Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: Complement component C1q and Prnp polymorphisms

The genetic basis of susceptibility to chronic wasting disease (CWD) in free-ranging cervids is of great interest. Association studies of disease susceptibility in free-ranging populations, however, face considerable challenges including: the need for large sample sizes when disease is rare, animals of unknown pedigree create a risk of spurious results due to population admixture, and the inability to control disease exposure or dose. We used an innovative matched case–control design and conditional logistic regression to evaluate associations between polymorphisms of complement C1q and prion protein (Prnp) genes and CWD infection in white-tailed deer from the CWD endemic area in southcentral Wisconsin. To reduce problems due to admixture or disease-risk confounding, we used neutral genetic (microsatellite) data to identify closely related CWD-positive (n = 68) and CWD-negative (n = 91) female deer to serve as matched cases and controls. Cases and controls were also matched on factors (sex, location, age) previously demonstrated to affect CWD infection risk. For Prnp, deer with at least one Serine (S) at amino acid 96 were significantly less likely to be CWD-positive relative to deer homozygous for Glycine (G). This is the first characterization of genes associated with the complement system in white-tailed deer. No tests for association between any C1q polymorphism and CWD infection were significant at p \u3c 0.05. After controlling for Prnp, we found weak support for an elevated risk of CWD infection in deer with at least one Glycine (G) at amino acid 56 of the C1qC gene. While we documented numerous amino acid polymorphisms in C1q genes none appear to be strongly associated with CWD susceptibility

Salt restriction in kidney disease—a missed therapeutic opportunity?

The importance of salt restriction in the treatment of patients with renal disease has remained highly controversial. In the following we marshal the current evidence that salt plays a definite role in the genesis of hypertension and target organ damage, point to practical problems of salt restriction, and report on novel pathomechanisms of how salt affects blood pressure and causes target organ damage

Genetic signatures of historical bottlenecks in sympatric lake trout (Salvelinus namaycush) morphotypes in Lake Superior

International audienc

RRx-001, a first-in-class small molecule inhibitor of MYC and a downregulator of CD47, is an "erythrophagoimmunotherapeutic"

The main mechanism of action of RRx-001, a pharmaceutically unprecedented sui generis Phase 3 small molecule that is derived from the aerospace industry, is clarified. RRx-001 has demonstrated anticancer activity through antiangiogenic, immune, epigenetic, antioxidant, apoptotic and nitric oxide (NO) pathways, resulting in its pleiomorphic description as an antiangiogenic/vascular normalizer

Inflammation in Viral Vector-Mediated Ocular Gene Therapy: A Review and Report From a Workshop Hosted by the Foundation Fighting Blindness, 9/2020

On September 14?15, 2020, the Foundation Fighting Blindness convened a virtual workshop to discuss intraocular inflammation during viral vector-mediated gene therapy for inherited retinal diseases. The workshop?s goals were to understand immune activation?s nature and significance during ocular gene therapy, consider whether ocular inflammation limits gene therapy?s potential, and identify knowledge gaps for future research. The event brought together a small group of experienced researchers in the field to present and discuss current data. Collectively, participants agreed that clinical, as well as subclinical, inflammation during ocular gene therapy is common. The severity of inflammation in both animal and clinical studies varied widely but is generally related to vector dose. Severe inflammation was associated with reduced gene therapy efficacy. However, the relationship between outcomes and subclinical inflammation, pre-existing antivector antibodies, or induced adaptive immune responses is still unclear. Uncertainties about the contribution of vector manufacturing issues to inflammation were also noted. Importantly, various immunosuppressive treatment protocols are being used, and this heterogeneity confounds conclusions about optimal strategies. Proposed near-term next steps include establishing an immunological consultant directory, establishing a data repository for pertinent animal and clinical data, and developing a larger meeting. Priority areas for future research include deeper understanding of immune activation during retinal diseases and during ocular gene therapy; better, harmonized application of animal models; and identifying best practices for managing gene therapy vector-related ocular inflammation. Translational Relevance: Subclinical or clinical inflammation often arises during ocular gene therapy with viral vectors. Understanding the biological bases and impacts on efficacy are important for clinical management and the improvement of future therapies

The American Genetic Association 93:260--269

this article is to describe several of the more widely used machine learning classifiers that may have utility when used with empirical population genetics data. We compare likelihoodbased "assignment tests" (Paetkau et al. 1995) with supervised machine learning classifiers including ANN, decision tree, and a k-NN clustering. Simulations were conducted which estimated and compared the assignment accuracy associated with different classifiers using ranges of parameter values (number of loci, allelic diversity, and interpopulation variance in allele frequency) typically encountered in natural populations. Comparative analyses were extended to empirical examples using lake trout (Salvelinus namaycush; Salmonidae