 2018 to 2019, the 182nd Member joined the OIE. This review examines only the 181 that were Members when the survey began.) The authors review current global animal emergency preparedness and discuss the gaps that have been identified. They discuss global trends, examining developing concepts and novel approaches that may aid improvements in global national contingency planning and enhance the global capacity to prepare for animal disease where gaps exist.

La préparation aux urgences de santé animale atténue les pertes économiques et productives des pays affectés et réduit la menace de propagation de maladies aux pays voisins. Les investissements dédiés à la préparation aux maladies animales réduisent les dépenses économiques durant l'urgence ainsi que pendant la phase de redressement. L'une des composantes essentielles de la préparation aux situations d'urgence zoosanitaire est le plan national d'intervention, qui doit être adapté aux objectifs visés. Il convient de mettre à jour régulièrement ce document de programmation et de le modifier au vu des renseignements nouveaux émanant des autoévaluations ou des rapports postérieurs à l'adoption de mesures ­ lesquels doivent préciser les ressources requises et les améliorations à apporter. Les directives internationales et les organisations vétérinaires et de santé animale recommandent de se doter de plans nationaux d'intervention d'urgence. Pourtant, certains pays ne disposent ni de plans nationaux d'intervention adaptés aux objectifs visés, ni des ressources nécessaires à leur mise en œuvre. L'analyse présentée par les auteurs est axée sur les tendances observées dans le monde en matière de planification nationale des interventions d'urgence. En 2018 et 2019, les auteurs ont fait le point sur les plans d'urgence existants dans le domaine de la santé animale. Il ressort de leur enquête que 163 des 181 Membres de l'Organisation mondiale de la santé animale (OIE) disposaient d'un plan national d'urgence, sous une forme ou une autre. (Au cours de cette enquête conduite de 2018 à 2019, un 182e Membre a adhéré à l'OIE. L'analyse présentée par les auteurs ne concerne que les 181 pays ayant la qualité de Membre au début de l'enquête.) Les auteurs passent en revue le niveau actuel de préparation aux urgences zoosanitaires dans le monde et analysent les lacunes constatées. Ils évoquent les tendances mondiales et soulignent les concepts en cours d'élaboration ainsi que les approches novatrices susceptibles de contribuer à l'amélioration des plans nationaux d'intervention d'urgence à l'échelle mondiale et au renforcement des capacités de préparation aux maladies animales dans les pays où des lacunes existent encore.

La preparación para episodios de emergencia relacionados con los animales reduce las pérdidas económicas y de producción que sufre un país y rebaja el nivel de las amenazas zoosanitarias que pesan sobre los países vecinos. El hecho de invertir en la preparación para enfermedades animales reduce los gastos no solo cuando adviene la emergencia, sino también durante la fase de recuperación. Uno de los componentes básicos de este proceso de preparación es un plan nacional de emergencia que esté adaptado a su finalidad. Se trata de un documento muy útil, que conviene actualizar con frecuencia y puede ser enriquecido a medida que los procesos de autoevaluación y los informes retrospectivos (que ayudan a determinar los recursos necesarios y las mejoras requeridas) vayan deparando nueva información. Tanto las guías internacionales de ámbito mundial como las organizaciones de sanidad animal y veterinaria recomiendan disponer de un plan nacional de emergencia. Pese a ello, hay países que carecen de un plan de este tipo adaptado a sus fines o de los recursos necesarios para ponerlo en práctica. Los autores se centran aquí en las tendencias en todo el mundo de los procesos de elaboración de planes nacionales de emergencia. En 2018 y 2019 examinaron los planes para emergencias zoosanitarias existentes en el mundo y constataron que, de los 181 Países Miembros de la Organización Mundial de Sanidad Animal (OIE), 163 disponen de algún tipo de plan nacional de emergencia. (Entre 2018 y 2019, en el curso del estudio, un nuevo País Miembro, el 182º, se incorporó a la OIE, pero los resultados aquí descritos se refieren solo a los 181 que eran Miembros cuando empezó el estudio.) Los autores describen la situación mundial actual en cuanto a preparación para emergencias relacionadas con los animales y señalan las carencias detectadas. Después exponen las tendencias de ámbito mundial, examinando conceptos nacientes y planteamientos novedosos que pueden ayudar a mejorar la elaboración en el mundo de planes nacionales de emergencia y a reforzar la capacidad general de preparación para enfermedades animales allí donde existen deficiencias.