A cross-sectional survey on respiratory disease in a cohort of Irish pig farms

Altres ajuts: Department of Agriculture, Food and the Marine PathSurvPig 14/S/832Respiratory disease is one of the most important factors impacting pig production worldwide. There is no available information on the prevalence of key pathogens implicated in Irish pig production. The objective of this study was to describe the prevalence of pleurisy, pneumonia, lung abscesses, pericarditis and liver milk spots in finisher pigs of a cohort of Irish pig farms, and to describe the seroprevalence of: influenza A virus (IAV), porcine reproductive and respiratory syndrome virus (PRRSv), Mycoplasma hyopneumoniae (Mhyo) and Actinobacillus pleuropneumoniae (APP). In brief, 56 farrow-to-finish farms (29% of the Irish breeding herd) were enrolled in the study in 2017. Data on lungs, heart, and liver lesions were assessed for each farm at slaughter. An average of 417 (range 129-1154) plucks per farm were assessed for pleurisy, pneumonia, lung abscesses, pericarditis, and liver milk spots. Blood samples from 32 finisher pigs were collected at slaughter for each farm. The observed prevalence of pleurisy and pneumonia was one of the lowest reported in similar studies in Europe (13 and 11% estimated average within farm, respectively). Pleurisy lesions were mostly moderate and severe. Pneumonia lesions affected a low level of lung surface (5.8%). Prevalence of pericarditis was mid-high (8%) and the prevalence of liver milk spots was high, with an average of 29% of the livers affected. For serology, 78.6% of the farms were positive for IAV, 50% were positive for PRRSv, 71.4% were positive for Mhyo, and 98.2% were positive for APP. Influenza virus was the main pathogen associated with pleurisy (P < 0.001) and Mhyo was the main pathogen associated with pneumonia (P < 0.001) and pericarditis (P = 0.024). Farms affected with pleurisy had moderate to severe lesions. Farms affected with pneumonia had mild lesions, which could be the effect of the generalised use of Mhyo vaccination in piglets. The seroprevalence of IAV, PRRSv, Mhyo and APP in the present study sample is similar to or lower than in other European countries. Further research on the PRRSv and APP strains circulating in Ireland is necessary to support the design of national or regional control plans

Lineage Abundance Estimation for SARS-CoV-2 in Wastewater Using Transcriptome Quantification Techniques

Effectively monitoring the spread of SARS-CoV-2 mutants is essential to efforts to counter the ongoing pandemic. Predicting lineage abundance from wastewater, however, is technically challenging. We show that by sequencing SARS-CoV-2 RNA in wastewater and applying algorithms initially used for transcriptome quantification, we can estimate lineage abundance in wastewater samples. We find high variability in signal among individual samples, but the overall trends match those observed from sequencing clinical samples. Thus, while clinical sequencing remains a more sensitive technique for population surveillance, wastewater sequencing can be used to monitor trends in mutant prevalence in situations where clinical sequencing is unavailable

An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus

DNA damage resulting from intrinsic or extrinsic sources activates DNA damage responses (DDRs) centered on protein kinase signaling cascades. The usual consequences of inducing DDRs include the activation of cell cycle checkpoints together with repair of the damaged DNA or induction of apoptosis. Many DNA viruses elicit host DDRs during infection and some viruses require the DDR for efficient replication. However, the mechanism by which DDRs are activated by viral infection is poorly understood. Human cytomegalovirus (HCMV) infection induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) protein kinase. Here we show that HCMV replication is compromised in cells with inactivated or depleted ATM and that ATM is essential for the host DDR early during infection. Likewise, a downstream target of ATM phosphorylation, H2AX, also contributes to viral replication. The ATM-dependent DDR is detected as discrete, nuclear γH2AX foci early in infection and can be activated by IE proteins. By 24 hpi, γH2AX is observed primarily in HCMV DNA replication compartments. We identified a role for the E2F1 transcription factor in mediating this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the accumulation of γH2AX during HCMV infection or IE protein expression. Moreover, E2F1 expression, but not the expression of E2F2 or E2F3, is required for efficient HCMV replication. These results reveal a novel role for E2F1 in mediating an ATM-dependent DDR that contributes to viral replication. Given that E2F activity is often deregulated by infection with DNA viruses, these observations raise the possibility that an E2F1-mediated mechanism of DDR activation may be conserved among DNA viruses

Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis

The combined application of next-generation sequencing platforms has provided an economical approach to unlocking the potential of the turkey genome

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Increased Virulence of a Fibronectin-Binding Protein Mutant of Staphylococcus aureus in a Rat Model of Pneumonia

Fibronectin-binding proteins mediate Staphylococcus aureus internalization into nonphagocytic cells in vitro. We have investigated whether fibronectin-binding proteins are virulence factors in the pathogenesis of pneumonia by using S. aureus strain 8325-4 and isogenic mutants in which fibronectin-binding proteins were either deleted (DU5883) or overexpressed [DU5883(pFnBPA4)]. We first demonstrated that fibronectin-binding proteins mediate S. aureus internalization into alveolar epithelial cells in vitro and that S. aureus internalization into alveolar epithelial cells requires actin rearrangement and protein kinase activity. Second, we established a rat model of S. aureus-induced pneumonia and measured lung injury and bacterial survival at 24 and 96 h postinoculation. S. aureus growth and the extent of lung injury were both increased in rats inoculated with the deletion mutant (DU5883) in comparison with rats inoculated with the wild-type (8325-4) and the fibronectin-binding protein-overexpressing strain DU5883(pFnBPA4) at 24 h postinfection. Morphological evaluation of infected lungs at the light and electron microscopic levels demonstrated that S. aureus was present within neutrophils from both 8325-4- and DU5883-inoculated lungs. Our data suggest that fibronectin-binding protein-mediated internalization into alveolar epithelial cells is not a virulence mechanism in a rat model of pneumonia. Instead, our data suggest that fibronectin-binding proteins decrease the virulence of S. aureus in pneumonia