Experimental Infection of a North American Raptor, American Kestrel (Falco sparverius), with Highly Pathogenic Avian Influenza Virus (H5N1)

Several species of wild raptors have been found in Eurasia infected with highly pathogenic avian influenza virus (HPAIV) subtype H5N1. Should HPAIV (H5N1) reach North America in migratory birds, species of raptors are at risk not only from environmental exposure, but also from consuming infected birds and carcasses. In this study we used American kestrels as a representative species of a North American raptor to examine the effects of HPAIV (H5N1) infection in terms of dose response, viral shedding, pathology, and survival. Our data showed that kestrels are highly susceptible to HPAIV (H5N1). All birds typically died or were euthanized due to severe neurologic disease within 4–5 days of inoculation and shed significant amounts of virus both orally and cloacally, regardless of dose administered. The most consistent microscopic lesions were necrosis in the brain and pancreas. This is the first experimental study of HPAIV infection in a North American raptor and highlights the potential risks to birds of prey if HPAIV (H5N1) is introduced into North America

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

Ozone is an air pollutant that causes pulmonary symptoms. In mice, ozone exposure causes pulmonary injury and increases bronchoalveolar lavage macrophages and neutrophils. We have shown that IL-17A is important in the recruitment of neutrophils after subacute ozone exposure (0.3 ppm for 24–72 h). We hypothesized that γδ T cells are the main producers of IL-17A after subacute ozone. To explore this hypothesis we exposed wildtype mice and mice deficient in γδ T cells (TCRδ−/−) to ozone or room air. Ozone-induced increases in BAL macrophages and neutrophils were attenuated in TCRδ−/− mice. Ozone increased the number of γδ T cells in the lungs and increased pulmonary Il17a mRNA expression and the number of IL-17A+ CD45+ cells in the lungs and these effects were abolished in TCRδ−/− mice. Ozone-induced increases in factors downstream of IL-17A signaling, including G-CSF, IL-6, IP-10 and KC were also decreased in TCRδ−/− versus wildtype mice. Neutralization of IL-17A during ozone exposure in wildtype mice mimicked the effects of γδ T cell deficiency. TNFR2 deficiency and etanercept, a TNFα antagonist, also reduced ozone-induced increases in Il17a mRNA, IL-17A+ CD45+ cells and BAL G-CSF as well as BAL neutrophils. TNFR2 deficient mice also had decreased ozone-induced increases in Ccl20, a chemoattractant for IL-17A+ γδ T cells. Il17a mRNA and IL-17A+ γδ T cells were also lower in obese Cpefat versus lean WT mice exposed to subacute ozone, consistent with the reduced neutrophil recruitment observed in the obese mice. Taken together, our data indicate that pulmonary inflammation induced by subacute ozone requires γδ T cells and TNFα-dependent recruitment of IL-17A+ γδ T cells to the lung

Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus-Host Protein Network.

We have mapped a global network of virus-host protein interactions by purification of the complete set of human papillomavirus (HPV) proteins in multiple cell lines followed by mass spectrometry analysis. Integration of this map with tumor genome atlases shows that the virus targets human proteins frequently mutated in HPV- but not HPV+ cancers, providing a unique opportunity to identify novel oncogenic events phenocopied by HPV infection. For example, we find that the NRF2 transcriptional pathway, which protects against oxidative stress, is activated by interaction of the NRF2 regulator KEAP1 with the viral protein E1. We also demonstrate that the L2 HPV protein physically interacts with the RNF20/40 histone ubiquitination complex and promotes tumor cell invasion in an RNF20/40-dependent manner. This combined proteomic and genetic approach provides a systematic means to study the cellular mechanisms hijacked by virally induced cancers.Significance: In this study, we created a protein-protein interaction network between HPV and human proteins. An integrative analysis of this network and 800 tumor mutation profiles identifies multiple oncogenesis pathways promoted by HPV interactions that phenocopy recurrent mutations in cancer, yielding an expanded definition of HPV oncogenic roles. Cancer Discov; 8(11); 1474-89. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1333

Severe Hypoalbuminemia at Day 90 Predicts Worse Nonrelapse Mortality and Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Because patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) remain in the vicinity of the transplant center for approximately 90 days posttransplantation, identifying prognostic factors to determine those at immediate higher risk of mortality is essential. A normal serum albumin level generally denotes healthiness. We evaluated the prognostic significance of day 90 hypoalbuminemia (and other clinical, pharmacologic, and laboratory variables) in 163 patients, median age 48 years (range, 19-69 years), who underwent allo-HCT for acute myelogenous leukemia (n = 124) or myelodysplastic syndrome (n = 39). Day 90 hypoalbuminemia (serum albumin <3.0 g/dL) was associated with worse nonrelapse mortality (NRM) and poor overall survival (OS). The estimated 1- and 2-year cumulative incidence rates of NRM were 48% and 52%, respectively, and the corresponding OS rates were 7% and 3%. Serum albumin level <3.0 g/dL and Karnofsky score <80 at day 90 were strong independent predictors of worse NRM and OS in multivariate analysis. These results support day 90 hypoalbuminemia as an adverse prognostic marker for NRM and OS after allo-HCT for acute myelogenous leukemia and myelodysplastic syndrome

Light whole genome sequence for SNP discovery across domestic cat breeds

<p>Abstract</p> <p>Background</p> <p>The domestic cat has offered enormous genomic potential in the veterinary description of over 250 hereditary disease models as well as the occurrence of several deadly feline viruses (feline leukemia virus -- FeLV, feline coronavirus -- FECV, feline immunodeficiency virus - FIV) that are homologues to human scourges (cancer, SARS, and AIDS respectively). However, to realize this bio-medical potential, a high density single nucleotide polymorphism (SNP) map is required in order to accomplish disease and phenotype association discovery.</p> <p>Description</p> <p>To remedy this, we generated 3,178,297 paired fosmid-end Sanger sequence reads from seven cats, and combined these data with the publicly available 2X cat whole genome sequence. All sequence reads were assembled together to form a 3X whole genome assembly allowing the discovery of over three million SNPs. To reduce potential false positive SNPs due to the low coverage assembly, a low upper-limit was placed on sequence coverage and a high lower-limit on the quality of the discrepant bases at a potential variant site. In all domestic cats of different breeds: female Abyssinian, female American shorthair, male Cornish Rex, female European Burmese, female Persian, female Siamese, a male Ragdoll and a female African wildcat were sequenced lightly. We report a total of 964 k common SNPs suitable for a domestic cat SNP genotyping array and an additional 900 k SNPs detected between African wildcat and domestic cats breeds. An empirical sampling of 94 discovered SNPs were tested in the sequenced cats resulting in a SNP validation rate of 99%.</p> <p>Conclusions</p> <p>These data provide a large collection of mapped feline SNPs across the cat genome that will allow for the development of SNP genotyping platforms for mapping feline diseases.</p

Nonlinear Waves in Bose-Einstein Condensates: Physical Relevance and Mathematical Techniques

The aim of the present review is to introduce the reader to some of the physical notions and of the mathematical methods that are relevant to the study of nonlinear waves in Bose-Einstein Condensates (BECs). Upon introducing the general framework, we discuss the prototypical models that are relevant to this setting for different dimensions and different potentials confining the atoms. We analyze some of the model properties and explore their typical wave solutions (plane wave solutions, bright, dark, gap solitons, as well as vortices). We then offer a collection of mathematical methods that can be used to understand the existence, stability and dynamics of nonlinear waves in such BECs, either directly or starting from different types of limits (e.g., the linear or the nonlinear limit, or the discrete limit of the corresponding equation). Finally, we consider some special topics involving more recent developments, and experimental setups in which there is still considerable need for developing mathematical as well as computational tools.Comment: 69 pages, 10 figures, to appear in Nonlinearity, 2008. V2: new references added, fixed typo

Direct Ophthalmic Healthcare Resource Use among Geographic Atrophy Patients in a Large Cohort from the United Kingdom

Objective To estimate the direct ophthalmic health care resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Design Retrospective analysis of anonymized data derived from electronic medical records acquired at 10 clinical sites in the United Kingdom. Participants Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA : GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA : CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA : E); and early/intermediate AMD in both eyes (E : E). Methods Electronic medical records were analyzed to derive the median number of visits over the first 2 years following diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011 to represent present day monitoring and costs associated with AMD. Main Outcome Measures Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA : CNV group were excluded. Results For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5 and monitoring costs were £460.80 per patient. The GA : CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA : E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA : GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA : CNV subgroup. Visits and costs in the E : E subgroup (n = 6079) were lower. Conclusions Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA

Does α-Amino-β-methylaminopropionic Acid (BMAA) Play a Role in Neurodegeneration?

The association of α-amino-β-methylaminopropionic acid (BMAA) with elevated incidence of amyotrophic lateral sclerosis/Parkinson’s disease complex (ALS/PDC) was first identified on the island of Guam. BMAA has been shown to be produced across the cyanobacterial order and its detection has been reported in a variety of aquatic and terrestrial environments worldwide, suggesting that it is ubiquitous. Various in vivo studies on rats, mice, chicks and monkeys have shown that it can cause neurodegenerative symptoms such as ataxia and convulsions. Zebrafish research has also shown disruption to neural development after BMAA exposure. In vitro studies on mice, rats and leeches have shown that BMAA acts predominantly on motor neurons. Observed increases in the generation of reactive oxygen species (ROS) and Ca2+ influx, coupled with disruption to mitochondrial activity and general neuronal death, indicate that the main mode of activity is via excitotoxic mechanisms. The current review pertaining to the neurotoxicity of BMAA clearly demonstrates its ability to adversely affect neural tissues, and implicates it as a potentially significant compound in the aetiology of neurodegenerative disease. When considering the potential adverse health effects upon exposure to this compound, further research to better understand the modes of toxicity of BMAA and the environmental exposure limits is essential

The Relationship between Phytoplankton Distribution and Water Column Characteristics in North West European Shelf Sea Waters

Phytoplankton underpin the marine food web in shelf seas, with some species having properties that are harmful to human health and coastal aquaculture. Pressures such as climate change and anthropogenic nutrient input are hypothesized to influence phytoplankton community composition and distribution. Yet the primary environmental drivers in shelf seas are poorly understood. To begin to address this in North Western European waters, the phytoplankton community composition was assessed in light of measured physical and chemical drivers during the “Ellett Line” cruise of autumn 2001 across the Scottish Continental shelf and into adjacent open Atlantic waters. Spatial variability existed in both phytoplankton and environmental conditions, with clear differences not only between on and off shelf stations but also between different on shelf locations. Temperature/salinity plots demonstrated different water masses existed in the region. In turn, principal component analysis (PCA), of the measured environmental conditions (temperature, salinity, water density and inorganic nutrient concentrations) clearly discriminated between shelf and oceanic stations on the basis of DIN∶DSi ratio that was correlated with both salinity and temperature. Discrimination between shelf stations was also related to this ratio, but also the concentration of DIN and DSi. The phytoplankton community was diatom dominated, with multidimensional scaling (MDS) demonstrating spatial variability in its composition. Redundancy analysis (RDA) was used to investigate the link between environment and the phytoplankton community. This demonstrated a significant relationship between community composition and water mass as indexed by salinity (whole community), and both salinity and DIN∶DSi (diatoms alone). Diatoms of the Pseudo-nitzschia seriata group occurred at densities potentially harmful to shellfish aquaculture, with the potential for toxicity being elevated by the likelihood of DSi limitation of growth at most stations and depths