OpenStructure: a flexible software framework for computational structural biology

Motivation: Developers of new methods in computational structural biology are often hampered in their research by incompatible software tools and non-standardized data formats. To address this problem, we have developed OpenStructure as a modular open source platform to provide a powerful, yet flexible general working environment for structural bioinformatics. OpenStructure consists primarily of a set of libraries written in C++ with a cleanly designed application programmer interface. All functionality can be accessed directly in C++ or in a Python layer, meeting both the requirements for high efficiency and ease of use. Powerful selection queries and the notion of entity views to represent these selections greatly facilitate the development and implementation of algorithms on structural data. The modular integration of computational core methods with powerful visualization tools makes OpenStructure an ideal working and development environment. Several applications, such as the latest versions of IPLT and QMean, have been implemented based on OpenStructure—demonstrating its value for the development of next-generation structural biology algorithms. Availability: Source code licensed under the GNU lesser general public license and binaries for MacOS X, Linux and Windows are available for download at http://www.openstructure.org. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

OpenStructure: a flexible software framework for computational structural biology

Motivation: Developers of new methods in computational structural biology are often hampered in their research by incompatible software tools and non-standardized data formats. To address this problem, we have developed OpenStructure as a modular open source platform to provide a powerful, yet flexible general working environment for structural bioinformatics. OpenStructure consists primarily of a set of libraries written in C++ with a cleanly designed application programmer interface. All functionality can be accessed directly in C++ or in a Python layer, meeting both the requirements for high efficiency and ease of use. Powerful selection queries and the notion of entity views to represent these selections greatly facilitate the development and implementation of algorithms on structural data. The modular integration of computational core methods with powerful visualization tools makes OpenStructure an ideal working and development environment. Several applications, such as the latest versions of IPLT and QMean, have been implemented based on OpenStructure—demonstrating its value for the development of next-generation structural biology algorithms

Anabolic and catabolic responses of human articular chondrocytes to varying oxygen percentages

Oxygen is a critical parameter proposed to modulate the functions of chondrocytes ex-vivo as well as in damaged joints. This article investigates the effect of low (more physiological) oxygen percentage on the biosynthetic and catabolic activity of human articular chondrocytes (HAC) at different phases of in vitro culture

Gauge-invariant Green's functions for the bosonic sector of the standard model

There are many applications in gauge theories where the usually employed framework involving gauge-dependent Green's functions leads to considerable problems. In order to overcome the difficulties invariably tied to gauge dependence, we present a manifestly gauge-invariant approach. We propose a generating functional of appropriately chosen gauge-invariant Green's functions for the bosonic sector of the standard model. Since the corresponding external sources emit one-particle states, these functions yield the same S-matrix elements as those obtained in the usual framework. We evaluate the generating functional for the bosonic sector of the standard model up to the one-loop level and carry out its renormalization in the on-shell scheme. Explicit results for some two-point functions are given. Gauge invariance is manifest at any step of our calculation.Comment: 29 pages, Revtex. v2: Discussions improved, conclusions unchanged. Some references added. v3: Published versio

Proximity to Sports Facilities and Sports Participation for Adolescents in Germany

Objectives - To assess the relationship between proximity to specific sports facilities and participation in the corresponding sports activities for adolescents in Germany. Methods - A sample of 1,768 adolescents aged 11–17 years old and living in 161 German communities was examined. Distances to the nearest sports facilities were calculated as an indicator of proximity to sports facilities using Geographic Information Systems (GIS). Participation in specific leisure-time sports activities in sports clubs was assessed using a self-report questionnaire and individual-level socio-demographic variables were derived from a parent questionnaire. Community-level socio-demographics as covariates were selected from the INKAR database, in particular from indicators and maps on land development. Logistic regression analyses were conducted to examine associations between proximity to the nearest sports facilities and participation in the corresponding sports activities. Results - The logisitic regression analyses showed that girls residing longer distances from the nearest gym were less likely to engage in indoor sports activities; a significant interaction between distances to gyms and level of urbanization was identified. Decomposition of the interaction term showed that for adolescent girls living in rural areas participation in indoor sports activities was positively associated with gym proximity. Proximity to tennis courts and indoor pools was not associated with participation in tennis or water sports, respectively. Conclusions - Improved proximity to gyms is likely to be more important for female adolescents living in rural areas

The electroweak chiral Lagrangian reanalyzed

In this paper we reanalyze the electroweak chiral Lagrangian with particular focus on two issues related to gauge invariance. Our analysis is based on a manifestly gauge-invariant approach that we introduced recently. It deals with gauge-invariant Green's functions and provides a method to evaluate the corresponding generating functional without fixing the gauge. First we show, for the case where no fermions are included in the effective Lagrangian, that the set of low-energy constants currently used in the literature is redundant. In particular, by employing the equations of motion for the gauge fields one can choose to remove two low-energy constants which contribute to the self-energies of the gauge bosons. If fermions are included in the effective field theory analysis the situation is more involved. Even in this case, however, these contributions to the self-energies of the gauge bosons can be removed. The relation of this result to the experimentally determined values for the oblique parameters S, T, and U is discussed. In the second part of the paper we consider the matching relation between a full and an effective theory. We show how the low-energy constants of the effective Lagrangian can be determined by matching gauge-invariant Green's functions in both theories. As an application we explicitly evaluate the low-energy constants for the standard model with a heavy Higgs boson. The matching at the one-loop level and at next-to-leading order in the low-energy expansion is performed employing functional methods.Comment: 44 pages, Revtex. v2: Sections II and III interchanged. New section II now self-contained. Discussions improved in sections I, II, V.C and VI. Conclusions unchanged. Published versio

Structural Basis of BRCC36 Function in DNA Repair and Immune Regulation

In mammals, ∼100 deubiquitinases act on ∼20,000 intracellular ubiquitination sites. Deubiquitinases are commonly regarded as constitutively active, with limited regulatory and targeting capacity. The BRCA1-A and BRISC complexes serve in DNA double-strand break repair and immune signaling and contain the lysine-63 linkage-specific BRCC36 subunit that is functionalized by scaffold subunits ABRAXAS and ABRO1, respectively. The molecular basis underlying BRCA1-A and BRISC function is currently unknown. Here we show that in the BRCA1-A complex structure, ABRAXAS integrates the DNA repair protein RAP80 and provides a high-affinity binding site that sequesters the tumor suppressor BRCA1 away from the break site. In the BRISC structure, ABRO1 binds SHMT2α, a metabolic enzyme enabling cancer growth in hypoxic environments, which we find prevents BRCC36 from binding and cleaving ubiquitin chains. Our work explains modularity in the BRCC36 DUB family, with different adaptor subunits conferring diversified targeting and regulatory functions.ISSN:1097-2765ISSN:1097-416

Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia

Background: Until today, adult and pediatric clinical trials investigating single-agent or combinatorial HDAC inhibitors including vorinostat in solid tumors have largely failed to demonstrate efficacy. These results may in part be explained by data from preclinical models showing significant activity only at higher concentrations compared to those achieved with current dosing regimens. In the current pediatric trial, we applied an intra-patient dose escalation design. The purpose of this trial was to determine a safe dose recommendation (SDR) of single-agent vorinostat for intra-patient dose escalation, pharmacokinetic analyses (PK), and activity evaluation in children (3-18 years) with relapsed or therapy-refractory malignancies. Results: A phase I intra-patient dose (de)escalation was performed until individual maximum tolerated dose (MTD). The starting dose was 180 mg/m(2)/day with weekly dose escalations of 50 mg/m(2) until DLT/maximum dose. After MTD determination, patients seamlessly continued in phase II with disease assessments every 3 months. PK and plasma cytokine profiles were determined. Fifty of 52 patients received treatment. n = 27/50 (54%) completed the intra-patient (de)escalation and entered phase II. An SDR of 130 mg/m(2)/day was determined (maximum, 580 mg/m(2)/day). n = 46/50 (92%) patients experienced treatment-related AEs which were mostly reversible and included thrombocytopenia, fatigue, nausea, diarrhea, anemia, and vomiting. n = 6/50 (12%) had treatment-related SAEs. No treatment-related deaths occurred. Higher dose levels resulted in higher C-max. Five patients achieved prolonged disease control (> 12 months) and showed a higher C-max (> 270 ng/mL) and MTDs. Best overall response (combining PR and SD, no CR observed) rate in phase II was 6/27 (22%) with a median PFS and OS of 5.3 and 22.4 months. Low levels of baseline cytokine expression were significantly correlated with favorable outcome. Conclusion: An SDR of 130 mg/m(2)/day for individual dose escalation was determined. Higher drug exposure was associated with responses and long-term disease stabilization with manageable toxicity. Patients with low expression of plasma cytokine levels at baseline were able to tolerate higher doses of vorinostat and benefited from treatment. Baseline cytokine profile is a promising potential predictive biomarker

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Gene set enrichment analysis and expression pattern exploration implicate an involvement of neurodevelopmental processes in bipolar disorder

Bipolar disorder (BD) is a common and highly heritable disorder of mood. Genome-wide association studies (GWAS) have identified several independent susceptibility loci. In order to extract more biological information from GWAS data, multi-locus approaches represent powerful tools since they utilize knowledge about biological processes to integrate functional sets of genes at strongly to moderately associated loci.We conducted gene set enrichment analyses (GSEA) using 2.3 million single-nucleotide polymorphisms, 397 Reactome pathways and 24,025 patients with BD and controls. RNA expression of implicated individual genes and gene sets were examined in post-mortem brains across lifespan.Two pathways showed a significant enrichment after correction for multiple comparisons in the GSEA: GRB2 events in ERBB2 signaling, for which 6 of 21 genes were BD associated (PFDR = 0.0377), and NCAM signaling for neurite out-growth, for which 11 out of 62 genes were BD associated (PFDR = 0.0451). Most pathway genes showed peaks of RNA co-expression during fetal development and infancy and mapped to neocortical areas and parts of the limbic system.Pathway associations were technically reproduced by two methods, although they were not formally replicated in independent samples. Gene expression was explored in controls but not in patients.Pathway analysis in large GWAS data of BD and follow-up of gene expression patterns in healthy brains provide support for an involvement of neurodevelopmental processes in the etiology of this neuropsychiatric disease. Future studies are required to further evaluate the relevance of the implicated genes on pathway functioning and clinical aspects of BD