Miracle-dz/UniFAR-FTUs huggingface dataset:
Key Structures and Interactions for Binding of Mycobacterium tuberculosis Protein Kinase B Inhibitors from Molecular Dynamics Simulation

Substituted aminopyrimidine inhibitors have recently been introduced as antituberculosis agents. These inhibitors show impressive activity against protein kinase B, a Ser/Thr protein kinase that is essential for cell growth of M. tuberculosis. However, up to now, X‐ray structures of the protein kinase B enzyme complexes with the substituted aminopyrimidine inhibitors are currently unavailable. Consequently, structural details of their binding modes are questionable, prohibiting the structural‐based design of more potent protein kinase B inhibitors in the future. Here, molecular dynamics simulations, in conjunction with molecular mechanics/Poisson–Boltzmann surface area binding free‐energy analysis, were employed to gain insight into the complex structures of the protein kinase B inhibitors and their binding energetics. The complex structures obtained by the molecular dynamics simulations show binding free energies in good agreement with experiment. The detailed analysis of molecular dynamics results shows that Glu93, Val95, and Leu17 are key residues responsible to the binding of the protein kinase B inhibitors. The aminopyrazole group and the pyrimidine core are the crucial moieties of substituted aminopyrimidine inhibitors for interaction with the key residues. Our results provide a structural concept that can be used as a guide for the future design of protein kinase B inhibitors with highly increased antagonistic activity.
Restricted update sequential matrix diagonalisation for parahermitian matrices

A number of algorithms capable of iteratively calculating a polynomial matrix eigenvalue decomposition (PEVD) have been introduced. The PEVD is an extension of the ordinary EVD to polynomial matrices and will diagonalise a parahermitian matrix using paraunitary operations. This paper introduces a novel restricted update approach for the sequential matrix diagonalisation (SMD) PEVD algorithm, which can be implemented with minimal impact on algorithm accuracy and convergence. We demonstrate that by using the proposed restricted update SMD (RU-SMD) algorithm instead of SMD, PEVD complexity and execution time can be significantly reduced. This reduction impacts on a number of broadband multichannel problems.
Chemotherapeutics and Radiation Stimulate MHC Class I Expression through Elevated Interferon-beta Signaling in Breast Cancer Cells

Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT), a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I) expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β) and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1) or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine) similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through T cell cytotoxicity during metronomic chemotherapy, as well as increased efficacy of combined chemo- (or radio-)/immuno-therapy.
Heat Shock Factor 1 Is a Substrate for p38 Mitogen-Activated Protein Kinases

ABSTRACT Heat shock factor 1 (HSF1) monitors the structural integrity of the proteome. Phosphorylation at S326 is a hallmark for HSF1 activation, but the identity of the kinase(s) phosphorylating this site has remained elusive. We show here that the dietary agent phenethyl isothiocyanate (PEITC) inhibits heat shock protein 90 (Hsp90), the main negative regulator of HSF1; activates p38 mitogen-activated protein kinase (MAPK); and increases S326 phosphorylation, trimerization, and nuclear translocation of HSF1, and the transcription of a luciferase reporter, as well as the endogenous prototypic HSF1 target Hsp70. In vitro, all members of the p38 MAPK family rapidly and stoichiometrically catalyze the S326 phosphorylation. The use of stable knockdown cell lines and inhibitors indicated that among the p38 MAPKs, p38γ is the principal isoform responsible for the phosphorylation of HSF1 at S326 in cells. A protease-mass spectrometry approach confirmed S326 phosphorylation and unexpectedly revealed that p38 MAPK also catalyzes the phosphorylation of HSF1 at S303/307, previously known repressive posttranslational modifications. Thus, we have identified p38 MAPKs as highly efficient catalysts for the phosphorylation of HSF1. Furthermore, our findings suggest that the magnitude and persistence of activation of p38 MAPK are important determinants of the extent and duration of the heat shock response.
LARP1 functions as a molecular switch for mTORC1-mediated translation of an essential class of mRNAs

The RNA binding protein, LARP1, has been proposed to function downstream of mTORC1 to regulate the translation of 5’TOP mRNAs such as those encoding ribosome proteins (RP). However, the roles of LARP1 in the translation of 5’TOP mRNAs are controversial and its regulatory roles in mTORC1-mediated translation remain unclear. Here we show that LARP1 is a direct substrate of mTORC1 and Akt/S6K1. Deep sequencing of LARP1-bound mRNAs reveal that non-phosphorylated LARP1 interacts with both 5’ and 3’UTRs of RP mRNAs and inhibits their translation. Importantly, phosphorylation of LARP1 by mTORC1 and Akt/S6K1 dissociates it from 5’UTRs and relieves its inhibitory activity on RP mRNA translation. Concomitantly, phosphorylated LARP1 scaffolds mTORC1 on the 3’UTRs of translationally-competent RP mRNAs to facilitate mTORC1-dependent induction of translation initiation. Thus, in response to cellular mTOR activity, LARP1 serves as a phosphorylation-sensitive molecular switch for turning off or on RP mRNA translation and subsequent ribosome biogenesis. DOI: http://dx.doi. org/10.7554/eLife.25237. 001
Association Between 30-Day Episode Payments and Acute Myocardial Infarction Outcomes Among Medicare Beneficiaries

Background: Recent policy efforts have focused on improving the value of acute myocardial infarction (AMI) care. Medicare payment programs, for example, increasingly evaluate hospital performance based on spending, as determined by payments made to institutions and providers, and outcome measures for a longitudinal episode of AMI care. Little is known about the relationship between total 30-day payments—both in the inpatient and immediate postdischarge timeframe—and outcomes after an admission for AMI. Methods and Results: Using Medicare claims data, we identified Medicare fee-for-service beneficiaries ≥65 years of age who were hospitalized at an acute-care hospital for AMI between July 1, 2011, and June 30, 2014, and examined the association between hospital-level 30-day payments for an episode of AMI care and patient 30-day mortality using mixed regression models with a logit link function and random hospital intercepts. Our cohort included 642 105 index hospitalizations for AMI at 2319 acute-care hospitals. Overall mean 30-day episode payments per beneficiary were $22 128 (SD, $1750). The observed 30-day mortality rate was 12.9%. Higher 30-day payments were associated with lower 30-day mortality after adjustment for patient characteristics and comorbidities (adjusted odds ratio for additional $1000 payments, 0.986; 95% confidence interval, 0.979–0.992; P<0.001). Additional adjustment for potential mediating factors, including hospital characteristics, coronary revascularization rates, and discharge disposition, did not significantly attenuate the relationship (adjusted odds ratio for additional $1000 payments, 0.987; 95% confidence interval, 0.980–0.994; P<0.001). Conclusions: Higher hospital-level 30-day payments—both inpatient and in multiple settings after discharge—for AMI care were associated with lower 30-day mortality among beneficiaries. This may have implications for payment programs that incent reduction in payments without considering value.
Osteoarthritic human chondrocytes proliferate in 3D co‐culture with mesenchymal stem cells in suspension bioreactors

Osteoarthritis (OA) is a painful disease, characterized by progressive surface erosion of articular cartilage. The use of human articular chondrocytes (hACs) sourced from OA patients has been proposed as a potential therapy for cartilage repair, but this approach is limited by the lack of scalable methods to produce clinically relevant quantities of cartilage‐generating cells. Previous studies in static culture have shown that hACs co‐cultured with human mesenchymal stem cells (hMSCs) as 3D pellets can upregulate proliferation and generate neocartilage with enhanced functional matrix formation relative to that produced from either cell type alone. However, because static culture flasks are not readily amenable to scale up, scalable suspension bioreactors were investigated to determine if they could support the co‐culture of hMSCs and OA hACs under serum‐free conditions to facilitate clinical translation of this approach. When hACs and hMSCs (1:3 ratio) were inoculated at 20,000 cells/ml into 125‐ml suspension bioreactors and fed weekly, they spontaneously formed 3D aggregates and proliferated, resulting in a 4.75‐fold increase over 16 days. Whereas the apparent growth rate was lower than that achieved during co‐culture as a 2D monolayer in static culture flasks, bioreactor co‐culture as 3D aggregates resulted in a significantly lower collagen I to II mRNA expression ratio and more than double the glycosaminoglycan/DNA content (5.8 vs. 2.5 μg/μg). The proliferation of hMSCs and hACs as 3D aggregates in serum‐free suspension culture demonstrates that scalable bioreactors represent an accessible platform capable of supporting the generation of clinical quantities of cells for use in cell‐based cartilage repair.
Conditional Activation for Diverse Neurons in Heterogeneous Networks

In this paper, we propose a new scheme for modelling the diverse behavior of neurons. We introduce the conditional activation, in which a neurons activation function is dynamically modified by a control signal. We apply this method to recreate behavior of special neurons existing in the human auditory and visual system. A heterogeneous multilayered perceptron (MLP) incorporating the developed models demonstrates simultaneous improvement in learning speed and performance across a various number of hidden units and layers, compared to a homogeneous network composed of the conventional neuron model. For similar performance, the proposed model lowers the memory for storing network parameters significantly.
Porcine Epidemic Diarrhea Virus 3C-Like Protease Regulates Its Interferon Antagonism by Cleaving NEMO

ABSTRACT Porcine epidemic diarrhea virus (PEDV) is an enteropathogenic coronavirus causing lethal watery diarrhea in piglets. Since 2010, a PEDV variant has spread rapidly in China, and it emerged in the United States in 2013, posing significant economic and public health concerns. The ability to circumvent the interferon (IFN) antiviral response, as suggested for PEDV, promotes viral survival and regulates pathogenesis of PEDV infections, but the underlying mechanisms remain obscure. Here, we show that PEDV-encoded 3C-like protease, nsp5, is an IFN antagonist that proteolytically cleaves the nuclear transcription factor kappa B (NF-κB) essential modulator (NEMO), an essential adaptor bridging interferon-regulatory factor and NF-κB activation. NEMO is cleaved at glutamine 231 (Q231) by PEDV, and this cleavage impaired the ability of NEMO to activate downstream IFN production and to act as a signaling adaptor of the RIG-I/MDA5 pathway. Mutations specifically disrupting the cysteine protease activity of PEDV nsp5 abrogated NEMO cleavage and the inhibition of IFN induction. Structural analysis suggests that several key residues outside the catalytic sites of PEDV nsp5 probably impact NEMO cleavage by modulating potential interactions of nsp5 with their substrates. These data show that PEDV nsp5 disrupts type I IFN signaling by cleaving NEMO. Previously, we and others demonstrated that NEMO is also cleaved by 3C or 3C-like proteinases of picornavirus and artertivirus. Thus, NEMO probably represents a prime target for 3C or 3C-like proteinases of different viruses. IMPORTANCE The continued emergence and reemergence of porcine epidemic diarrhea virus (PEDV) underscore the importance of studying how this virus manipulates the immune responses of its hosts. During coevolution with its hosts, PEDV has acquired mechanisms to subvert host innate immune responses for its survival advantage. At least two proteins encoded by PEDV have been identified as interferon (IFN) antagonists, papain-like protease (PLP) and N protein. Here, we report that the PEDV nsp5 gene, which encodes the 3C-like protease of PEDV, is another IFN antagonist. Mechanistically, the cysteine protease activity of PEDV nsp5 mediates proteolysis of NEMO, the key adaptor for IFN synthesis, and NEMO is cleaved at glutamine 231 (Q231). The new molecular details and determinants impacting NEMO scission by PEDV nsp5 delineated in this study are fundamental to our understanding of critical virus-host interactions that determine PEDV pathogenesis.
Sub-Category Optimization through Cluster Performance Analysis for Multi-View Multi-Pose Object Detection

The detection of object categories with large variations in appearance is a fundamental problem in computer vision. The appearance of object categories can change due to intra-class variations, background clutter, and changes in viewpoint and illumination. For object categories with large appearance changes, some kind of sub-categorization based approach is necessary. This paper proposes a sub-category optimization approach that automatically divides an object category into an appropriate number of sub-categories based on appearance variations. Instead of using predefined intra-category sub-categorization based on domain knowledge or validation datasets, we divide the sample space by unsupervised clustering using discriminative image features. We then use a cluster performance analysis (CPA) algorithm to verify the performance of the unsupervised approach. The CPA algorithm uses two performance metrics to determine the optimal number of sub-categories per object category. Furthermore, we employ the optimal sub-category representation as the basis and a supervised multi-category detection system with χ2 merging kernel function to efficiently detect and localize object categories within an image. Extensive experimental results are shown using a standard and the authors' own databases. The comparison results reveal that our approach outperforms the state-of-the-art methods.
Constructing Negative Links from Multi-facet of Social Media

Various types of social media make the people share their personal experience in different ways. In some social networking sites. Some users post their reviews, some users can support these reviews with comments, and some users just rate the reviews as kind of support or not. Unfortunately, there is rare explicit negative comments towards other reviews. This means if there is a link between two users, it must be positive link. Apparently, the negative link is invisible in these social network. Or in other word, the negative links are redundant to positive links. In this work, we first discuss the feature extraction from social media data and propose new method to compute the distance between each pair of comments or reviews on social media. Then we investigate whether we can predict negative links via regression analysis when only positive links are manifested from social media data. In particular, we provide a principled way to mathematically incorporate multi-facet data in a novel framework, C on s tructing N egative L inks, CsNL to predict negative links for discovering the hidden information. Additionally, we investigate the ways of solution to general negative link predication problems with CsNL and its extension. Experiments are performed on real-world data and results show that negative links is predictable with multi-facet of social media data by the proposed framework CsNL. Essentially, high prediction accuracy suggests that negative links are redundant to positive links. Further experiments are performed to evaluate coefficients on different kernels. The results show that user generated content dominates the prediction performance of CsNL.
Selenium-binding protein 1 is down-regulated in malignant melanoma

Selenium-binding protein 1 (SELENBP1) expression is reduced in various epithelial cancer entities compared to corresponding normal tissue and has already been described as a tumor suppressor involved in the regulation of cell proliferation, senescence, migration and apoptosis. We identified SELENBP1 to be down-regulated in cutaneous melanoma, a malignant cancer of pigment-producing melanocytes in the skin, which leads to the assumption that SELENBP1 also functions as tumor suppressor in the skin, as shown by others e.g. for prostate or lung carcinoma. However, in vitro analyses indicate that SELENBP1 re-expression in human melanoma cell lines has no impact on cell proliferation, migration or tube formation of the tumor cells themselves when compared to control-transfected cells. Interestingly, supernatant taken from melanoma cell lines transfected with a SELENBP1 re-expression plasmid led to suppression of vessel formation of HMEC cells. Furthermore, SELENBP1 re-expression alters the sensitivity of melanoma cells for Vemurafenib treatment. The data also hint to a functional interaction of SELENBP1 with GPX1 (Glutathione peroxidase 1). Low SELENBP1 mRNA levels correlate inversely with GPX1 expression in melanoma. The re-expression of SELENBP1 combined with down-regulation of GPX1 expression led to reduction of the proliferation of melanoma cells. In summary, SELENBP1 influences the tumor microenvironment and SELENBP1 action is functionally influenced by GPX1.
LMO2 Oncoprotein Stability in T-Cell Leukemia Requires Direct LDB1 Binding

ABSTRACT LMO2 is a component of multisubunit DNA-binding transcription factor complexes that regulate gene expression in hematopoietic stem and progenitor cell development. Enforced expression of LMO2 causes leukemia by inducing hematopoietic stem cell-like features in T-cell progenitor cells, but the biochemical mechanisms of LMO2 function have not been fully elucidated. In this study, we systematically dissected the LMO2/LDB1-binding interface to investigate the role of this interaction in T-cell leukemia. Alanine scanning mutagenesis of the LIM interaction domain of LDB1 revealed a discrete motif, R320LITR, required for LMO2 binding. Most strikingly, coexpression of full-length, wild-type LDB1 increased LMO2 steady-state abundance, whereas coexpression of mutant proteins deficient in LMO2 binding compromised LMO2 stability. These mutant LDB1 proteins also exerted dominant negative effects on growth and transcription in diverse leukemic cell lines. Mass spectrometric analysis of LDB1 binding partners in leukemic lines supports the notion that LMO2/LDB1 function in leukemia occurs in the context of multisubunit complexes, which also protect the LMO2 oncoprotein from degradation. Collectively, these data suggest that the assembly of LMO2 into complexes, via direct LDB1 interaction, is a potential molecular target that could be exploited in LMO2-driven leukemias resistant to existing chemotherapy regimens.
Attachment and Temperament in the Early Life Course: A Meta-Analytic Review.

This meta-analytic review examines the association between early attachment (assessed at 1-5 years) and child temperament (assessed at birth-12 years), and compares the strength of this association with recently documented meta-analytic associations between early attachment and social competence, externalizing behavior, and internalizing symptoms. Based on 109 independent samples (N = 11,440) of diverse socioeconomic and ethnic backgrounds, temperament was weakly associated with attachment (in)security (d = .14, CI [0.08, 0.19]) but modestly associated with resistant attachment (d = .30, CI [0.21, 0.40]). Temperament was not significantly associated with avoidant (d = .10, CI [-0.02, 0.19]) or disorganized (d = .11, CI [-0.03, 0.25]) attachment. Across developmental domains, early attachment security was more strongly associated with social competence and externalizing behaviors than internalizing symptoms and temperament.
Effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures.

BACKGROUND/OBJECTIVE To investigate the effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures. MATERIALS/METHODS Five thermoplastic materials, polyethylene terephthalate glycol (Duran®, Scheu Dental), polypropylene (Hardcast®, Scheu Dental), and polyurethane (SMP MM®, SMP Technologies) with three different glass transition temperatures (T g) were selected. The T g and crystal structure were assessed using differential scanning calorimetry and X-ray diffraction. The deterioration of mechanical properties by thermal cycling and the orthodontic forces during stepwise temperature changes were investigated using nanoindentation testing and custom-made force-measuring system. The mechanical properties were also evaluated by three-point bending tests; shape recovery with heating was then investigated. RESULTS The mechanical properties for each material were decreased significantly by 2500 cycles and great decrease was observed for Hardcast (crystal plastic) with higher T g (155.5°C) and PU 1 (crystalline or semi-crystalline plastic) with lower T g (29.6°C). The Duran, PU 2, and PU 3 with intermediate T g (75.3°C for Duran, 56.5°C for PU 2, and 80.7°C for PU 3) showed relatively stable mechanical properties with thermal cycling. The polyurethane polymers showed perfect shape memory effect within the range of intraoral temperature changes. The orthodontic force produced by thermoplastic appliances decreased with the stepwise temperature change for all materials. CONCLUSIONS/IMPLICATIONS Orthodontic forces delivered by thermoplastic appliances may influence by the T g of the materials, but not the crystal structure. Polyurethane is attractive thermoplastic materials due to their unique shape memory phenomenon, but stress relaxation with temperature changes is expected.