AZOrange - High performance open source machine learning for QSAR modeling in a graphical programming environment

<p>Abstract</p> <p>Background</p> <p>Machine learning has a vast range of applications. In particular, advanced machine learning methods are routinely and increasingly used in quantitative structure activity relationship (QSAR) modeling. QSAR data sets often encompass tens of thousands of compounds and the size of proprietary, as well as public data sets, is rapidly growing. Hence, there is a demand for computationally efficient machine learning algorithms, easily available to researchers without extensive machine learning knowledge. In granting the scientific principles of transparency and reproducibility, Open Source solutions are increasingly acknowledged by regulatory authorities. Thus, an Open Source state-of-the-art high performance machine learning platform, interfacing multiple, customized machine learning algorithms for both graphical programming and scripting, to be used for large scale development of QSAR models of regulatory quality, is of great value to the QSAR community.</p> <p>Results</p> <p>This paper describes the implementation of the Open Source machine learning package AZOrange. AZOrange is specially developed to support batch generation of QSAR models in providing the full work flow of QSAR modeling, from descriptor calculation to automated model building, validation and selection. The automated work flow relies upon the customization of the machine learning algorithms and a generalized, automated model hyper-parameter selection process. Several high performance machine learning algorithms are interfaced for efficient data set specific selection of the statistical method, promoting model accuracy. Using the high performance machine learning algorithms of AZOrange does not require programming knowledge as flexible applications can be created, not only at a scripting level, but also in a graphical programming environment.</p> <p>Conclusions</p> <p>AZOrange is a step towards meeting the needs for an Open Source high performance machine learning platform, supporting the efficient development of highly accurate QSAR models fulfilling regulatory requirements.</p

Integrating isotopes and documentary evidence : dietary patterns in a late medieval and early modern mining community, Sweden

We would like to thank the Archaeological Research Laboratory, Stockholm University, Sweden and the Tandem Laboratory (Ångström Laboratory), Uppsala University, Sweden, for undertaking the analyses of stable nitrogen and carbon isotopes in both human and animal collagen samples. Also, thanks to Elin Ahlin Sundman for providing the δ13C and δ15N values for animal references from Västerås. This research (Bäckström’s PhD employment at Lund University, Sweden) was supported by the Berit Wallenberg Foundation (BWS 2010.0176) and Jakob and Johan Söderberg’s foundation. The ‘Sala project’ (excavations and analyses) has been funded by Riksens Clenodium, Jernkontoret, Birgit and Gad Rausing’s Foundation, SAU’s Research Foundation, the Royal Physiographic Society of Lund, Berit Wallenbergs Foundation, Åke Wibergs Foundation, Lars Hiertas Memory, Helge Ax:son Johnson’s Foundation and The Royal Swedish Academy of Sciences.Peer reviewedPublisher PD

HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13

Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD less than= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, pless than9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (pless than0.002, pless than0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both

Can cognitive insight predict symptom remission in a first episode psychosis cohort?

BACKGROUND: The outcome of first episode psychosis (FEP) is highly variable and difficult to predict. Cognitive insight measured at illness onset has previously been found to predict psychopathology 12-months later. The aims of this study were to examine whether the prospective relationship between cognitive insight and symptom severity is evident at four-years following FEP and to examine some psychological correlates of cognitive insight. METHODS: FEP participants (n = 90) completed the Beck Cognitive Insight Scale (BCIS) at illness onset, and associations between BCIS scores with symptom severity outcomes (4-years after FEP) were assessed. The BCIS scales (self-reflectiveness and self-certainty) were examined as a composite score, and individually compared to other cognitive measures (IQ and jumping to conclusions (JTC) bias). RESULTS: Regression analyses revealed that the cognitive insight composite did not predict 4-year symptom remission in this study while the self-reflection subscale of the BCIS predicted severity of symptoms at 4-years. Self-certainty items of the BCIS were not associated with symptom severity. Significant correlations between the JTC bias, self-certainty and IQ were found, but self-reflection did not correlate with these other cognitive measures. CONCLUSIONS: Self-reflective capacity is a more relevant and independent cognitive construct than self-certainty for predicting prospective symptom severity in psychosis. Improving self-reflection may be a useful target for early intervention research

Mode II fracture energy in the adhesive bonding of dissimilar substrates: carbon fibre composite to aluminium joints

The end-notched flexure (ENF) test calculates the value of mode II fracture energy in adhesive bonding between the substrates of same nature. Traditional methods of calculating fracture energy in the ENF test are not suitable in cases where the thickness of the adhesive is non-negligible compared with adherent thicknesses. To address this issue, a specific methodology for calculating mode II fracture energy has been proposed in this paper. To illustrate the applicability of the proposed method, the fracture energy was calculated by the ENF test for adhesive bonds between aluminium and a composite material, which considered two different types of adhesive (epoxy and polyurethane) and various surface treatments. The proposed calculation model provides higher values of fracture energy than those obtained from the simplified models that consider the adhesive thickness to be zero, supporting the conclusion that the calculation of mode II fracture energy for adhesives with non-negligible thickness relative to their adherents should be based on mathematical models, such as the method proposed in this paper, that incorporate the influence of this thickness

Groucho binds two conserved regions of LEF-1 for HDAC-dependent repression

<p>Abstract</p> <p>Background</p> <p><it>Drosophila </it>Groucho and its human Transducin-like-Enhancer of Split orthologs (TLEs) function as transcription co-repressors within the context of Wnt signaling, a pathway with strong links to cancer. The current model for how Groucho/TLE's modify Wnt signaling is by direct competition with β-catenin for LEF/TCF binding. The molecular events involved in this competitive interaction are not defined and the actions of Groucho/TLEs within the context of Wnt-linked cancer are unknown.</p> <p>Methods</p> <p>We used <it>in vitro </it>protein interaction assays with the LEF/TCF family member LEF-1, and <it>in vivo </it>assays with Wnt reporter plasmids to define Groucho/TLE interaction and repressor function.</p> <p>Results</p> <p>Mapping studies reveal that Groucho/TLE binds two regions in LEF-1. The primary site of recognition is a 20 amino acid region in the Context Dependent Regulatory domain. An auxiliary site is in the High Mobility Group DNA binding domain. Mutation of an eight amino acid sequence within the primary region (RFSHHMIP) results in a loss of Groucho action in a transient reporter assay. <it>Drosophila </it>Groucho, human TLE-1, and a truncated human TLE isoform Amino-enhancer-of-split (AES), work equivalently to repress LEF-1•β-catenin transcription in transient reporter assays, and these actions are sensitive to the HDAC inhibitor Trichostatin A. A survey of Groucho/TLE action in a panel of six colon cancer cell lines with elevated β-catenin shows that Groucho is not able to repress transcription in a subset of these cell lines.</p> <p>Conclusion</p> <p>Our data shows that Groucho/TLE repression requires two sites of interaction in LEF-1 and that a central, conserved amino acid sequence within the primary region (F S/T/P/xx y I/L/V) is critical. Our data also reveals that AES opposes LEF-1 transcription activation and that both Groucho and AES repression require histone deacetylase activity suggesting multiple steps in Groucho competition with β-catenin. The variable ability of Groucho/TLE to oppose Wnt signaling in colon cancer cells suggests there may be defects in one or more of these steps.</p

Infusion fluids contain harmful glucose degradation products

PURPOSE: Glucose degradation products (GDPs) are precursors of advanced glycation end products (AGEs) that cause cellular damage and inflammation. We examined the content of GDPs in commercially available glucose-containing infusion fluids and investigated whether GDPs are found in patients' blood. METHODS: The content of GDPs was examined in infusion fluids by high-performance liquid chromatography (HPLC) analysis. To investigate whether GDPs also are found in patients, we included 11 patients who received glucose fluids (standard group) during and after their surgery and 11 control patients receiving buffered saline (control group). Blood samples were analyzed for GDP content and carboxymethyllysine (CML), as a measure of AGE formation. The influence of heat-sterilized fluids on cell viability and cell function upon infection was investigated. RESULTS: All investigated fluids contained high concentrations of GDPs, such as 3-deoxyglucosone (3-DG). Serum concentration of 3-DG increased rapidly by a factor of eight in patients receiving standard therapy. Serum CML levels increased significantly and showed linear correlation with the amount of infused 3-DG. There was no increase in serum 3-DG or CML concentrations in the control group. The concentration of GDPs in most of the tested fluids damaged neutrophils, reducing their cytokine secretion, and inhibited microbial killing. CONCLUSIONS: These findings indicate that normal standard fluid therapy involves unwanted infusion of GDPs. Reduction of the content of GDPs in commonly used infusion fluids may improve cell function, and possibly also organ function, in intensive-care patients

Foxc Transcription Factors Directly Regulate Dll4 and Hey2 Expression by Interacting with the VEGF-Notch Signaling Pathways in Endothelial Cells

Recent studies have shown that in the developing embryo, arterial and venous identity is established by genetic mechanisms before circulation begins. Vascular endothelial growth factor (VEGF) signaling and its downstream Notch pathway play critical roles in arterial cell fate determination. We have recently shown that Foxc1 and Foxc2, two closely related Fox transcription factors, are essential for arterial cell specification during development by directly inducing the transcription of Delta-like 4 (Dll4), a ligand for Notch receptors. However, the basic mechanisms whereby the VEGF and Notch signaling pathways control transcriptional regulation of arterial-specific genes have yet to be elucidated.In the current study, we examined whether and how Foxc transcription factors are involved in VEGF and Notch signaling in induction of Dll4 as well as the Notch target gene Hey2 in endothelial cells. We found that Foxc1 and Foxc2 directly activate the Hey2 promoter via Foxc binding elements. Significantly, Foxc2 physically and functionally interacts with a Notch transcriptional activation complex containing Su(H) and Notch intracellular domain to induce Hey2 promoter activity. Moreover, activation of the Dll4 and Hey2 promoters is induced by VEGF in conjunction with either Foxc1 or Foxc2 more than by either component alone. VEGF-activated PI3K and ERK intracellular pathways modulate the transcriptional activity of Foxc proteins in Dll4 and Hey2 induction.Our new findings demonstrate that Foxc transcriptional factors interact with VEGF and Notch signaling to regulate arterial gene expression in multiple steps of the VEGF-Dll4-Notch-Hey2 signaling pathway

Stable Isotope Evidence for Dietary Overlap between Alien and Native Gastropods in Coastal Lakes of Northern KwaZulu-Natal, South Africa

Tarebia granifera (Lamarck, 1822) is originally from South-East Asia, but has been introduced and become invasive in many tropical and subtropical parts of the world. In South Africa, T. granifera is rapidly invading an increasing number of coastal lakes and estuaries, often reaching very high population densities and dominating shallow water benthic invertebrate assemblages. An assessment of the feeding dynamics of T. granifera has raised questions about potential ecological impacts, specifically in terms of its dietary overlap with native gastropods.A stable isotope mixing model was used together with gut content analysis to estimate the diet of T. granifera and native gastropod populations in three different coastal lakes. Population density, available biomass of food and salinity were measured along transects placed over T. granifera patches. An index of isotopic (stable isotopes) dietary overlap (IDO, %) aided in interpreting interactions between gastropods. The diet of T. granifera was variable, including contributions from microphytobenthos, filamentous algae (Cladophora sp.), detritus and sedimentary organic matter. IDO was significant (>60%) between T. granifera and each of the following gastropods: Haminoea natalensis (Krauss, 1848), Bulinus natalensis (Küster, 1841) and Melanoides tuberculata (Müller, 1774). However, food did not appear to be limiting. Salinity influenced gastropod spatial overlap. Tarebia granifera may only displace native gastropods, such as Assiminea cf. ovata (Krauss, 1848), under salinity conditions below 20. Ecosystem-level impacts are also discussed.The generalist diet of T. granifera may certainly contribute to its successful establishment. However, although competition for resources may take place under certain salinity conditions and if food is limiting, there appear to be other mechanisms at work, through which T. granifera displaces native gastropods. Complementary stable isotope and gut content analysis can provide helpful ecological insights, contributing to monitoring efforts and guiding further invasive species research

The Felix-trial. Double-blind randomization of interspinous implant or bony decompression for treatment of spinal stenosis related intermittent neurogenic claudication

Abstract. Background. Decompressive laminotomy is the standard surgical procedure in the treatment of patients with canal stenosis related intermittent neurogenic claudication. New techniques, such as interspinous process implants, claim a shorter hospital stay, less post-operative pain and equal long-term functional outcome. A comparative (cost-) effectiveness study has not been performed yet. This protocol describes the design of a randomized controlled trial (RCT) on (cost-) effectiveness of the use of interspinous process implants versus conventi