CLU: A new algorithm for EST clustering

BACKGROUND: The continuous flow of EST data remains one of the richest sources for discoveries in modern biology. The first step in EST data mining is usually associated with EST clustering, the process of grouping of original fragments according to their annotation, similarity to known genomic DNA or each other. Clustered EST data, accumulated in databases such as UniGene, STACK and TIGR Gene Indices have proven to be crucial in research areas from gene discovery to regulation of gene expression. RESULTS: We have developed a new nucleotide sequence matching algorithm and its implementation for clustering EST sequences. The program is based on the original CLU match detection algorithm, which has improved performance over the widely used d2_cluster. The CLU algorithm automatically ignores low-complexity regions like poly-tracts and short tandem repeats. CONCLUSION: CLU represents a new generation of EST clustering algorithm with improved performance over current approaches. An early implementation can be applied in small and medium-size projects. The CLU program is available on an open source basis free of charge. It can be downloaded fro

From error bounds to the complexity of first-order descent methods for convex functions

This paper shows that error bounds can be used as effective tools for deriving complexity results for first-order descent methods in convex minimization. In a first stage, this objective led us to revisit the interplay between error bounds and the Kurdyka-\L ojasiewicz (KL) inequality. One can show the equivalence between the two concepts for convex functions having a moderately flat profile near the set of minimizers (as those of functions with H\"olderian growth). A counterexample shows that the equivalence is no longer true for extremely flat functions. This fact reveals the relevance of an approach based on KL inequality. In a second stage, we show how KL inequalities can in turn be employed to compute new complexity bounds for a wealth of descent methods for convex problems. Our approach is completely original and makes use of a one-dimensional worst-case proximal sequence in the spirit of the famous majorant method of Kantorovich. Our result applies to a very simple abstract scheme that covers a wide class of descent methods. As a byproduct of our study, we also provide new results for the globalization of KL inequalities in the convex framework. Our main results inaugurate a simple methodology: derive an error bound, compute the desingularizing function whenever possible, identify essential constants in the descent method and finally compute the complexity using the one-dimensional worst case proximal sequence. Our method is illustrated through projection methods for feasibility problems, and through the famous iterative shrinkage thresholding algorithm (ISTA), for which we show that the complexity bound is of the form $O(q^{k})$ where the constituents of the bound only depend on error bound constants obtained for an arbitrary least squares objective with $\ell^1$ regularization

Design of a flight control architecture using a non-convex bundle method

We design a feedback control architecture for longitudinal flight of an aircraft. The multi-level architecture includes the flight control loop to govern the short term dynamics of the aircraft, and the autopilot to control the long term modes. Using H1 performance and robustness criteria, the problem is cast as a non-convex and non-smooth optimization program. We present a non-convex bundle method, prove its convergence, and show that it is apt to solve the longitudinal flight control problem

Radio pulsar populations

The goal of this article is to summarize the current state of play in the field of radio pulsar statistics. Simply put, from the observed sample of objects from a variety of surveys with different telescopes, we wish to infer the properties of the underlying sample and to connect these with other astrophysical populations (for example supernova remnants or X-ray binaries). The main problem we need to tackle is the fact that, like many areas of science, the observed populations are often heavily biased by a variety of selection effects. After a review of the main effects relevant to radio pulsars, I discuss techniques to correct for them and summarize some of the most recent results. Perhaps the main point I would like to make in this article is that current models to describe the population are far from complete and often suffer from strong covariances between input parameters. That said, there are a number of very interesting conclusions that can be made concerning the evolution of neutron stars based on current data. While the focus of this review will be on the population of isolated Galactic pulsars, I will also briefly comment on millisecond and binary pulsars as well as the pulsar content of globular clusters and the Magellanic Clouds.Comment: 16 pages, 6 figures, to appear in Proceedings of ICREA Workshop on The High-Energy Emission from Pulsars and their Systems, Sant Cugat, Spain, 2010 April 12-16 (Springer

Systematic review of pre-operative exercise in colorectal cancer patients

The aim of this systematic review was to evaluate the evidence for exercise interventions prior to surgery for colorectal cancer resection. The evidence for use of exercise to improve physical fitness and surgical outcomes is as yet unknown. A systematic search was performed of MEDLINE, EMBASE, CINAHL, AMED and BNI databases for studies involving pre-operative exercise in colorectal cancer patients. Eight studies were included in the review. There is evidence that pre-operative exercise improves functional fitness, and to a lesser extent objectively measurable cardio-respiratory fitness prior to colorectal cancer resection. There is no clear evidence at present that this improvement in fitness translates into reduced peri-operative risk or improved post-operative outcomes. Current studies are limited by risk of bias. This review highlights the common difficulty in transferring promising results in a research setting, into significant improvements in the clinical arena. Future research should focus on which type of exercise is most likely to maximise patient adherence and improvements in cardio-respiratory fitness. Ultimately, adequately powered, randomised controlled trials are needed to investigate whether pre-operative exercise improves post-operative morbidity and mortality

BSRS-5 (5-item Brief Symptom Rating Scale) scores affect every aspect of quality of life measured by WHOQOL-BREF in healthy workers

This study aims to evaluate and quantify the possible effect of psychological symptoms on healthy workers' quality of life (QOL). The workers were recruited from a factory in south Taiwan. We assessed their psychological symptoms with a 5-item brief symptom rating scale (BSRS-5) and measured the QOL using the Taiwanese version of the World Health Organization Quality of Life (WHOQOL)-BREF. Multiple linear regression analysis was conducted to explore the association between the two tools after control of confounding by other predictors. A total of 1,080 workers , who attended a physical examination, completed questionnaires and informed consent forms. Scores on the BSRS-5 significantly predicted scores in each domain and items of the WHOQOL-BREF. The magnitude of psychological domain score seemed to be affected the most; every 1 point increase in BSRS-5 was associated with a 0.39 raw score (equivalent to 2. 44 percentile) decrease in QOL. The sleep facet of WHOQOL appeared to have the highest association, followed by items of negative feelings, energy, and concentration. The BSRS-5 score is predictive for scores of all four domains and 26 items of the Taiwanese version of the WHOQOL-BREF for regular factory workers

Reduced expression of lamin A/C correlates with poor histological differentiation and prognosis in primary gastric carcinoma

<p>Abstract</p> <p>Background</p> <p>Lamin A/C is very important in DNA replication, RNA dependent transcription and nuclear stabilization. Reduced or absent lamin A/C expression has been found to be a common feature of a variety of different cancers. To investigate the role of lamin A/C in gastric carcinoma (GC) pathogenesis, we analyzed the correlations between the lamin A/C expression level and clinicopathological factors and studied its prognostic role in primary GC.</p> <p>Methods</p> <p>The expression of lamin A/C at mRNA level was detected by the reverse transcription-polymerase chain reaction (RT-PCR) and real time RT-PCR, and western blot was used to examine the protein expression. Lamin A/C expression and its prognostic significance were investigated by performing immunohistochemical analysis on a total of 126 GC clinical tissue samples.</p> <p>Results</p> <p>Both lamin A/C mRNA and protein expression were downregulated in the majority of tumours compared with corresponding normal gastric tissues (<it>p </it>= 0.011 and <it>p </it>= 0.036, respectively). Real time RT-PCR further validated that downregulation of lamin A/C is associated with poor histological differentiation (r = 0.438, <it>p </it>= 0.025). The immunohistochemical staining showed an evident decrease of lamin A/C expression in 55.6% (70/126) GC cases. Importantly, the negative lamin A/C expression correlated strongly with histological classification (r = 0.361, <it>p </it>= 0.034). Survival analysis revealed that patients with lamin A/C downregulation have a poorer prognosis (<it>p </it>= 0.034). In addition, lamin A/C expression was found to be an independent prognostic factor by multivariate analysis.</p> <p>Conclusion</p> <p>Data of this study suggest that lamin A/C is involved in the pathogenesis of GC, and it may serve as a valuable biomarker for assessing the prognosis for primary GC.</p

Directing cell therapy to anatomic target sites in vivo with magnetic resonance targeting

Cell-based therapy exploits modified human cells to treat diseases but its targeted application in specific tissues, particularly those lying deep in the body where direct injection is not possible, has been problematic. Here we use a magnetic resonance imaging (MRI) system to direct macrophages carrying an oncolytic virus, Seprehvir, into primary and metastatic tumour sites in mice. To achieve this, we magnetically label macrophages with super-paramagnetic iron oxide nanoparticles and apply pulsed magnetic field gradients in the direction of the tumour sites. Magnetic resonance targeting guides macrophages from the bloodstream into tumours, resulting in increased tumour macrophage infiltration and reduction in tumour burden and metastasis. Our study indicates that clinical MRI scanners can not only track the location of magnetically labelled cells but also have the potential to steer them into one or more target tissues

Dengue Virus Infection and Virus-Specific HLA-A2 Restricted Immune Responses in Humanized NOD-scid IL2rγnull Mice

BACKGROUND:The lack of a suitable animal model to study viral and immunological mechanisms of human dengue disease has been a deterrent to dengue research. METHODOLOGY/PRINCIPAL FINDINGS:We sought to establish an animal model for dengue virus (DENV) infection and immunity using non-obese diabetic/severe combined immunodeficiency interleukin-2 receptor gamma-chain knockout (NOD-scid IL2rgamma(null)) mice engrafted with human hematopoietic stem cells. Human CD45(+) cells in the bone marrow of engrafted mice were susceptible to in vitro infection using low passage clinical and established strains of DENV. Engrafted mice were infected with DENV type 2 by different routes and at multiple time points post infection, we detected DENV antigen and RNA in the sera, bone marrow, spleen and liver of infected engrafted mice. Anti-dengue IgM antibodies directed against the envelope protein of DENV peaked in the sera of mice at 1 week post infection. Human T cells that developed following engraftment of HLA-A2 transgenic NOD-scid IL2rgamma(null) mice with HLA-A2(+) human cord blood hematopoietic stem cells, were able to secrete IFN-gamma, IL-2 and TNF-alpha in response to stimulation with three previously identified A2 restricted dengue peptides NS4b 2353((111-119)), NS4b 2423((181-189)), and NS4a 2148((56-64)). CONCLUSIONS/SIGNIFICANCE:This is the first study to demonstrate infection of human cells and functional DENV-specific T cell responses in DENV-infected humanized mice. Overall, these mice should be a valuable tool to study the role of prior immunity on subsequent DENV infections

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM