Error correction and diversity analysis of population mixtures determined by NGS

The impetus for this work was the need to analyse nucleotide diversity in a viral mix taken from honeybees. The paper has two findings. First, a method for correction of next generation sequencing error in the distribution of nucleotides at a site is developed. Second, a package of methods for assessment of nucleotide diversity is assembled. The error correction method is statistically based and works at the level of the nucleotide distribution rather than the level of individual nucleotides. The method relies on an error model and a sample of known viral genotypes that is used for model calibration. A compendium of existing and new diversity analysis tools is also presented, allowing hypotheses about diversity and mean diversity to be tested and associated confidence intervals to be calculated. The methods are illustrated using honeybee viral samples. Software in both Excel and Matlab and a guide are available at http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software/,the Warwick University Systems Biology Centre software download site.Publisher PDFPeer reviewe

Nonlinear Realizations of the W3(2)W_3^{(2)} Algebra

In this letter we consider the nonlinear realizations of the classical Polyakov's algebra $W_3^{(2)}$. The coset space method and the covariant reduction procedure allow us to deduce the Boussinesq equation with interchanged space and evolution coordinates. By adding one more space coordinate and introducing two copies of the $W_3^{(2)}$ algebra, the same method yields the $sl(3,R)$ Toda lattice equations.Comment: LaTeX, 10p., Preprint LNF-94/013 (P

Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis C

The cost-effectiveness of noninvasive tests (NITs) as alternatives to liver biopsy is unknown. We compared the cost-effectiveness of using NITs to inform treatment decisions in adult patients with chronic hepatitis C (CHC). We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes (quality-adjusted life-years; QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four treatment strategies: testing with NITs and treating patients with fibrosis stage ≥F2; testing with liver biopsy and treating patients with ≥F2; treat none; and treat all irrespective of fibrosis. We compared all NITs and tested the cost-effectiveness using current triple therapy with boceprevir or telaprevir, but also modeled new, more-potent antivirals. Treating all patients without any previous NIT was the most effective strategy and had an incremental cost-effectiveness ratio (ICER) of £9,204 per additional QALY gained. The exploratory analysis of currently licensed sofosbuvir treatment regimens found that treat all was cost-effective, compared to using an NIT to decide on treatment, with an ICER of £16,028 per QALY gained. The exploratory analysis to assess the possible effect on results of new treatments, found that if SVR rates increased to >90% for genotypes 1-4, the incremental treatment cost threshold for the "treat all" strategy to remain the most cost-effective strategy would be £37,500. Above this threshold, the most cost-effective option would be noninvasive testing with magnetic resonance elastography (ICER=£9,189). Conclusions: Treating all adult patients with CHC, irrespective of fibrosis stage, is the most cost-effective strategy with currently available drugs in developed countries. © 2014 The Authors

Comprehensive analysis of the HEPN superfamily: identification of novel roles in intra-genomic conflicts, defense, pathogenesis and RNA processing

BACKGROUND: The major role of enzymatic toxins that target nucleic acids in biological conflicts at all levels has become increasingly apparent thanks in large part to the advances of comparative genomics. Typically, toxins evolve rapidly hampering the identification of these proteins by sequence analysis. Here we analyze an unexpectedly widespread superfamily of toxin domains most of which possess RNase activity. RESULTS: The HEPN superfamily is comprised of all α-helical domains that were first identified as being associated with DNA polymerase β-type nucleotidyltransferases in prokaryotes and animal Sacsin proteins. Using sensitive sequence and structure comparison methods, we vastly extend the HEPN superfamily by identifying numerous novel families and by detecting diverged HEPN domains in several known protein families. The new HEPN families include the RNase LS and LsoA catalytic domains, KEN domains (e.g. RNaseL and Ire1) and the RNase domains of RloC and PrrC. The majority of HEPN domains contain conserved motifs that constitute a metal-independent endoRNase active site. Some HEPN domains lacking this motif probably function as non-catalytic RNA-binding domains, such as in the case of the mannitol repressor MtlR. Our analysis shows that HEPN domains function as toxins that are shared by numerous systems implicated in intra-genomic, inter-genomic and intra-organismal conflicts across the three domains of cellular life. In prokaryotes HEPN domains are essential components of numerous toxin-antitoxin (TA) and abortive infection (Abi) systems and in addition are tightly associated with many restriction-modification (R-M) and CRISPR-Cas systems, and occasionally with other defense systems such as Pgl and Ter. We present evidence of multiple modes of action of HEPN domains in these systems, which include direct attack on viral RNAs (e.g. LsoA and RNase LS) in conjunction with other RNase domains (e.g. a novel RNase H fold domain, NamA), suicidal or dormancy-inducing attack on self RNAs (RM systems and possibly CRISPR-Cas systems), and suicidal attack coupled with direct interaction with phage components (Abi systems). These findings are compatible with the hypothesis on coupling of pathogen-targeting (immunity) and self-directed (programmed cell death and dormancy induction) responses in the evolution of robust antiviral strategies. We propose that altruistic cell suicide mediated by HEPN domains and other functionally similar RNases was essential for the evolution of kin and group selection and cell cooperation. HEPN domains were repeatedly acquired by eukaryotes and incorporated into several core functions such as endonucleolytic processing of the 5.8S-25S/28S rRNA precursor (Las1), a novel ER membrane-associated RNA degradation system (C6orf70), sensing of unprocessed transcripts at the nuclear periphery (Swt1). Multiple lines of evidence suggest that, similar to prokaryotes, HEPN proteins were recruited to antiviral, antitransposon, apoptotic systems or RNA-level response to unfolded proteins (Sacsin and KEN domains) in several groups of eukaryotes. CONCLUSIONS: Extensive sequence and structure comparisons reveal unexpectedly broad presence of the HEPN domain in an enormous variety of defense and stress response systems across the tree of life. In addition, HEPN domains have been recruited to perform essential functions, in particular in eukaryotic rRNA processing. These findings are expected to stimulate experiments that could shed light on diverse cellular processes across the three domains of life. REVIEWERS: This article was reviewed by Martijn Huynen, Igor Zhulin and Nick Grishi

Lifestyle Risk Factors and Cardiovascular Disease in Cubans and Cuban Americans

Cardiovascular disease is the leading cause of mortality in Cuba. Lifestyle risk factors for coronary heart disease (CHD) in Cubans have not been compared to risk factors in Cuban Americans. Articles spanning the last 20 years were reviewed. The data on Cuban Americans are largely based on the Hispanic Health and Nutrition Examination Survey (HHANES), 1982–1984, while more recent data on epidemiological trends in Cuba are available. The prevalence of obesity and type 2 diabetes mellitus remains greater in Cuban Americans than in Cubans. However, dietary preferences, low physical activity, and tobacco use are contributing to the rising rates of obesity, type 2 diabetes mellitus, and CHD in Cuba, putting Cubans at increased cardiovascular risk. Comprehensive national strategies for cardiovascular prevention that address these modifiable lifestyle risk factors are necessary to address the increasing threat to public health in Cuba

Solitons from Dressing in an Algebraic Approach to the Constrained KP Hierarchy

The algebraic matrix hierarchy approach based on affine Lie $sl (n)$ algebras leads to a variety of 1+1 soliton equations. By varying the rank of the underlying $sl (n)$ algebra as well as its gradation in the affine setting, one encompasses the set of the soliton equations of the constrained KP hierarchy. The soliton solutions are then obtained as elements of the orbits of the dressing transformations constructed in terms of representations of the vertex operators of the affine $sl (n)$ algebras realized in the unconventional gradations. Such soliton solutions exhibit non-trivial dependence on the KdV (odd) time flows and KP (odd and even) time flows which distinguishes them from the conventional structure of the Darboux-B\"{a}cklund Wronskian solutions of the constrained KP hierarchy.Comment: LaTeX, 13pg

Quantification of fibrosis by collagen proportionate area predicts hepatic decompensation in hepatitis C cirrhosis

Background It is unclear whether the course of cirrhosis and its prognosis are related to the amount of collagen in the liver. Aim To determine whether fibrosis, assessed by collagen proportionate area (CPA) in patients with compensated cirrhosis, is associated with the presence of oesophageal varices, and predict disease decompensation during the follow-up period. Methods We prospectively evaluated 118 consecutive patients with compensated cirrhosis to correlate fibrosis, assessed by CPA in liver biopsies, with the presence of oesophageal varices (OV) and with the rate of liver decompensation (LD) development during a median follow-up of 72 months. Results At baseline 38 (32.2%) patients had OV and during the follow-up (median 72 months, IQR 47–91), 17 patients (14.4%) developed LD. The mean CPA value was different in patients with and without OV (14.8 5.9% vs. 21.6 9.5%, P < 0.001). The best CPA cut-off for OV by area under the receiver operating characteristic (AUROC) was ≥14% and with multivariate logistic analysis CPA was the only variable associated with OV (OR: 28.32, 95% CI: 6.30–127.28; P < 0.001). By AUROC analysis the best CPA cut-off to predict LD was 18.0%. By Cox regression multivariate analysis CPA ≥18% (HR: 3.99, 95% CI: 1.04–11.45; P = 0.036), albumin (HR: 0.12, 95% CI: 0.04–0.43; P = 0.001) and presence of OV (HR: 8.15, 95% CI: 2.31– 28.78; P = 0.001) were independently associated with LD. Conclusion Quantification of fibrosis by collagen proportionate area allows identification of patients with compensated HCV cirrhosis with a higher likelihood of clinically relevant portal hypertension and a higher risk of decompensation

Recombinants between Deformed wing virus and Varroa destructor virus-1 may prevail in Varroa destructor-infested honeybee colonies

We have used high-throughput Illumina sequencing to identify novel recombinants between deformed wing virus (DWV) and Varroa destructor virus-1 (VDV-1), which accumulate to higher levels than DWV in both honeybees and Varroa destructor mites. The recombinants, VDV-1VVD and VDV-1DVD, exhibit crossovers between the 5’-untranslated region (5’-UTR), and/or the regions encoding the structural (capsid) and non-structural viral proteins. This implies the genomes are modular and that each region may evolve independently, as demonstrated in human enteroviruses. Individual honeybee pupae were infected with a mixture of observed recombinants and DWV. The strong correlation between VDV-1DVD levels in honeybee pupae and the associated mites was observed, suggesting that this recombinant, with a DWV-derived 5’-UTR and non-structural protein region flanking VDV- 1-derived capsid encoding region, is better adapted to transmission between V. destructor and honeybees than the parental DWV or a recombinant bearing the VDV-1-derived 5’-UTR (VDV-1VVD)

In-Line-Test of Variability and Bit-Error-Rate of HfOx-Based Resistive Memory

Spatial and temporal variability of HfOx-based resistive random access memory (RRAM) are investigated for manufacturing and product designs. Manufacturing variability is characterized at different levels including lots, wafers, and chips. Bit-error-rate (BER) is proposed as a holistic parameter for the write cycle resistance statistics. Using the electrical in-line-test cycle data, a method is developed to derive BERs as functions of the design margin, to provide guidance for technology evaluation and product design. The proposed BER calculation can also be used in the off-line bench test and build-in-self-test (BIST) for adaptive error correction and for the other types of random access memories.Comment: 4 pages. Memory Workshop (IMW), 2015 IEEE Internationa

Role of 1q21 in multiple myeloma: From pathogenesis to possible therapeutic targets

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon