INTEGRATOR: interactive graphical search of large protein interactomes over the Web

BACKGROUND: The rapid growth of protein interactome data has elevated the necessity and importance of network analysis tools. However, unlike pure text data, network search spaces are of exponential complexity. This poses special challenges for storing, searching, and navigating this data efficiently. Moreover, development of effective web interfaces has been difficult. RESULTS: We present Integrator, a web-integrated graphical search tool for protein-protein interaction networks across 50+ genomes. CONCLUSION: Integrator provides single and multiple protein searches of the Bioverse database containing experimentally-derived and predicted protein-protein interactions. The interface provides animated local network views, rapid subgraph manipulation, and cross-referencing of functional annotations. Integrator is available at

BIOVERSE: enhancements to the framework for structural, functional and contextual modeling of proteins and proteomes

We have made a number of enhancements to the previously described Bioverse web server and computational biology framework (). In this update, we provide an overview of the new features available that include: (i) expansion of the number of organisms represented in the Bioverse and addition of new data sources and novel prediction techniques not available elsewhere, including network-based annotation; (ii) reengineering the database backend and supporting code resulting in significant speed, search and ease-of use improvements; and (iii) creation of a stateful and dynamic web application frontend to improve interface speed and usability. Integrated Java-based applications also allow dynamic visualization of real and predicted protein interaction networks

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40-60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions

Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition.

The epithelial-mesenchymal transition (EMT) endows carcinoma cells with phenotypic plasticity that can facilitate the formation of cancer stem cells (CSCs) and contribute to the metastatic cascade. While there is substantial support for the role of EMT in driving cancer cell dissemination, less is known about the intracellular molecular mechanisms that govern formation of CSCs via EMT. Here we show that β2 and β5 proteasome subunit activity is downregulated during EMT in immortalized human mammary epithelial cells. Moreover, selective proteasome inhibition enabled mammary epithelial cells to acquire certain morphologic and functional characteristics reminiscent of cancer stem cells, including CD44 expression, self-renewal, and tumor formation. Transcriptomic analyses suggested that proteasome-inhibited cells share gene expression signatures with cells that have undergone EMT, in part, through modulation of the TGF-β signaling pathway. These findings suggest that selective downregulation of proteasome activity in mammary epithelial cells can initiate the EMT program and acquisition of a cancer stem cell-like phenotype. As proteasome inhibitors become increasingly used in cancer treatment, our findings highlight a potential risk of these therapeutic strategies and suggest a possible mechanism by which carcinoma cells may escape from proteasome inhibitor-based therapy

Targeting p53 via JNK Pathway: A Novel Role of RITA for Apoptotic Signaling in Multiple Myeloma

The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK activators in the treatment of MM

Manganese catalysed dehydrogenative synthesis of polyureas from diformamide and diamines

Authors acknowledge the funding from UKRI Future Leaders Fellowship (MR/W007460/1). M.T. and J.C.T. thank the ERC Consolidator Grant (PROMOFS grant agreement 771575) for funding the research. ABN gratefully acknowledges funding from the EPSRC through grant numbers EP/L017008/1, EP/R023751/1 and EP/T019298/1.We report here the synthesis of polyureas from the dehydrogenative coupling of diamines and diformamides. The reaction is catalysed by a manganese pincer complex and releases H2 gas as the only by-product making the process atom-economic and sustainable. The reported method is greener in comparison to the current state-of-the-art production routes that involve diisocyanate and phosgene feedstock. We also report here the physical, morphological, and mechanical properties of synthesized polyureas. Based on our mechanistic studies, we suggest that the reaction proceeds via isocyanate intermediates formed by the manganese catalysed dehydrogenation of formamides.Publisher PDFPeer reviewe

The Wikipedia Gender Gap Revisited: Characterizing Survey Response Bias with Propensity Score Estimation

Opt-in surveys are the most widespread method used to study participation in online communities, but produce biased results in the absence of adjustments for non-response. A 2008 survey conducted by the Wikimedia Foundation and United Nations University at Maastricht is the source of a frequently cited statistic that less than 13% of Wikipedia contributors are female. However, the same study suggested that only 39.9% of Wikipedia readers in the US were female – a finding contradicted by a representative survey of American adults by the Pew Research Center conducted less than two months later. Combining these two datasets through an application and extension of a propensity score estimation technique used to model survey non-response bias, we construct revised estimates, contingent on explicit assumptions, for several of the Wikimedia Foundation and United Nations University at Maastricht claims about Wikipedia editors. We estimate that the proportion of female US adult editors was 27.5% higher than the original study reported (22.7%, versus 17.8%), and that the total proportion of female editors was 26.8% higher (16.1%, versus 12.7%).Sloan School of ManagementHarvard University. Berkman Center for Internet & SocietyFord Visionary Leadership FundNorthwestern University (Evanston, Ill.

Critical change in the Fermi surface of iron arsenic superconductors at the onset of superconductivity

The phase diagram of a correlated material is the result of a complex interplay between several degrees of freedom, providing a map of the material's behavior. One can understand (and ultimately control) the material's ground state by associating features and regions of the phase diagram, with specific physical events or underlying quantum mechanical properties. The phase diagram of the newly discovered iron arsenic high temperature superconductors is particularly rich and interesting. In the AE(Fe1-xTx)2As2 class (AE being Ca, Sr, Ba, T being transition metals), the simultaneous structural/magnetic phase transition that occurs at elevated temperature in the undoped material, splits and is suppressed by carrier doping, the suppression being complete around optimal doping. A dome of superconductivity exists with apparent equal ease in the orthorhombic / antiferromagnetic (AFM) state as well as in the tetragonal state with no long range magnetic order. The question then is what determines the critical doping at which superconductivity emerges, if the AFM order is fully suppressed only at higher doping values. Here we report evidence from angle resolved photoemission spectroscopy (ARPES) that critical changes in the Fermi surface (FS) occur at the doping level that marks the onset of superconductivity. The presence of the AFM order leads to a reconstruction of the electronic structure, most significantly the appearance of the small hole pockets at the Fermi level. These hole pockets vanish, i. e. undergo a Lifshitz transition, at the onset of superconductivity. Superconductivity and magnetism are competing states in the iron arsenic superconductors. In the presence of the hole pockets superconductivity is fully suppressed, while in their absence the two states can coexist.Comment: Updated version accepted in Nature Physic

Top Quarks and Electroweak Symmetry Breaking in Little Higgs Models

`Little Higgs' models, in which the Higgs particle arises as a pseudo-Goldstone boson, have a natural mechanism of electroweak symmetry breaking associated with the large value of the top quark Yukawa coupling. The mechanism typically involves a new heavy SU(2)_{L} singlet top quark, T. We discuss the relationship of the Higgs boson and the two top quarks. We suggest experimental tests of the Little Higgs mechanism of electroweak symmetry breaking using the production and decay of the T at the Large Hadron Collider.Comment: 28 pages, 6 figures; new ST fits (Fig. 3,4

First Principles Assessment of CdTe as a Tunnel Barrier at the α\mathbf{\alpha}-Sn/InSb Interface

Majorana zero modes, with prospective applications in topological quantum computing, are expected to arise in superconductor/semiconductor interfaces, such as $\beta$-Sn and InSb. However, proximity to the superconductor may also adversely affect the semiconductor's local properties. A tunnel barrier inserted at the interface could resolve this issue. We assess the wide band gap semiconductor, CdTe, as a candidate material to mediate the coupling at the lattice-matched interface between $\alpha$-Sn and InSb. To this end, we use density functional theory (DFT) with Hubbard U corrections, whose values are machine-learned via Bayesian optimization (BO) [npj Computational Materials 6, 180 (2020)]. The results of DFT+U(BO) are validated against angle resolved photoemission spectroscopy (ARPES) experiments for $\alpha$-Sn and CdTe. For CdTe, the z-unfolding method [Advanced Quantum Technologies, 5, 2100033 (2022)] is used to resolve the contributions of different $k_z$ values to the ARPES. We then study the band offsets and the penetration depth of metal-induced gap states (MIGS) in bilayer interfaces of InSb/$\alpha$-Sn, InSb/CdTe, and CdTe/$\alpha$-Sn, as well as in tri-layer interfaces of InSb/CdTe/$\alpha$-Sn with increasing thickness of CdTe. We find that 16 atomic layers (3.5 nm) of CdTe can serve as a tunnel barrier, effectively shielding the InSb from MIGS from the $\alpha$-Sn. This may guide the choice of dimensions of the CdTe barrier to mediate the coupling in semiconductor-superconductor devices in future Majorana zero modes experiments