Predicting the subcellular localization of viral proteins within a mammalian host cell

BACKGROUND: The bioinformatic prediction of protein subcellular localization has been extensively studied for prokaryotic and eukaryotic organisms. However, this is not the case for viruses whose proteins are often involved in extensive interactions at various subcellular localizations with host proteins. RESULTS: Here, we investigate the extent of utilization of human cellular localization mechanisms by viral proteins and we demonstrate that appropriate eukaryotic subcellular localization predictors can be used to predict viral protein localization within the host cell. CONCLUSION: Such predictions provide a method to rapidly annotate viral proteomes with subcellular localization information. They are likely to have widespread applications both in the study of the functions of viral proteins in the host cell and in the design of antiviral drugs

High accuracy genotyping directly from genomic DNA using a rolling circle amplification based assay

BACKGROUND: Rolling circle amplification of ligated probes is a simple and sensitive means for genotyping directly from genomic DNA. SNPs and mutations are interrogated with open circle probes (OCP) that can be circularized by DNA ligase when the probe matches the genotype. An amplified detection signal is generated by exponential rolling circle amplification (ERCA) of the circularized probe. The low cost and scalability of ligation/ERCA genotyping makes it ideally suited for automated, high throughput methods. RESULTS: A retrospective study using human genomic DNA samples of known genotype was performed for four different clinically relevant mutations: Factor V Leiden, Factor II prothrombin, and two hemochromatosis mutations, C282Y and H63D. Greater than 99% accuracy was obtained genotyping genomic DNA samples from hundreds of different individuals. The combined process of ligation/ERCA was performed in a single tube and produced fluorescent signal directly from genomic DNA in less than an hour. In each assay, the probes for both normal and mutant alleles were combined in a single reaction. Multiple ERCA primers combined with a quenched-peptide nucleic acid (Q-PNA) fluorescent detection system greatly accellerated the appearance of signal. Probes designed with hairpin structures reduced misamplification. Genotyping accuracy was identical from either purified genomic DNA or genomic DNA generated using whole genome amplification (WGA). Fluorescent signal output was measured in real time and as an end point. CONCLUSIONS: Combining the optimal elements for ligation/ERCA genotyping has resulted in a highly accurate single tube assay for genotyping directly from genomic DNA samples. Accuracy exceeded 99 % for four probe sets targeting clinically relevant mutations. No genotypes were called incorrectly using either genomic DNA or whole genome amplified sample

Unsupervised feature selection for noisy data

Feature selection techniques are enormously applied in a variety of data analysis tasks in order to reduce the dimensionality. According to the type of learning, feature selection algorithms are categorized to: supervised or unsupervised. In unsupervised learning scenarios, selecting features is a much harder problem, due to the lack of class labels that would facilitate the search for relevant features. The selecting feature difficulty is amplified when the data is corrupted by different noises. Almost all traditional unsupervised feature selection methods are not robust against the noise in samples. These approaches do not have any explicit mechanism for detaching and isolating the noise thus they can not produce an optimal feature subset. In this article, we propose an unsupervised approach for feature selection on noisy data, called Robust Independent Feature Selection (RIFS). Specifically, we choose feature subset that contains most of the underlying information, using the same criteria as the Independent component analysis (ICA). Simultaneously, the noise is separated as an independent component. The isolation of representative noise samples is achieved using factor oblique rotation whereas noise identification is performed using factor pattern loadings. Extensive experimental results over divers real-life data sets have showed the efficiency and advantage of the proposed algorithm.We thankfully acknowledge the support of the Comision Interministerial de Ciencia y Tecnologa (CICYT) under contract No. TIN2015-65316-P which has partially funded this work.Peer ReviewedPostprint (author's final draft

Trial of Ultrasound guided carpal tunnel release versus Traditional Open Release (TUTOR)

BACKGROUND: Carpal tunnel release (CTR) is a surgical treatment option for patients with carpal tunnel syndrome (CTS) symptoms that are unresponsive to conservative treatment. Most patients experience symptomatic relief after CTR regardless of the surgical technique. However, direct comparisons of the safety and effectiveness between CTR surgical techniques are limited. The purpose of this randomized controlled trial is to compare the safety and effectiveness of CTR with ultrasound guidance (CTR-US) versus mini-open CTR (mOCTR) in subjects with symptomatic CTS. DESIGN AND METHODS: TUTOR (Trial of Ultrasound guided CTR versus Traditional Open Release) is a randomized controlled trial in which 120 subjects at up to 12 sites in the United States will be randomized (2:1) to receive CTR-US or mOCTR. The primary endpoint of the study is the percentage of patients who return to normal daily activities within 3 days of the procedure. Secondary endpoints of the study are median time to return to normal daily activities, percentage of patients who return to work within 3 days of the procedure, median time to return to work, Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) change score at 3 months, BCTQ Functional Status Scale (BCTQ-FSS) change score at 3 months, Numeric Pain Scale change score at 3 months, EuroQoL-5 Dimension 5-Level (EQ-5D-5L) change score at 3 months, and the incidence of device- or procedure-related adverse events at 3 months. Patient follow-up in this trial will continue for 1 year. ETHICS AND DISSEMINATION: This study was approved by a central institutional review board and ongoing trial oversight will be provided by a data safety monitoring board (DSMB). The authors intend to report the results of this trial at medical conferences and peer-reviewed journals. The outcomes of TUTOR will have important clinical and economic implications for all stakeholders involved in treating patients with CTS. STUDY REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov): NCT05405218. LEVEL OF EVIDENCE: 1

Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.

Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes

Multicenter randomized trial of carpal tunnel release with ultrasound guidance versus mini-open technique

BACKGROUND: Comparative studies of carpal tunnel release with ultrasound guidance (CTR-US) vs. mini-open CTR (mOCTR) are limited, prompting development of this randomized trial to compare efficacy and safety of these techniques. RESEARCH DESIGN AND METHODS: Patients were randomized (2:1) to CTR-US or mOCTR, treated by experienced hand surgeons (median previous cases: 12 CTR-US; 1000 mOCTR), and followed for 3 months. RESULTS: Among 149 randomized patients, 122 received CTR-US ( CONCLUSIONS: The efficacy and safety of CTR-US were comparable to mOCTR despite less previous surgical experience with CTR-US. The choice of CTR technique should be determined by shared decision-making between patient and physician. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05405218

Evolvement of Uniformity and Volatility in the Stressed Global Financial Village

Background: In the current era of strong worldwide market couplings the global financial village became highly prone to systemic collapses, events that can rapidly sweep throughout the entire village. Methodology/Principal Findings: We present a new methodology to assess and quantify inter-market relations. The approach is based on the correlations between the market index, the index volatility, the market Index Cohesive Force and the meta-correlations (correlations between the intra-correlations.) We investigated the relations between six important world markets—U.S., U.K., Germany, Japan, China and India—from January 2000 until December 2010. We found that while the developed ‘‘western’’ markets (U.S., U.K., Germany) are highly correlated, the interdependencies between these markets and the developing ‘‘eastern’’ markets (India and China) are volatile and with noticeable maxima at times of global world events. The Japanese market switches ‘‘identity’’—it switches between periods of high meta-correlations with the ‘‘western’’ markets and periods when it behaves more similarly to the ‘‘eastern’’ markets. Conclusions/Significance: The methodological framework presented here provides a way to quantify the evolvement of interdependencies in the global market, evaluate a world financial network and quantify changes in the world inter market relations. Such changes can be used as precursors to the agitation of the global financial village. Hence, the new approach can help to develop a sensitive ‘‘financial seismograph’’ to detect early signs of global financial crises so they can be treated before they develop into worldwide event