Identification of PTEN Modifier Genes Using the Collaborative Cross Mouse Panel

Inactivation or mutation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, is implicated in unregulated cell proliferation, leading to tumor growth and the development of cancer. Identification of modifier genes, genes that alter the phenotype of another gene, of PTEN and their role in altering PTEN activity could provide insights into relationship between PTEN and cancer. The purpose of this study was to identify PTEN modifier genes by quantitative trait loci (QTL) mapping. To do so, we crossed transgenic mice that overexpress PTEN (super-PTEN) to lines of the Collaborative Cross (CC), a mouse population modeling human genetic diversity. We evaluated body weight at weaning as a surrogate for PTEN activity because it has been previously reported that super-PTEN expression is associated with reduced weight at weaning. Difference in body weight at weaning of super-PTEN pups compared to wild-type littermates was used for QTL analysis to identify modifier genes of PTEN. This approach has identified candidate genomic intervals harboring PTEN modifier genes. Further studies will identify candidate genes and confirm these genes as modifiers. A pilot study has been initiated to verify that the effect of PTEN on body weight is indicative of the effect of PTEN on cancer susceptibility

Kinetics of the Formation and Dissociation of Actin Filament Branches Mediated by Arp2/3 Complex

AbstractThe actin filament network at the leading edge of motile cells relies on localized branching by Arp2/3 complex from “mother” filaments growing near the plasma membrane. The nucleotide bound to the mother filaments (ATP, ADP and phosphate, or ADP) may influence the branch dynamics. To determine the effect of the nucleotide bound to the subunits of the mother filament on the formation and stability of branches, we compared the time courses of actin polymerization in bulk samples measured using the fluorescence of pyrene actin with observations of single filaments by total internal reflection fluorescence microscopy. Although the branch nucleation rate in bulk samples was nearly the same regardless of the nucleotide on the mother filaments, we observed fewer branches by microscopy on ADP-bound filaments than on ADP-Pi-bound filaments. Observation of branches in the microscope depends on their binding to the slide. Since the probability that a branch binds to the slide is directly related to its lifetime, we used counts of branches to infer their rates of dissociation from mother filaments. We conclude that the nucleotide on the mother filament does not affect the initial branching event but that branches are an order of magnitude more stable on the sides of new ATP- or ADP-Pi filaments than on ADP-actin filaments

Stomach Content Analysis of Recent Snowy Owl (\u3ci\u3eBubo scandiacus\u3c/i\u3e) Specimens from Nebraska

The Snowy Owl (Bubo scandiacus) is a circumpolar bird of prey that breeds in extreme northern latitudes, including Canadian and Alaskan tundra. During winter months, some immature and non-breeding birds disperse south. North American birds may travel to southern Canada and northern parts of the United States, and in some extreme cases as far south as Oklahoma and Texas (Parmelee 1992). Although not fully understood, these irruptive events may be caused by the abundance of prey in northern Canada and Alaska (Parmelee 1992). Prey typical of Snowy Owls are small mammals (e.g., lemmings and hares) of their home range and an occasional bird from a variety of species including waterfowl (Parmelee, 1992). Research on prey items selected by birds outside of breeding range in North America primarily includes ducks and grebes in southwest British Columbia (Campbell and Maccoll 1978), voles in Montana (Detienne et al. 2008), and mice and voles in southern Alberta and Michigan (Boxall and Lein 1982, Chamberlin 1980, respectively). Over the past century, several irruptions of Snowy Owls have been recorded in Nebraska, most notably during the winters of 1917-18, 1954-55, and 2011-12 (Jorgensen et al., 2012). The most recent of these irruptions, during the winter of 2011-12, produced the largest number of confirmed Snowy Owl sightings in Kansas and Missouri, possibly explained by the increased ease of communication through the use of mobile technology in the general public (Robbins and Otte 2013). Once reaching areas as far south as Nebraska, Snowy Owls typically suffer high rates of mortality, possibly due to lack of prey species, disease, or anthropogenic factors (Kerlinger and Lein 1988, Meade 1942). During the 2011-12 irruption, several carcasses were donated to the University of Nebraska State Museum (UNSM) and provided a source for examination of body condition and diet. Also included was one carcass donated to UNSM during the following winter, 2012-13

CMU DeepLens: Deep Learning For Automatic Image-based Galaxy-Galaxy Strong Lens Finding

Galaxy-scale strong gravitational lensing is not only a valuable probe of the dark matter distribution of massive galaxies, but can also provide valuable cosmological constraints, either by studying the population of strong lenses or by measuring time delays in lensed quasars. Due to the rarity of galaxy-scale strongly lensed systems, fast and reliable automated lens finding methods will be essential in the era of large surveys such as LSST, Euclid, and WFIRST. To tackle this challenge, we introduce CMU DeepLens, a new fully automated galaxy-galaxy lens finding method based on Deep Learning. This supervised machine learning approach does not require any tuning after the training step which only requires realistic image simulations of strongly lensed systems. We train and validate our model on a set of 20,000 LSST-like mock observations including a range of lensed systems of various sizes and signal-to-noise ratios (S/N). We find on our simulated data set that for a rejection rate of non-lenses of 99%, a completeness of 90% can be achieved for lenses with Einstein radii larger than 1.4" and S/N larger than 20 on individual $g$-band LSST exposures. Finally, we emphasize the importance of realistically complex simulations for training such machine learning methods by demonstrating that the performance of models of significantly different complexities cannot be distinguished on simpler simulations. We make our code publicly available at https://github.com/McWilliamsCenter/CMUDeepLens .Comment: 12 pages, 9 figures, submitted to MNRA

Applying modern Omic technologies to the Neuronal Ceroid Lipofuscinoses

The Neuronal Ceroid Lipofuscinoses are a group of severe and progressive neurodegenerative disorders, which generally present during childhood. With new treatments emerging on the horizon, there is a growing need to understand the specific disease mechanisms as well as identify prospective biomarkers for use to stratify patients and monitor treatment. The use of Omics technologies to NCLs has the potential to address this need. We discuss the recent use and outcomes of Omics to various forms of NCL including identification of interactomes, affected biological pathways and potential biomarker candidates. We also identify common pathways affected in NCL across the reviewed studies

Performance Characteristics of Fecal Immunochemical Tests for Colorectal Cancer and Advanced Adenomatous Polyps: A Systematic Review and Meta-analysis

Background: Studies report inconsistent performance of fecal immunochemical tests (FITs) for colorectal cancer (CRC) and advanced adenomas. Purpose: To summarize performance characteristics of FITs for CRC and advanced adenomas in average-risk persons undergoing screening colonoscopy (reference standard) and to identify factors affecting these characteristics. Data Sources: Ovid MEDLINE, PubMed, Embase, and the Cochrane Library from inception through October 2018; reference lists of studies and reviews. Study Selection: Two reviewers independently screened records to identify published English-language prospective or retrospective observational studies that evaluated FIT sensitivity and specificity for colonoscopic findings in asymptomatic, average-risk adults. Data Extraction: Two authors independently extracted data and evaluated study quality. Data Synthesis: Thirty-one studies (120 255 participants; 18 FITs) were included; all were judged to have low to moderate risk of bias. Performance characteristics depended on the threshold for a positive result. A threshold of 10 µg/g resulted in sensitivity of 0.91 (95% CI, 0.84 to 0.95) and a negative likelihood ratio of 0.10 (CI, 0.06 to 0.19) for CRC, whereas a threshold of greater than 20 µg/g resulted in specificity of 0.95 (CI, 0.94 to 0.96) and a positive likelihood ratio of 15.49 (CI, 9.82 to 22.39). For advanced adenomas, sensitivity was 0.40 (CI, 0.33 to 0.47) and the negative likelihood ratio was 0.67 (CI, 0.57 to 0.78) at 10 µg/g, and specificity was 0.95 (CI, 0.94 to 0.96) and the positive likelihood ratio was 5.86 (CI, 3.77 to 8.97) at greater than 20 µg/g. Studies had low to high heterogeneity, depending on the threshold. Although several FITs had adequate performance, sensitivity and specificity for CRC for 1 qualitative FIT were 0.90 and 0.91, respectively, at its single threshold of 10 µg/g; positive and negative likelihood ratios were 10.13 and 0.11, respectively. Comparison of 3 FITs at 3 thresholds was inconclusive: CIs overlapped, and the comparisons were across rather than within studies. Limitations: Only English-language studies were included. Incomplete reporting limited quality assessment of some evidence. Performance characteristics are for 1-time rather than serial testing. Conclusion: Single-application FITs have moderate to high sensitivity and specificity for CRC, depending on the positivity threshold. Sensitivity of 1-time testing for advanced adenomas is low, regardless of the threshold

A novel FRET-based screen in high-throughput format to identify inhibitors of malarial and human glucose transporters

The glucose transporter PfHT is essential to the survival of the malaria parasite Plasmodium falciparum and has been shown to be a druggable target with high potential for pharmacological intervention. Identification of compounds against novel drug targets is crucial to combating resistance against current therapeutics. Here, we describe the development of a cell-based assay system readily adaptable to high-throughput screening that directly measures compound effects on PfHT-mediated glucose transport. Intracellular glucose concentrations are detected using a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose sensor. This allows assessment of the ability of small molecules to inhibit glucose uptake with high accuracy (Z′ factor of >0.8), thereby eliminating the need for radiolabeled substrates. Furthermore, we have adapted this assay to counterscreen PfHT hits against the human orthologues GLUT1, -2, -3, and -4. We report the identification of several hits after screening the Medicines for Malaria Venture (MMV) Malaria Box, a library of 400 compounds known to inhibit erythrocytic development of P. falciparum. Hit compounds were characterized by determining the half-maximal inhibitory concentration (IC(50)) for the uptake of radiolabeled glucose into isolated P. falciparum parasites. One of our hits, compound MMV009085, shows high potency and orthologue selectivity, thereby successfully validating our assay for antimalarial screening

The social meaning of infertility in Southwest Nigeria

There has been very little documentation of the social meaning given to infertility in many developing countries, including Nigeria, where the prevalence of infertility is known to be high. We have conducted a number of qualitative studies aimed at exploring socio-cultural issues associated with infertility in Ile-Ife, Southwestern Nigeria. Twenty-five focus-group discussions were held with knowledgeable persons in the rural and urban parts of the community to ascertain their attitudes towards infertility. The results show that community members accord great significance to child-bearing, but, they have incorrect knowledge of the causes and appropriate treatment of infertility. Focus-group participants mentioned several traditional beliefs regarding the causes of infertility from which they derived a variety of traditional and religious methods for its treatment; many affected couples use these methods of treatment, sometimes singly but most often in combination. Orthodox treatments are less often used because of perceptions of the causes of infertility and lack of confidentiality at the treatment centres. Women are more likely to suffer the social consequences of infertility; they suffer physical and mental abuse, neglect, abandonment, economic deprivation and social ostracism as a result of their infertile status. These findings have profound implications for reproductive health and reproductive rights of women in the area. Measures recommended to ameliorate the adverse consequences of infertility in the community include provision of broad reproductive health education and appropriate services; integration of infertility treatment and prevention into primary health care and the traditional system of health care delivery; and programs aimed at the empowerment of women in the area