Constructing a robust protein-protein interaction network by integrating multiple public databases

<p>Abstract</p> <p>Background</p> <p>Protein-protein interactions (PPIs) are a critical component for many underlying biological processes. A PPI network can provide insight into the mechanisms of these processes, as well as the relationships among different proteins and toxicants that are potentially involved in the processes. There are many PPI databases publicly available, each with a specific focus. The challenge is how to effectively combine their contents to generate a robust and biologically relevant PPI network.</p> <p>Methods</p> <p>In this study, seven public PPI databases, BioGRID, DIP, HPRD, IntAct, MINT, REACTOME, and SPIKE, were used to explore a powerful approach to combine multiple PPI databases for an integrated PPI network. We developed a novel method called <it>k</it>-votes to create seven different integrated networks by using values of <it>k</it> ranging from 1-7. Functional modules were mined by using SCAN, a Structural Clustering Algorithm for Networks. Overall module qualities were evaluated for each integrated network using the following statistical and biological measures: (1) modularity, (2) similarity-based modularity, (3) clustering score, and (4) enrichment.</p> <p>Results</p> <p>Each integrated human PPI network was constructed based on the number of votes (<it>k</it>) for a particular interaction from the committee of the original seven PPI databases. The performance of functional modules obtained by SCAN from each integrated network was evaluated. The optimal value for <it>k</it> was determined by the functional module analysis. Our results demonstrate that the <it>k</it>-votes method outperforms the traditional union approach in terms of both statistical significance and biological meaning. The best network is achieved at <it>k</it>=2, which is composed of interactions that are confirmed in at least two PPI databases. In contrast, the traditional union approach yields an integrated network that consists of all interactions of seven PPI databases, which might be subject to high false positives.</p> <p>Conclusions</p> <p>We determined that the k-votes method for constructing a robust PPI network by integrating multiple public databases outperforms previously reported approaches and that a value of k=2 provides the best results. The developed strategies for combining databases show promise in the advancement of network construction and modeling.</p

Disentangling Cooper-pair formation above Tc from the pseudogap state in the cuprates

The discovery of the pseudogap in the cuprates created significant excitement amongst physicists as it was believed to be a signature of pairing, in some cases well above the room temperature. In this "pre-formed pairs" scenario, the formation of pairs without quantum phase rigidity occurs below T*. These pairs condense and develop phase coherence only below Tc. In contrast, several recent experiments reported that the pseudogap and superconducting states are characterized by two different energy scales, pointing to a scenario, where the two compete. However a number of transport, magnetic, thermodynamic and tunneling spectroscopy experiments consistently detect a signature of phase-fluctuating superconductivity above leaving open the question of whether the pseudogap is caused by pair formation or not. Here we report the discovery of a spectroscopic signature of pair formation and demonstrate that in a region of the phase diagram commonly referred to as the "pseudogap", two distinct states coexist: one that persists to an intermediate temperature Tpair and a second that extends up to T*. The first state is characterized by a doping independent scaling behavior and is due to pairing above Tc, but significantly below T*. The second state is the "proper" pseudogap - characterized by a "checker board" pattern in STM images, the absence of pair formation, and is likely linked to Mott physics of pristine CuO2 planes. Tpair has a universal value around 130-150K even for materials with very different Tc, likely setting limit on highest, attainable Tc in cuprates. The observed universal scaling behavior with respect to Tpair indicates a breakdown of the classical picture of phase fluctuations in the cuprates.Comment: 9 pages, 4 figure

(pi,pi)-electronic order in iron arsenide superconductors

The distribution of valence electrons in metals usually follows the symmetry of an ionic lattice. Modulations of this distribution often occur when those electrons are not stable with respect to a new electronic order, such as spin or charge density waves. Electron density waves have been observed in many families of superconductors[1-3], and are often considered to be essential for superconductivity to exist[4]. Recent measurements[5-9] seem to show that the properties of the iron pnictides[10, 11] are in good agreement with band structure calculations that do not include additional ordering, implying no relation between density waves and superconductivity in those materials[12-15]. Here we report that the electronic structure of Ba1-xKxFe2As2 is in sharp disagreement with those band structure calculations[12-15], instead revealing a reconstruction characterized by a (pi,pi) wave vector. This electronic order coexists with superconductivity and persists up to room temperature

Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.

The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported. Here we report on the identification of a novel PALB2 variant, c.104T>C (p.L35P), that segregates in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2-BRCA1 interaction and completely disables its abilities to promote HR and confer resistance to platinum salts and PARP inhibitors. Whole-exome sequencing of a breast cancer from a c.104T>C carrier revealed a second, somatic, truncating mutation affecting PALB2, and the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects, cementing the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish L35P as the first pathogenic missense mutation in PALB2 and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression

Integration of decision support systems to improve decision support performance

Decision support system (DSS) is a well-established research and development area. Traditional isolated, stand-alone DSS has been recently facing new challenges. In order to improve the performance of DSS to meet the challenges, research has been actively carried out to develop integrated decision support systems (IDSS). This paper reviews the current research efforts with regard to the development of IDSS. The focus of the paper is on the integration aspect for IDSS through multiple perspectives, and the technologies that support this integration. More than 100 papers and software systems are discussed. Current research efforts and the development status of IDSS are explained, compared and classified. In addition, future trends and challenges in integration are outlined. The paper concludes that by addressing integration, better support will be provided to decision makers, with the expectation of both better decisions and improved decision making processes

Direct evidence for a competition between the pseudogap and high temperature superconductivity in the cuprates

A pairing gap and coherence are the two hallmarks of superconductivity. In a classical BCS superconductor they are established simultaneously at Tc. In the cuprates, however, an energy gap (pseudogap) extends above Tc. The origin of this gap is one of the central issues in high temperature superconductivity. Recent experimental evidence demonstrates that the pseudogap and the superconducting gap are associated with different energy scales. It is however not clear whether they coexist independently or compete. In order to understand the physics of cuprates and improve their superconducting properties it is vital to determine whether the pseudogap is friend or foe of high temperature supercondctivity. Here we report evidence from angle resolved photoemission spectroscopy (ARPES) that the pseudogap and high temperature superconductivity represent two competing orders. We find that there is a direct correlation between a loss in the low energy spectral weight due to the pseudogap and a decrease of the coherent fraction of paired electrons. Therefore, the pseudogap competes with the superconductivity by depleting the spectral weight available for pairing in the region of momentum space where the superconducting gap is largest. This leads to a very unusual state in the underdoped cuprates, where only part of the Fermi surface develops coherence.Comment: Improved version was published in Natur

Progress and prospects of thermo-mechanical energy storage-a critical review

Abstract The share of electricity generated by intermittent renewable energy sources is increasing (now at 26% of global electricity generation) and the requirements of affordable, reliable and secure energy supply designate grid-scale storage as an imperative component of most energy transition pathways. The most widely deployed bulk energy storage solution is pumped-hydro energy storage (PHES), however, this technology is geographically constrained. Alternatively, flow batteries are location independent and have higher energy densities than PHES, but remain associated with high costs and short lifetimes, which highlights the importance of developing and utilizing additional larger-scale, longer-duration and long-lifetime energy storage alternatives. In this paper, we review a class of promising bulk energy storage technologies based on thermo-mechanical principles, which includes: compressed-air energy storage, liquid-air energy storage and pumped-thermal electricity storage. The thermodynamic principles upon which these thermo-mechanical energy storage (TMES) technologies are based are discussed and a synopsis of recent progress in their development is presented, assessing their ability to provide reliable and cost-effective solutions. The current performance and future prospects of TMES systems are examined within a unified framework and a thermo-economic analysis is conducted to explore their competitiveness relative to each other as well as when compared to PHES and battery systems. This includes carefully selected thermodynamic and economic methodologies for estimating the component costs of each configuration in order to provide a detailed and fair comparison at various system sizes. The analysis reveals that the technical and economic characteristics of TMES systems are such that, especially at higher discharge power ratings and longer discharge durations, they can offer promising performance (round-trip efficiencies higher than 60%) along with long lifetimes (&gt;30 years), low specific costs (often below 100 $ kWh−1), low ecological footprints and unique sector-coupling features compared to other storage options. TMES systems have significant potential for further progress and the thermo-economic comparisons in this paper can be used as a benchmark for their future evolution.</jats:p

Clinical, Virological and Immunological Features from Patients Infected with Re-Emergent Avian-Origin Human H7N9 Influenza Disease of Varying Severity in Guangdong Province

The second wave of avian influenza H7N9 virus outbreak in humans spread to the Guangdong province of China by August of 2013 and this virus is now endemic in poultry in this region.Background The second wave of avian influenza H7N9 virus outbreak in humans spread to the Guangdong province of China by August of 2013 and this virus is now endemic in poultry in this region. Methods Five patients with H7N9 virus infection admitted to our hospital during August 2013 to February 2014 were intensively investigated. Viral load in the respiratory tract was determined by quantitative polymerase chain reaction (Q-PCR) and cytokine levels were measured by bead-based flow cytometery. Results Four patients survived and one died. Viral load in different clinical specimens was correlated with cytokine levels in plasma and broncho-alveolar fluid (BALF), therapeutic modalities used and clinical outcome. Intravenous zanamivir appeared to be better than peramivir as salvage therapy in patients who failed to respond to oseltamivir. Higher and more prolonged viral load was found in the sputum or endotracheal aspirates compared to throat swabs. Upregulation of proinflammatory cytokines IP-10, MCP-1, MIG, MIP-1α/β, IL-1β and IL-8 was found in the plasma and BALF samples. The levels of cytokines in the plasma and viral load were correlated with disease severity. Reactivation of herpes simplex virus type 1(HSV-1) was found in three out of five patients (60%). Conclusion Expectorated sputum or endotracheal aspirate specimens are preferable to throat swabs for detecting and monitoring H7N9 virus. Severity of the disease was correlated to the viral load in the respiratory tract as well as the extents of cytokinemia. Reactivation of HSV-1 may contribute to clinical outcome.published_or_final_versio

Structure of hadron resonances with a nearby zero of the amplitude

We discuss the relation between the analytic structure of the scattering amplitude and the origin of an eigenstate represented by a pole of the amplitude.If the eigenstate is not dynamically generated by the interaction in the channel of interest, the residue of the pole vanishes in the zero coupling limit. Based on the topological nature of the phase of the scattering amplitude, we show that the pole must encounter with the Castillejo-Dalitz-Dyson (CDD) zero in this limit. It is concluded that the dynamical component of the eigenstate is small if a CDD zero exists near the eigenstate pole. We show that the line shape of the resonance is distorted from the Breit-Wigner form as an observable consequence of the nearby CDD zero. Finally, studying the positions of poles and CDD zeros of the KbarN-piSigma amplitude, we discuss the origin of the eigenstates in the Lambda(1405) region.Comment: 7 pages, 3 figures, v2: published versio

Activation of DNA-PK by Ionizing Radiation Is Mediated by Protein Phosphatase 6

DNA-dependent protein kinase (DNA-PK) plays a critical role in DNA damage repair, especially in non-homologous end-joining repair of double-strand breaks such as those formed by ionizing radiation (IR) in the course of radiation therapy. Regulation of DNA-PK involves multisite phosphorylation but this is incompletely understood and little is known about protein phosphatases relative to DNA-PK. Mass spectrometry analysis revealed that DNA-PK interacts with the protein phosphatase-6 (PP6) SAPS subunit PP6R1. PP6 is a heterotrimeric enzyme that consists of a catalytic subunit, plus one of three PP6 SAPS regulatory subunits and one of three ankyrin repeat subunits. Endogenous PP6R1 co-immunoprecipitated DNA-PK, and IR enhanced the amount of complex and promoted its import into the nucleus. In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation. Knockdown of other phosphatases PP5 or PP1γ1 and subunits PP6R3 or ARS-A did not reduce IR activation of DNA-PK, demonstrating specificity for PP6R1. Finally, siRNA knockdown of PP6R1 or PP6 but not other phosphatases increased the sensitivity of glioblastoma cells to radiation-induced cell death to a level similar to DNA-PK deficient cells. Our data demonstrate that PP6 associates with and activates DNA-PK in response to ionizing radiation. Therefore, the PP6/PP6R1 phosphatase is a potential molecular target for radiation sensitization by chemical inhibition