Epidemiological evaluation of subclinical mastitis of dairy cows in Greece

ΔΕΝ ΔΙΑΤΙΘΕΤΑΙ ΠΕΡΙΛΗΨΗSubclinical mastitis, diagnosed by elevated somatic cell count (SCC) in milk, is an important monitoring parameter of dairy cows’ udder health, related to their productivity and welfare. The present retrospective study aims to evaluate the epidemiology of subclinical mastitis (SCM) among the 37 herds of the Holstein Association of Greece participating in the milk quality recording system “ΙΩ”, from the start of 2015 until the end of 2018. The herds’ inclusion criterion was the consistency of monthly SCC recording throughout at least one full year between 2015 and 2018, with a maximum interval of 61 days between two consecutive monthly SCC recordings. Twenty-six herds (8630 cows) in 2015, thirty herds (10763 cows) in 2016, thirty herds (10945 cows) in 2017 and twenty-six herds (9597 cows) in 2018 were included. The prevalence of SCM and chronic SCM, the incidence rate of new cases of SCM, as well as the average somatic cell score and bulk tank milk SCC were determined for each of the four years. The results indicate a progressive deterioration of udder health from the onset of the cow’s productive life until culling. A year-over-year increase in the number of cows with subclinical mastitis led to an overall SCM prevalence of 34.5%, chronic SCM prevalence of 26.9% and a bulk tank milk SCC of 463000 cells/mL, in 2018. The average somatic cell score, a base 2logarithm of individual cow’s SCC, was found persistently above the subclinical mastitis indicative cut-off in all four years, with a peak in 2018. At herd level, the incidence rate of new SCM cases was 12 new cases / 100 cows / month; the highest incidence rate was observed in the early lactation stage group (1-60 days-in-milk), in all four years, reaching a peak of 31 new cases / 100 cows / month, in 2018. In 2018, prevalence of heifers’ SCM and chronic SCM was23.4% and 16.9%, respectively. Despite the adequate average 305-days milk yield (9608 kg in 2018), the results were indicative of poor udder health status, pointed out by reduced duration of cows’ productive life (less than 3 lactations)and lower milk quality (elevated SCC). The severity and wide spreading of subclinical mastitis in Greek dairy herds highlights the necessity of a national mastitis control program, aiming to improve the productive efficacy, management decisions accuracy and quality of produced milk

Mapping interindividual dynamics of innate immune response at single-cell resolution

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution

Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.Peer reviewe

CSL311, a novel, potent, therapeutic monoclonal antibody for the treatment of diseases mediated by the common beta chain of the IL-3, GM-CSF and IL-5 receptors

The β common-signaling cytokines interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-5 stimulate pro-inflammatory activities of haematopoietic cells via a receptor complex incorporating cytokine-specific α and shared β common (βc, CD131) receptor. Evidence from animal models and recent clinical trials demonstrate that these cytokines are critical mediators of the pathogenesis of inflammatory airway disease such as asthma. However, no therapeutic agents, other than steroids, that specifically and effectively target inflammation mediated by all 3 of these cytokines exist. We employed phage display technology to identify and optimize a novel, human monoclonal antibody (CSL311) that binds to a unique epitope that is specific to the cytokine-binding site of the human βc receptor. The binding epitope of CSL311 on the βc receptor was defined by X-ray crystallography and site-directed mutagenesis. CSL311 has picomolar binding affinity for the human βc receptor, and at therapeutic concentrations is a highly potent antagonist of the combined activities of IL-3, GM-CSF and IL-5 on primary eosinophil survival in vitro. Importantly, CSL311 inhibited the survival of inflammatory cells present in induced sputum from human allergic asthmatic subjects undergoing allergen bronchoprovocation. Due to its high potency and ability to simultaneously suppress the activity of all 3 β common cytokines, CSL311 may provide a new strategy for the treatment of chronic inflammatory diseases where the human βc receptor is central to pathogenesis. The coordinates for the βc/CSL311 Fab complex structure have been deposited with the RCSB Protein Data Bank (PDB 5DWU).Con Panousis, Urmi Dhagat, Kirsten M. Edwards, Veronika Rayzman, Matthew P. Hardy, Hal Braley, Gail M. Gauvreau, Timothy R. Hercus, Steven Smith, Roma Sehmi, Laura McMillan, Mara Dottore, Barbara J. McClure, Louis J. Fabri, Gino Vairo, Angel F Lopez, Michael W. Parker, Andrew D. Nash, Nicholas J. Wilson, Michael J. Wilson and Catherine M. Owczare