A Population Proportion approach for ranking differentially expressed genes

<p>Abstract</p> <p>Background</p> <p>DNA microarrays are used to investigate differences in gene expression between two or more classes of samples. Most currently used approaches compare mean expression levels between classes and are not geared to find genes whose expression is significantly different in only a subset of samples in a class. However, biological variability can lead to situations where key genes are differentially expressed in only a subset of samples. To facilitate the identification of such genes, a new method is reported.</p> <p>Methods</p> <p>The key difference between the Population Proportion Ranking Method (PPRM) presented here and almost all other methods currently used is in the quantification of variability. PPRM quantifies variability in terms of inter-sample ratios and can be used to calculate the relative merit of differentially expressed genes with a specified difference in expression level between at least some samples in the two classes, which at the same time have lower than a specified variability within each class.</p> <p>Results</p> <p>PPRM is tested on simulated data and on three publicly available cancer data sets. It is compared to the t test, PPST, COPA, OS, ORT and MOST using the simulated data. Under the conditions tested, it performs as well or better than the other methods tested under low intra-class variability and better than t test, PPST, COPA and OS when a gene is differentially expressed in only a subset of samples. It performs better than ORT and MOST in recognizing non differentially expressed genes with high variability in expression levels across all samples. For biological data, the success of predictor genes identified in appropriately classifying an independent sample is reported.</p

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Dronar—Geoforensic Search Sonar from a Drone

Lightweight sonar devices may be tethered to an unmanned aerial vehicle or drone and quickly deployed over water for real-time imaging in 2D and the on site creation of geolocated, interactive bathymetric maps without the need for a boat. We show how such data is useful in the preliminary stages of water searches, by providing geophysicists, hydrologists and divers with spatial depth information, the distribution of dive and equipment hazards such as entanglement objects (weed, discarded items) and sediment types. One bathymetry case study location is described in detail, with a further two summarized to demonstrate reconnaissance surveys. Limitations of drone-based sonar surveys are outlined, including dense water weed cover; limits on flight times and adverse weather conditions

Protection of bats (Eptesicus fuscus) against rabies following topical or oronasal exposure to a recombinant raccoon poxvirus vaccine.

Rabies is an ancient neglected tropical disease that causes tens of thousands of human deaths and millions of cattle deaths annually. In order to develop a new vaccine for potential use in bats, a reservoir of rabies infection for humans and animals alike, an in silico antigen designer tool was used to create a mosaic glycoprotein (MoG) gene using available sequences from the rabies Phylogroup I glycoprotein. This sequence, which represents strains more likely to occur in bats, was cloned into raccoonpox virus (RCN) and the efficacy of this novel RCN-MoG vaccine was compared to RCN-G that expresses the glycoprotein gene from CVS-11 rabies or luciferase (RCN-luc, negative control) in mice and big brown bats (Eptesicus fuscus). Mice vaccinated and boosted intradermally with 1 x 107 plaque forming units (PFU) of each RCN-rabies vaccine construct developed neutralizing antibodies and survived at significantly higher rates than controls. No significant difference in antibody titers or survival was noted between rabies-vaccinated groups. Bats were vaccinated either oronasally (RCN-G, RCN-MoG) with 5x107 PFU or by topical application in glycerin jelly (RCN-MoG, dose 2x108 PFU), boosted (same dose and route) at 46 days post vaccination (dpv), and then challenged with wild-type big brown variant RABV at 65 dpv. Prior to challenge, 90% of RCN-G and 75% of RCN-MoG oronasally vaccinated bats had detectable levels of serum rabies neutralizing antibodies. Bats from the RCN-luc and topically vaccinated RCN-MoG groups did not have measurable antibody responses. The RCN-rabies constructs were highly protective and not significantly different from each other. RCN-MoG provided 100% protection (n = 9) when delivered oronasally and 83% protection (n = 6) when delivered topically; protection provided by the RCN-G construct was 70% (n = 10). All rabies-vaccinated bats survived at a significantly (P ≤ 0.02) higher rate than control bats (12%; n = 8). We have demonstrated the efficacy of a novel, in silico designed rabies MoG antigen that conferred protection from rabies challenge in mice and big brown bats in laboratory studies. With further development, topical or oronasal administration of the RCN-MoG vaccine could potentially mitigate rabies in wild bat populations, reducing spillover of this deadly disease into humans, domestic mammals, and other wildlife

Rabies neutralizing antibody levels in mice following vaccination with various RCN-vectored rabies vaccines.

<p>Serum titers of rabies neutralizing antibodies (IU/ml) in mice 45 days post vaccination with RCN-MoG, RCN-IRES-MoG, or RCN-G. No significant differences were detected between groups (P = 0.399).</p

Antigenic coverage of putative T cell epitopes by the designed mosaic phylogroup I lyssavirus glycoprotein.

<p>A) Antigenic coverage with the epitope length set to 12 amino acids. B) Antigenic coverage with the epitope length set to 9 amino acids. C) Comparison of 12-mer epitope coverage between the mosaic sequence and all input sequences.</p

Rabies neutralizing antibody levels in mice following vaccination with various RCN-vectored rabies vaccines.

<p>Serum titers of rabies neutralizing antibodies (IU/ml) in mice 45 days post vaccination with RCN-MoG, RCN-IRES-MoG, or RCN-G. No significant differences were detected between groups (P = 0.399).</p

Survival after rabies challenge in mice.

<p>Efficacies of raccoon poxvirus (RCN) vectored rabies vaccines in mice after intracerebral challenge with the CVS-11 strain of rabies virus. Every mouse (6/6) in the RCN-MoG group survived challenge to day 14 compared to 3 of 6 in the RCN-IRES-MoG group, and 4 of 5 in the RCN-G group. All (5/5) negative controls (RCN-<i>luc</i>) succumbed by day 9 post challenge. A chart of p-values associated with the survival curve is also provided. Survival of all vaccinated mice was significantly higher (P < 0.05) than negative controls, but there was no significant difference (P > 0.05) between vaccine treated groups.</p