Detection and correction of false segmental duplications caused by genome mis-assembly

A method for determining false segmental duplications in vertebrate genomes, thus correcting mis-assemblies and providing more accurate estimates of duplications

Transposable elements modulate human RNA abundance and splicing via specific RNA-protein interactions

Background: Transposable elements (TEs) have significantly influenced the evolution of transcriptional regulatory networks in the human genome. Post-transcriptional regulation of human genes by TE-derived sequences has been observed in specific contexts, but has yet to be systematically and comprehensively investigated. Here, we study a collection of 75 CLIP-Seq experiments mapping the RNA binding sites for a diverse set of 51 human proteins to explore the role of TEs in post-transcriptional regulation of human mRNAs and lncRNAs via RNA-protein interactions. Results: We detect widespread interactions between RNA binding proteins (RBPs) and many families of TE-derived sequence in the CLIP-Seq data. Further, alignment coverage peaks on specific positions of the TE consensus sequences, illuminating a diversity of TE-specific RBP binding motifs. Evidence of binding and conservation of these motifs in the nonrepetitive transcriptome suggests that TEs have generally appropriated existing sequence preferences of the RBPs. Depletion assays for numerous RBPs show that TE-derived binding sites affect transcript abundance and splicing similarly to nonrepetitive sites. However, in a few cases the effect of RBP binding depends on the specific TE family bound; for example, the ubiquitously expressed RBP HuR confers transcript stability unless bound to an Alu element. Conclusions: Our meta-analysis suggests a widespread role for TEs in shaping RNA-protein regulatory networks in the human genome. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0537-5) contains supplementary material, which is available to authorized users

A Practitioner's Guide and MATLAB Toolbox for Mixed Frequency State Space Models

The use of mixed frequency data is now common in many applications, ranging from the analysis of high frequency financial time series to large cross-sections of macroeconomic time series. In this article, we show how state space methods can easily facilitate both estimation and inference in these settings. After presenting a unified treatment of the state space approach to mixed frequency data modeling, we provide a series of applications to demonstrate how our MATLAB toolbox can make the estimation and post-processing of these models straightforward

Absorption Efficiencies of Forsterite. I: DDA Explorations in Grain Shape and Size

We compute the absorption efficiency (Qabs) of forsterite using the discrete dipole approximation (DDA) in order to identify and describe what characteristics of crystal grain shape and size are important to the shape, peak location, and relative strength of spectral features in the 8-40 {\mu}m wavelength range. Using the DDSCAT code, we compute Qabs for non-spherical polyhedral grain shapes with a_eff = 0.1 {\mu}m. The shape characteristics identified are: 1) elongation/reduction along one of three crystallographic axes; 2) asymmetry, such that all three crystallographic axes are of different lengths; and 3) the presence of crystalline faces that are not parallel to a specific crystallographic axis, e.g., non-rectangular prisms and (di)pyramids. Elongation/reduction dominates the locations and shapes of spectral features near 10, 11, 16, 23.5, 27, and 33.5 {\mu}m, while asymmetry and tips are secondary shape effects. Increasing grain sizes (0.1-1.0 {\mu}m) shifts the 10, 11 {\mu}m features systematically towards longer wavelengths and relative to the 11 {\mu}m feature increases the strengths and slightly broadens the longer wavelength features. Seven spectral shape classes are established for crystallographic a-, b-, and c-axes and include columnar and platelet shapes plus non-elongated or equant grain shapes. The spectral shape classes and the effects of grain size have practical application in identifying or excluding columnar, platelet or equant forsterite grain shapes in astrophysical environs. Identification of the shape characteristics of forsterite from 8-40 {\mu}m spectra provides a potential means to probe the temperatures at which forsterite formed.Comment: 55 pages, 15 figure

The Intracellular Localization of APE 1 /Ref-1: More than a Passive Phenomenon?

Human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1) is a perfect paradigm of the functional complexity of a biological macromolecule. First, it plays a crucial role, by both redox-dependent and –independent mechanisms, as a transcriptional coactivator for different transcription factors, either ubiquitous (i.e., AP-1, Egr-1, NF-κB, p53, HIF) or tissue-specific (i.e., PEBP-2, Pax-5 and -8, TTF-1), in controlling different cellular processes such as apoptosis, proliferation, and differentiation. Second, it acts, as an apurinic/apyrimidinic endonuclease, during the second step of the DNA base excision repair pathway, which is responsible for the repair of cellular alkylation and oxidative DNA damages. Third, it controls the intracellular reactive oxygen species production by negatively regulating the activity of the Ras-related GTPase Rac1. Despite these known functions of APE1/Ref-1, information is still scanty about the molecular mechanisms responsible for the coordinated control of its several activities. Some evidence suggests that the expression and subcellular localization of APE1/Ref-1 are finely tuned. APE1/Ref-1 is a ubiquitous protein, but its expression pattern differs according to the different cell types. APE1/Ref-1 subcellular localization is mainly nuclear, but cytoplasmic staining has also been reported, the latter being associated with mitochondria and/or presence within the endoplasmic reticulum. It is not by chance that both expression and subcellular localization are altered in several metabolic and proliferative disorders, such as in tumors and aging. Moreover, a fundamental role played by different posttranslational modifications in modulating APE1/Ref-1 functional activity is becoming evident. In the present review, we tried to put together a growing body of information concerning APE1/Ref-1's different functions, shedding new light on present and future directions to understand fully this unique molecule

Quake: quality-aware detection and correction of sequencing errors

We introduce Quake, a program to detect and correct errors in DNA sequencing reads. Using a maximum likelihood approach incorporating quality values and nucleotide specific miscall rates, Quake achieves the highest accuracy on realistically simulated reads. We further demonstrate substantial improvements in de novo assembly and SNP detection after using Quake. Quake can be used for any size project, including more than one billion human reads, and is freely available as open source software from http://www.cbcb.umd.edu/software/quake

Therapeutic efficacy of intravenously administered transferrin-conjugated dendriplexes on prostate carcinomas

Aim: Improved treatments for prostate cancer are critically needed in order to overcome metastasis and lethal recurrence. Intravenously administered gene therapy would be an attractive anticancer treatment strategy; however, the lack of suitable carrier systems able to selectively deliver therapeutic genes to tumors has so far limited this investigation. Given that transferrin receptors are overexpressed on prostate cancer cells, the purpose of this study is to determine whether transferrin-conjugated dendriplexes encoding TNF-α, TNF-related apoptosis-inducing ligand and IL-12 would suppress the growth of prostate cancer cell lines in vitro and in vivo. Materials & methods: Transferrin-conjugated dendriplexes encoding TNF-α, TNF-related apoptosis-inducing ligand and IL-12 were intravenously administered to mice bearing subcutaneous PC-3 and DU145 tumors. Results: The administration of the transferrin-conjugated generation 3 diaminobutyric polypropylenimine dendriplex encoding TNF-α resulted in tumor suppression for 60% of PC-3 and 50% of DU145 prostate tumors. Conclusion: These dendriplexes hold great potential as a novel approach for prostate cancer therapy

Early Clinical Detection of Pharmacologic Response in Insulin Action in a Nondiabetic Insulin-Resistant Population

AbstractBackgroundInsulin resistance heightens the risk for type 2 diabetes mellitus and cardiovascular disease. Amelioration of insulin resistance may reduce this risk. The thiazolidinedone class of insulin sensitizers improves insulin action in individuals with insulin-resistant diabetes and nondiabetic individuals. However, there are few reports on the time of onset of such effects independent of reversal of glucotoxicity.ObjectiveThe goal of our study was to test whether the thiazolidinedione pioglitazone has prominent early metabolic effects that can be detected in an obese, nondiabetic, insulin-resistant population.MethodsWe conducted a randomized, double-blind, placebo-controlled, parallel-group trial in men with nondiabetic insulin resistance using a hyperinsulinemic euglycemic clamp technique (at low and high doses of insulin at 10 and 40 mU/m2/min, respectively). The patients were given 30 mg daily oral pioglitazone or placebo for 28 days. Patients underwent a baseline clamp before initiation of treatment, and again at 14 and 28 days of treatment.ResultsCompared with placebo, under high-dose hyperinsulinemia, pioglitazone led to significant increases in glucose disposal rates (GDR) of 1.29 mg/kg/min (90% CI, 0.43–2.15; 39%; P=0.008) that were detectable at 2 weeks of treatment and persisted at 4 weeks of treatment. Under low-dose hyperinsulinemia, significant increases in GDR of 0.40 mg/kg/min (90% CI, 0.17–0.62; 95%; P=0.003) were observed at 4 weeks of treatment. These responses were accompanied by robust suppression of free fatty acids under hyperinsulinemic conditions, and by significant increases in circulating basal total adiponectin at 2 and 4 weeks of treatment.ConclusionsSignificant changes in insulin action across multiple insulin-sensitive tissues can be detected within 2 weeks of initiation of insulin-sensitizing therapy with pioglitazone in obese patients with nondiabetic insulin resistance. ClinicalTrials.gov identifier: NCT01115712

Reliability of measures of impairments associated with patellofemoral pain syndrome

BACKGROUND: The reliability and measurement error of several impairment measures used during the clinical examination of patients with patellofemoral pain syndrome (PFPS) has not been established. The purpose was to determine the inter-tester reliability and measurement error of measures of impairments associated with PFPS in patients with PFPS. METHODS: A single group repeated measures design was used. Two pairs of physical therapists participated in data collection. Examiners were blinded to each others' measurements. RESULTS: Thirty patients (age 29 +/- 8; 17 female) with PFPS participated in this study. Inter-tester reliability coefficients were substantial for measures of hamstrings, quadriceps, plantarflexors, and ITB/TFL complex length, hip abductors strength, and foot pronation (ICCs from .85 to .97); moderate for measures of Q-angle, tibial torsion, hip external rotation strength, lateral retinacular tightness, and quality of movement during a step down task (ICCs from .67 to .79); and poor for femoral anteversion (ICC of .45). Standard error of measurement (SEM) for measures of muscle length ranged from 1.6 degrees to 4.3 degrees. SEM for Q-angle, tibial torsion, and femoral anteversion were 2.4 degrees, 2.9 degrees, and 4.5 degrees respectively. SEM for foot pronation was 1 mm. SEM for measures of muscle strength was 1.8 Kg for abduction and 2.4 Kg for external rotation. CONCLUSION: Several of the impairments associated with PFPS had sufficient reliability and low measurement error. Further investigation is needed to test if these impairment measurements are related to physical function and whether or not they are useful for decision-making