Spatial mixture multiscale modeling for aggregated health data

One of the main goals in spatial epidemiology is to study the geographical pattern of disease risks. For such purpose, the convolution model composed of correlated and uncorrelated components is often used. However, one of the two components could be predominant in some regions. To investigate the predominance of the correlated or uncorrelated component for multiple scale data, we propose four different spatial mixture multiscale models by mixing spatially varying probability weights of correlated (CH) and uncorrelated heterogeneities (UH). The first model assumes that there is no linkage between the different scales and, hence, we consider independent mixture convolution models at each scale. The second model introduces linkage between finer and coarser scales via a shared uncorrelated component of the mixture convolution model. The third model is similar to the second model but the linkage between the scales is introduced through the correlated component. Finally, the fourth model accommodates for a scale effect by sharing both CH and UH simultaneously. We applied these models to real and simulated data, and found that the fourth model is the best model followed by the second model.     

Comparative Genomics of 12 Strains of Erwinia amylovora Identifies a Pan-Genome with a Large Conserved Core

The plant pathogen Erwinia amylovora can be divided into two host-specific groupings; strains infecting a broad range of hosts within the Rosaceae subfamily Spiraeoideae (e.g., Malus, Pyrus, Crataegus, Sorbus) and strains infecting Rubus (raspberries and blackberries). Comparative genomic analysis of 12 strains representing distinct populations (e.g., geographic, temporal, host origin) of E. amylovora was used to describe the pan-genome of this major pathogen. The pan-genome contains 5751 coding sequences and is highly conserved relative to other phytopathogenic bacteria comprising on average 89% conserved, core genes. The chromosomes of Spiraeoideae-infecting strains were highly homogeneous, while greater genetic diversity was observed between Spiraeoideae- and Rubus-infecting strains (and among individual Rubus-infecting strains), the majority of which was attributed to variable genomic islands. Based on genomic distance scores and phylogenetic analysis, the Rubus-infecting strain ATCC BAA-2158 was genetically more closely related to the Spiraeoideae-infecting strains of E. amylovora than it was to the other Rubus-infecting strains. Analysis of the accessory genomes of Spiraeoideae- and Rubus-infecting strains has identified putative host-specific determinants including variation in the effector protein HopX1_Ea and a putative secondary metabolite pathway only present in Rubus-infecting strains.     

Genetic susceptibility to S. aureus mastitis in sheep: differential expression of mammary epithelial cells in response to live bacteria or supernatant

Staphylococcus aureus is a prevalent pathogen for mastitis in dairy ruminants and is responsible for both clinical and subclinical mastitis. Mammary epithelial cells (MEC) represent not only a physical barrier against bacterial invasion but are also active players of the innate immune response permitting infection clearance. To decipher their functions in general and in animals showing different levels of genetic predisposition to Staphylococcus in particular, MEC from ewes undergoing a divergent selection on milk somatic cell count were stimulated by S. aureus. MEC response was also studied according to the stimulation condition with live bacteria or culture supernatant. The early MEC response was studied during a 5 h time course by microarray to identify differentially expressed genes with regard to the host genetic background and as a function of the conditions of stimulation. In both conditions of stimulation, metabolic processes were altered, the apoptosis-associated pathways were considerably modified, and inflammatory and immune responses were enhanced with the upregulation of il1a, il1b, and tnfa and several chemokines known to enhance neutrophil (cxcl8) or mononuclear leukocyte (ccl20) recruitment. Genes associated with oxidative stress were increased after live bacteria stimulation, whereas immune response-related genes were higher after supernatant stimulation in the early phase. Only 20 genes were differentially expressed between Staphylococcus spp-mastitis resistant and susceptible animals without any clearly defined role on the control of infection. To conclude, this suggests that MEC may not represent the cell type at the origin of the difference of mastitis susceptibility, at least as demonstrated in our genetic model. Supernatant or heat-killed S. aureus produce biological effects that are essentially different from those induced by live bacteria.     

Processing and presentation of a mycobacterial antigen 85B epitope by murine macrophages is dependent on the phagosomal acquisition of vacuolar proton ATPase and in situ activation of cathepsin D

Mycobacterium tuberculosis (strain H37Rv) and bacillus Calmette-Guérin (BCG) vaccine inhibit phagosome maturation in macrophages and their effect on processing, and presentation of a secreted Ag85 complex B protein, Ag85B, by mouse macrophages was analyzed. Macrophages were infected with GFP-expressing mycobacterial strains and analyzed for in situ localization of vacuolar proton ATPase (v-ATPase) and cathepsin D (Cat D) using Western blot analysis and immunofluorescence. H37Rv and BCG phagosomes excluded the v-ATPase and maintained neutral pH while the attenuated H37Ra strain acquired v-ATPase and acidified. Mycobacterial phagosomes acquired Cat D, although strains BCG and H37Rv phagosomes contained the inactive 46-kDa form, whereas H37Ra phagosomes had the active 30-kDa form. Infected macrophages were overlaid with a T cell hybridoma specific for an Ag85B epitope complexed with MHC class II. Coincident with active Cat D, H37Ra-infected macrophages presented the epitope to T cells inducing IL-2, whereas H37Rv- and BCG-infected macrophages were less efficient in IL-2 induction. Bafilomycin inhibited the induction of macrophage-induced IL-2 from T cells indicating that v-ATPase was essential for macrophage processing of Ag85B. Furthermore, the small interfering RNA interference of Cat D synthesis resulted in a marked decrease in the levels of macrophage-induced IL-2. Thus, a v-ATPase-dependent phagosomal activation of Cat D was required for the generation of an Ag85B epitope by macrophages. Reduced processing of Ag85B by H37Rv- and BCG-infected macrophages suggests that phagosome maturation arrest interferes with the efficient processing of Ags in macrophages. Because Ag85B is immunodominant, this state may lead to a decreased ability of the wild-type as well as the BCG vaccine to induce protective immunity.     

DESI-MSI and METASPACE indicates lipid abnormalities and altered mitochondrial membrane components in diabetic renal proximal tubules

Metabolomics - Food and dietary ingredients have significant effects on metabolism and health. To evaluate whether and how different diets affected the serum lipidomic profile of dogs. Sixteen...     

Comparative pathogenesis of three human and zoonotic SARS-CoV strains in cynomolgus macaques

The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. While there were significant differences in the number of host genes differentially regulated during the host responses between the three SARS-CoV strains, the top pathways and functions were similar and only apparent early during infection with the majority of genes associated with interferon signaling pathways. This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use.     

AAV-Mediated Clarin-1 Expression in the Mouse Retina: Implications for USH3A Gene Therapy

Usher syndrome type III (USH3A) is an autosomal recessive disorder caused by mutations in clarin-1 (CLRN1) gene, leading to progressive retinal degeneration and sensorineural deafness. Efforts to develop therapies for preventing photoreceptor cell loss are hampered by the lack of a retinal phenotype in the existing USH3 mouse models and by conflicting reports regarding the endogenous retinal localization of clarin-1, a transmembrane protein of unknown function. In this study, we used an AAV-based approach to express CLRN1 in the mouse retina in order to determine the pattern of its subcellular localization in different cell types. We found that all major classes of retinal cells express AAV-delivered CLRN1 driven by the ubiquitous, constitutive small chicken β-actin promoter, which has important implications for the design of future USH3 gene therapy studies. Within photoreceptor cells, AAV-expressed CLRN1 is mainly localized at the inner segment region and outer plexiform layer, similar to the endogenous expression of other usher proteins. Subretinal delivery using a full strength viral titer led to significant loss of retinal function as evidenced by ERG analysis, suggesting that there is a critical limit for CLRN1 expression in photoreceptor cells. Taken together, these results suggest that CLRN1 expression is potentially supported by a variety of retinal cells, and the right combination of AAV vector dose, promoter, and delivery method needs to be selected to develop safe therapies for USH3 disorder.     

Genetic differentiation and signatures of local adaptation revealed by RADseq for a highly dispersive mud crab Scylla olivacea (Herbst, 1796) in the Sulu Sea

Connectivity of marine populations is shaped by complex interactions between biological and physical processes across the seascape. The influence of environmental features on the genetic structure of populations has key implications for the dynamics and persistence of populations, and an understanding of spatial scales and patterns of connectivity is crucial for management and conservation. This study employed a seascape genomics approach combining larval dispersal modeling and population genomic analysis using single nucleotide polymorphisms (SNPs) obtained from RADseq to examine environmental factors influencing patterns of genetic structure and connectivity for a highly dispersive mud crab Scylla olivacea (Herbst, 1796) in the Sulu Sea. Dispersal simulations reveal widespread but asymmetric larval dispersal influenced by persistent southward and westward surface circulation features in the Sulu Sea. Despite potential for widespread dispersal across the Sulu Sea, significant genetic differentiation was detected among eight populations based on 1,655 SNPs (F_ST = 0.0057, p < .001) and a subset of 1,643 putatively neutral SNP markers (F_ST = 0.0042, p < .001). Oceanography influences genetic structure, with redundancy analysis (RDA) indicating significant contribution of asymmetric ocean currents to neutral genetic variation (Radj2 = 0.133, p = .035). Genetic structure may also reflect demographic factors, with divergent populations characterized by low effective population sizes (N _e < 50). Pronounced latitudinal genetic structure was recovered for loci putatively under selection (F_ST = 0.2390, p < .001), significantly correlated with sea surface temperature variabilities during peak spawning months for S. olivacea (Radj2 = 0.692–0.763; p < .050), suggesting putative signatures of selection and local adaptation to thermal clines. While oceanography and dispersal ability likely shape patterns of gene flow and genetic structure of S. olivacea across the Sulu Sea, the impacts of genetic drift and natural selection influenced by sea surface temperature also appear as likely drivers of population genetic structure. This study contributes to the growing body of literature documenting population genetic structure and local adaptation for highly dispersive marine species, and provides information useful for spatial management of the fishery resource.