Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanisms of Doxorubicin Toxicity in Pancreatic β-Cells.

Exposure to chemotherapeutic agents has been linked to an increased risk of type 2 diabetes (T2D), a disease characterized by both the peripheral insulin resistance and impaired glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. Using the rat β-cell line INS-1 832/13 and isolated mouse pancreatic islets, we investigated the effect of the chemotherapeutic drug doxorubicin (Adriamycin) on pancreatic β-cell survival and function. Exposure of INS-1 832/13 cells to doxorubicin caused impairment of GSIS, cellular viability, an increase in cellular toxicity, as soon as 6 h post-exposure. Doxorubicin impaired plasma membrane electron transport (PMET), a pathway dependent on reduced equivalents NADH and NADPH, but failed to redox cycle in INS-1 832/13 cells and with their lysates. Although NADPH/NADP(+ )content was unaffected, NADH/NAD(+ )content decreased at 4 h post-exposure to doxorubicin, and was followed by a reduction in ATP content. Previous studies have demonstrated that doxorubicin functions as a topoisomerase II inhibitor via induction of DNA cross-linking, resulting in apoptosis. Doxorubicin induced the expression of mRNA for mdm2, cyclin G1, and fas whereas downregulating p53, and increased the melting temperature of genomic DNA, consistent with DNA damage and induction of apoptosis. Doxorubicin also induced caspase-3 and -7 activity in INS-1 832/13 cells and mouse islets; co-treatment with the pan-caspase inhibitor Z-VAD-FMK temporarily attenuated the doxorubicin-mediated loss of viability in INS-1 832/13 cells. Together, these data suggest that DNA damage, not H2O2 produced via redox cycling, is a major mechanism of doxorubicin toxicity in pancreatic β-cells.
Comparison between endocardial and epicardial cardiac resynchronization in an experimental model of non-ischaemic cardiomyopathy

Aims Pacing from the left ventricular (LV) endocardium might increase the likelihood of response to cardiac resynchronization therapy. However, experimental and clinical data supporting this assumption are limited and controversial. The aim of this study was to compare the acute response of biventricular pacing from the LV epicardium and endocardium in a swine non-ischaemic cardiomyopathy (NICM) model of dyssynchrony. Methods and results A NICM was induced in six swine by 3 weeks of rapid ventricular pacing. Biventricular stimulation was performed from 16 paired locations in the LV (8 epicardial and 8 endocardial) with two different atrioventricular (80 and 110 ms) intervals and three interventricular (0, +30, -30 ms) delays. The acute response of the aortic blood flow, LV and right ventricular (RV) pressures, LVdP/dtmax and LVdP/dtmin and QRS complex width and QT duration induced by biventricular stimulation were analysed. The haemodynamic and electrical beneficial responses to either LV endocardial or epicardial biventricular pacing were similar (ΔLVdP/dtmax: +7.8 ± 2.2% ENDO vs. +7.3 ± 1.5% EPI, and ΔQRS width: -16.8 ± 1.3% ENDO vs. -17.1 ± 1.9% EPI; P = ns). Pacing from LV basal regions either from the epicardium or endocardium produced better haemodynamic responses as compared with mid or apical LV regions (P < 0.05). The LV regions producing the maximum QRS complex shortening did not correspond to those inducing the best haemodynamic responses (EPI: r2 = 0.013, P = ns; ENDO: r2 = 0.002, P = ns). Conclusion Endocardial LV pacing induced similar haemodynamic changes than pacing from the epicardium. The response to endocardial LV pacing is region dependent as observed in epicardial pacing.
Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter.

BACKGROUND The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. METHODS Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. RESULTS Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter. CONCLUSIONS Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less--levels generally thought to be in the normal range.
Implementation of binary edwards curves for very-constrained devices

Elliptic Curve Cryptography (ECC) is considered as the best candidate for Public-Key Cryptosystems (PKC) for ubiquitous security. Recently, Elliptic Curve Cryptography (ECC) based on Binary Edwards Curves (BEC) has been proposed and it shows several interesting properties, e.g., completeness and security against certain exceptional-points attacks. In this paper, we propose a hardware implementation of the BEC for extremely constrained devices. The w-coordinates and Montgomery powering ladder are used. Next, we also give techniques to reduce the register file size, which is the largest component of the embedded core. Thirdly, we apply gated clocking to reduce the overall power consumption. The implementation has a size of 13,427 Gate Equivalent (GE), and 149.5 ms are required for one point multiplication. To the best of our knowledge, this is the first hardware implementation of binary Edwards curves.
The IL-4/STAT6/PPARγ signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages

Abstract Retinoid X receptor (RXR) is an obligate heterodimeric partner of several nuclear receptors (NRs), and as such a central component of NR signaling regulating the immune and metabolic phenotype of macrophages. Importantly, the binding motifs of RXR heterodimers are enriched in the tissue-selective open chromatin regions of resident macrophages, suggesting roles in subtype specification. Recent genome-wide studies revealed that RXR binds to thousands of sites in the genome, but the mechanistic details how the cistrome is established and serves ligand-induced transcriptional activity remained elusive. Here we show that IL-4-mediated macrophage plasticity results in a greatly extended RXR cistrome via both direct and indirect actions of the transcription factor STAT6. Activation of STAT6 leads to chromatin remodeling and RXR recruitment to de novo enhancers. In addition, STAT6 triggers a secondary transcription factor wave, including PPARγ. PPARγ appears to be indispensable for the development of RXR-bound de novo enhancers, whose activities can be modulated by the ligands of the PPARγ:RXR heterodimer conferring ligand selective cellular responses. Collectively, these data reveal the mechanisms leading to the dynamic extension of the RXR cistrome and identify the lipid-sensing enhancer sets responsible for the appearance of ligand-preferred gene signatures in alternatively polarized macrophages.
Multi-species interactions in West Nile virus infection

In this paper, we analyse the interaction of different species of birds and mosquitoes on the dynamics of West Nile virus (WNV) infection. We study the different transmission efficiencies of the vectors and birds and the impact on the possible outbreaks. We show that the basic reproductive number is the weighted mean of the basic reproductive number of each species, weighted by the relative abundance of its population in the location. These results suggest a possible explanation of why there are no outbreaks of WNV in Mexico.
Influence of breast cancer resistance protein (Abcg2) and p‐glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec®) across the mouse blood–brain barrier

Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p‐glycoprotein (p‐gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood–brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild‐type mice was limited by saturable efflux processes. The inhibition of p‐gp, by valspodar and zosuquidar, increased imatinib uptake (2.5‐fold), as did the deficiency of p‐gp in Mdr1a/1b(−/−) mice (5.5‐fold). Perfusing imatinib with the p‐gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild‐type (4.1‐fold) and Mdr1a/1b(−/−) mice (1.2‐fold). However, the brain uptake of imatinib was similar in wild‐type and Bcrp1(−/−) mice when it was perfused at a non‐saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(−/−) mice than in wild‐type mice. These data suggest that imatinib transport at the mouse BBB is limited by p‐gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1.
A Genome-Wide Methylation Study on Essential Hypertension in Young African American Males

Objective There is emerging evidence from animal studies suggesting a key role for methylation in the pathogenesis of essential hypertension. However, to date, very few studies have investigated the role of methylation in the development of human hypertension, and none has taken a genome-wide approach. Based on the recent studies that highlight the involvement of inflammation in the development of hypertension, we hypothesize that changes in DNA methylation of leukocytes are involved in the pathogenesis of hypertension. Method & Results We conducted a genome-wide methylation analysis on 8 hypertensive cases and 8 normotensive age-matched controls aged 14–23 years and performed validation of the most significant CpG sites in 2 genes in an independent sample of 36 hypertensive cases and 60 normotensive controls aged 14–30 years. Validation of the CpG sites in the SULF1 gene was further conducted in a second replication sample of 36 hypertensive cases and 34 controls aged 15.8–40 years. A CpG site in the SULF1 gene showed higher methylation levels in cases than in healthy controls in the genome-wide step (p = 6.2×10−5), which was confirmed in the validation step (p = 0.011) for subjects ≤30 years old but was not significant for subjects of all ages combined (p = 0.095). Conclusion The identification of a difference in a blood leukocyte DNA methylation site between hypertensive cases and normotensive controls suggests that changes in DNA methylation may play an important role in the pathogenesis of hypertension. The age dependency of the effect further suggests complexity of epigenetic regulation in this age-related disease.
Increasing Interoperability for Embedding Corpus Annotation Pipelines in Wmatrix and other corpus retrieval tools

Computational tools and methods employed in corpus linguistics are split into three main types: compilation, annotation and retrieval. These mirror and support the usual corpus linguistics methodology of corpus collection, manual and/or automatic tagging, followed by query and analysis. Typically, corpus software to support retrieval implements some or all of the five major methods in corpus linguistics only at the word level: frequency list, concordance, keyword, collocation and n-gram, and such software may or may not provide support for text which has already been tagged, for example at the part-of-speech (POS) level. Wmatrix is currently one of the few retrieval tools which have annotation tools built in. However, annotation in Wmatrix is currently limited to the UCREL English POS and semantic tagging pipeline. In this paper, we describe an approach to extend support for embedding other tagging pipelines and tools in Wmatrix via the use of APIs, and describe how such an approach is also applicable to other retrieval tools, potentially enabling support for tagged data.
Molecular Determinants Underlying Binding Specificities of the ABL Kinase Inhibitors: Combining Alanine Scanning of Binding Hot Spots with Network Analysis of Residue Interactions and Coevolution

Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown that functionally critical regulatory residues can simultaneously embody strong coevolutionary signal and high network centrality with a propensity to be energetic hot spots for drug binding. We have found that selective (Nilotinib) and promiscuous (Bosutinib, Dasatinib) kinase inhibitors can use their energetic hot spots to differentially modulate stability of the residue interaction networks, thus inhibiting or promoting conformational equilibrium between inactive and active states. According to our results, Nilotinib binding may induce a significant network-bridging effect and enhance centrality of the hot spot residues that stabilize structural environment favored by the specific kinase form. In contrast, Bosutinib and Dasatinib can incur modest changes in the residue interaction network in which ligand binding is primarily coupled only with the identity of the gate-keeper residue. These factors may promote structural adaptability of the active kinase states in binding with these promiscuous inhibitors. Our results have related ligand-induced changes in the residue interaction networks with drug resistance effects, showing that network robustness may be compromised by targeted mutations of key mediating residues. This study has outlined mechanisms by which inhibitor binding could modulate resilience and efficiency of allosteric interactions in the kinase structures, while preserving structural topology required for catalytic activity and regulation.
On the Verification of Logically Decorated Graph Transformations

We address the problem of reasoning on graph transformations featuring actions such as \emph{addition} and \emph{deletion} of nodes and edges, node \emph{merging} and \emph{cloning}, node or edge \emph{labelling} and edge \emph{redirection}. First, we introduce the considered graph rewrite systems which are parameterized by a given logic $\mathcal{L}$. Formulas of $\mathcal{L}$ are used to label graph nodes and edges. In a second step, we tackle the problem of formal verification of the considered rewrite systems by using a Hoare-like weakest precondition calculus. It acts on triples of the form $\{\texttt{Pre}\}(\texttt{R},\texttt{strategy}) \{\texttt{Post}\}$ where \texttt{Pre} and \texttt{Post} are conditions specified in the given logic $\mathcal{L}$, \texttt{R} is a graph rewrite system and \texttt{strategy} is an expression stating how rules in \texttt{R} are to be performed. We prove that the calculus we introduce is sound. Moreover, we show how the proposed framework can be instantiated successfully with different logics. We investigate first-order logic and several of its decidable fragments with a particular focus on different dialects of description logic (DL). We also show, by using bisimulation relations, that some DL fragments cannot be used due to their lack of expressive power.
Is block matching an alternative tool to LBP for face recognition?

In this paper, we introduce the Block Matching (BM) as an alternative patch-based local matching approach for solving the face recognition problem. The Block Matching enables an image patch of the probe face image to search for its best matching from displaced positions in the gallery face image. This matching strategy is very effective for handling spatial shift between two images and it is radically different from that of the widely used LBP type patch-based local matching approaches. Our evaluations on the FERET and CMU-PIE databases show that the performance of this simple method is well comparable (superior) to that of the popular LBP approach. We argue that the Block Matching could provide face recognition a new approach with more flexible algorithm architecture. One can expect that it could lead to much higher performance when combining with other feature extraction techniques, like Gabor wavelet and deep learning.
Learning to Compute Word Embeddings On the Fly

Words in natural language follow a Zipfian distribution whereby some words are frequent but most are rare. Learning representations for words in the ``long tail'' of this distribution requires enormous amounts of data. Representations of rare words trained directly on end tasks are usually poor, requiring us to pre-train embeddings on external data, or treat all rare words as out-of-vocabulary words with a unique representation. We provide a method for predicting embeddings of rare words on the fly from small amounts of auxiliary data with a network trained end-to-end for the downstream task. We show that this improves results against baselines where embeddings are trained on the end task for reading comprehension, recognizing textual entailment and language modeling.
Al2O3 Graded Coatings on Aluminum Alloy Deposited by the Fluidized Bed (FB) Technique: Film Formation and Mechanical Performance

Al2O3 coatings have been deposited onto an Al alloy by the fluidized bed (FB) technique using alumina powder. Film formation through a cold deposition process and its growth kinetics have been investigated by varying the deposition time. This allowed us to establish how the morphology, microstructure, hardness, scratch resistance, and adhesion strength of the Al2O3 films were progressively imprinted. The FB process led to the deposition of a good-looking and well-adhered graded Al2O3 coating, which was found to be progressively richer in Al2O3 on moving from the interface with the Al alloy toward the outermost layers. The resulting Al2O3 coatings have been shown to produce a consistent improvement of the overall mechanical and tribological performance of the Al alloy, thus leading to the build-up of an overlying hard and tough protective layer.
Joint power and antenna selection optimization for energy-efficient large distributed MIMO networks

Large multiple-input multiple-output (MIMO) network promises high energy efficiency using a large number of antennas. To reduce the signaling overhead of obtaining the full channel state information, we propose a downlink antenna selection scheme for large distributed MIMO networks with regularized zero-forcing (RZF) precoding. We study the joint optimization of antenna selection, regularization factor, and power allocation to maximize the average weighted sum-rate. The problem is non-trivial due to its combinatorial and non-convex nature. We decompose the problem into subproblems, each of which is solved by an efficient algorithm. For very large distributed MIMO networks, we obtain a capacity scaling law and show that there is an asymptotic decoupling effect, which can be exploited to simplify algorithms and physical layer processing. Simulations show that the proposed scheme achieves significant gain over the baseline.
Photomechanical Azobenzene Crystals

Photomechanically responsive materials are promising candidates for future smart actuator applications. The photo-responsive behaviors originate from the photoisomerization of photochromic molecules. A typical photochromic compound, azobenzene, has been studied extensively in the solution state and has played a crucial role in the photomechanical behaviors of materials such as polymers and gels, via chemical bridging with their matrix. In contrast to polymers and gels, the photomechanical attributes of molecular crystals have not progressed to the same degree, due to their rigidity and fragility. However, the past decade has witnessed an increasing number of reports of the photomechanical motion of molecular crystals, including azobenzene crystals. This paper reviews the current state-of-the-art of mechanically responsive azobenzene crystals, including the history, crystal design strategy, and future promising applications.
Visual Interfaces for Recommendation Systems

Recommendation applications can guide users in making important life choices by referring to the activities of similar peers. For example, students making academic plans may learn from the data of similar students, while patients and their physicians may explore data from similar patients to select the best treatment. Selecting an appropriate peer group has a strong impact on the value of the guidance that can result from analyzing the peer group data. In this article, we describe a visual interface that helps users review the similarity and differences between a seed record and a group of similar records and refine the selection. We introduce the LikeMeDonuts, Ranking Glyph, and History Heatmap visualizations. The interface was refined through three rounds of formative usability evaluation with 12 target users, and its usefulness was evaluated by a case study with a student review manager using real student data. We describe three analytic workflows observed during use and summarize how users’ input shaped the final design.
Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenalin

In the arcuate nucleus of the hypothalamus (ARH) satiety signaling (anorexigenic) pro-opiomelanocortin (POMC)-expressing and hunger signaling (orexigenic) agouti-related peptide (AgRP)-expressing neurons are key components of the neuronal circuits that control food intake and energy homeostasis. Here, we assessed whether the catecholamine noradrenalin directly modulates the activity of these neurons in mice. Perforated patch clamp recordings showed that noradrenalin changes the activity of these functionally antagonistic neurons in opposite ways, increasing the activity of the orexigenic NPY/AgRP neurons and decreasing the activity of the anorexigenic POMC neurons. Cell type-specific transcriptomics and pharmacological experiments revealed that the opposing effect on these neurons is mediated by the activation of excitatory α1A - and β- adrenergic receptors in NPY/AgRP neurons, while POMC neurons are inhibited via α2A – adrenergic receptors. Thus, the coordinated differential modulation of the key hypothalamic neurons in control of energy homeostasis assigns noradrenalin an important role to promote feeding. DOI: http://dx.doi. org/10.7554/eLife.25770. 001