Isoeugenol is a selective potentiator of camptothecin cytotoxicity in vertebrate cells lacking TDP1

Camptothecin (CPT), a topoisomerase I (TOP1) inhibitor, exhibits anti-tumor activity against a wide range of tumors. Redundancy of TOP1-mediated repair mechanisms is a major challenge facing the efficiency of TOP1-targetting therapies. This study aims to uncover new TOP1 targeting approaches utilising a selection of natural compounds in the presence or absence of tyrosyl DNA phosphodiesterase I (TDP1); a key TOP1-mediated protein-linked DNA break (PDB) repair enzyme. We identify, isoeugenol, a phenolic ether found in plant essential oils, as a potentiator of CPT cytotoxicity in Tdp1 deficient but not proficient cells. Consistent with our cellular data, isoeugenol did not inhibit Tdp1 enzymatic activity in vitro nor it sensitized cells to the PARP1 inhibitor olaparib. However, biochemical analyses suggest that isoeugenol inhibits TDP2 catalytic activity; a pathway that can compensate for the absence of TDP1. Consistent with this, isoeugenol exacerbated etoposide-induced cytotoxicity, which generates TOP2-mediated PDBs for which TDP2 is required for processing. Together, these findings identify isoeugenol as a potential lead compound for developing TDP2 inhibitors and encourage structure-activity relationship studies to shed more light on its utility in drug discovery programs

Ino80 is essential for proximal-distal axis asymmetry in part by regulating Bmp4 expression

Western blotting confirming custom Ino80 antibody. Western analysis of Ino80 protein expression in wild-type and Ino80 KO ESCs using custom antibody VCU23 (a) and a commercially available Ino80 antibody (ProteinTech Cat# 18810-1-AP) (b). In each case Ponceau S was used as a loading control. (TIF 6874 kb

Ectopy on a single 12‐lead ECG, incident cardiac myopathy, and death in the community

BackgroundAtrial fibrillation and heart failure are 2 of the most common diseases, yet ready means to identify individuals at risk are lacking. The 12-lead ECG is one of the most accessible tests in medicine. Our objective was to determine whether a premature atrial contraction observed on a standard 12-lead ECG would predict atrial fibrillation and mortality and whether a premature ventricular contraction would predict heart failure and mortality.Methods and resultsWe utilized the CHS (Cardiovascular Health) Study, which followed 5577 participants for a median of 12 years, as the primary cohort. The ARIC (Atherosclerosis Risk in Communities Study), the replication cohort, captured data from 15 792 participants over a median of 22 years. In the CHS, multivariable analyses revealed that a baseline 12-lead ECG premature atrial contraction predicted a 60% increased risk of atrial fibrillation (hazard ratio, 1.6; 95% CI, 1.3-2.0; P<0.001) and a premature ventricular contraction predicted a 30% increased risk of heart failure (hazard ratio, 1.3; 95% CI, 1.0-1.6; P=0.021). In the negative control analyses, neither predicted incident myocardial infarction. A premature atrial contraction was associated with a 30% increased risk of death (hazard ratio, 1.3; 95% CI, 1.1-1.5; P=0.008) and a premature ventricular contraction was associated with a 20% increased risk of death (hazard ratio, 1.2; 95% CI, 1.0-1.3; P=0.044). Similarly statistically significant results for each analysis were also observed in ARIC.ConclusionsBased on a single standard ECG, a premature atrial contraction predicted incident atrial fibrillation and death and a premature ventricular contraction predicted incident heart failure and death, suggesting that this commonly used test may predict future disease

Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease

EveTAR: Building a Large-Scale Multi-Task Test Collection over Arabic Tweets

This article introduces a new language-independent approach for creating a large-scale high-quality test collection of tweets that supports multiple information retrieval (IR) tasks without running a shared-task campaign. The adopted approach (demonstrated over Arabic tweets) designs the collection around significant (i.e., popular) events, which enables the development of topics that represent frequent information needs of Twitter users for which rich content exists. That inherently facilitates the support of multiple tasks that generally revolve around events, namely event detection, ad-hoc search, timeline generation, and real-time summarization. The key highlights of the approach include diversifying the judgment pool via interactive search and multiple manually-crafted queries per topic, collecting high-quality annotations via crowd-workers for relevancy and in-house annotators for novelty, filtering out low-agreement topics and inaccessible tweets, and providing multiple subsets of the collection for better availability. Applying our methodology on Arabic tweets resulted in EveTAR , the first freely-available tweet test collection for multiple IR tasks. EveTAR includes a crawl of 355M Arabic tweets and covers 50 significant events for which about 62K tweets were judged with substantial average inter-annotator agreement (Kappa value of 0.71). We demonstrate the usability of EveTAR by evaluating existing algorithms in the respective tasks. Results indicate that the new collection can support reliable ranking of IR systems that is comparable to similar TREC collections, while providing strong baseline results for future studies over Arabic tweets

Proposal for generalised Supersymmetry Les Houches Accord for see-saw models and PDG numbering scheme

The SUSY Les Houches Accord (SLHA) 2 extended the first SLHA to include various generalisations of the Minimal Supersymmetric Standard Model (MSSM) as well as its simplest next-to-minimal version. Here, we propose further extensions to it, to include the most general and well-established see-saw descriptions (types I/II/III, inverse, and linear) in both an effective and a simple gauged extension of the MSSM framework. In addition, we generalise the PDG numbering scheme to reflect the properties of the particles.Comment: 44 pages. Changed titl

Two loop electroweak corrections to Bˉ→Xsγ\bar B\rightarrow X_s\gamma and Bs0→μ+μ−B_s^0\rightarrow \mu^+\mu^- in the B-LSSM

The rare decays $\bar B\rightarrow X_s\gamma$ and $B_s^0\rightarrow \mu^+\mu^-$ are important to research new physics beyond standard model. In this work, we investigate two loop electroweak corrections to $\bar B\rightarrow X_s\gamma$ and $B_s^0\rightarrow \mu^+\mu^-$ in the minimal supersymmetric extension of the SM with local $B-L$ gauge symmetry (B-LSSM), under a minimal flavor violating assumption for the soft breaking terms. In this framework, new particles and new definition of squarks can affect the theoretical predictions of these two processes, with respect to the MSSM. Considering the constraints from updated experimental data, the numerical results show that the B-LSSM can fit the experimental data for the branching ratios of $\bar B\rightarrow X_s\gamma$ and $B_s^0\rightarrow \mu^+\mu^-$. The results of the rare decays also further constrain the parameter space of the B-LSSM.Comment: 33 pages, 9 figures, Published in EPJ

Prospects for terahertz imaging the human skin cancer with the help of gold-nanoparticles-based terahertz-to-infrared converter

The design is suggested, and possible operation parameters are discussed, of an instrument to inspect a skin cancer tumour in the terahertz (THz) range, transferring the image into the infrared (IR) and making it visible with the help of standard IR camera. The central element of the device is the THz-to-IR converter, a Teflon or silicon film matrix with embedded 8.5 nm diameter gold nanoparticles. The use of external THz source for irradiating the biological tissue sample is presumed. The converter's temporal characteristics enable its performance in a real-time scale. The details of design suited for the operation in transmission mode (in vitro) or on the human skin in reflection mode {in vivo) are specified.Comment: To be published in the proceedings of the FANEM2018 workshop - Minsk, 3-5 June 201

Enhancing lepton flavour violation in the supersymmetric inverse seesaw beyond the dipole contribution

In minimal supersymmetric models the $Z$-penguin usually provides sub-dominant contributions to charged lepton flavour violating observables. In this study, we consider the supersymmetric inverse seesaw in which the non-minimal particle content allows for dominant contributions of the $Z$-penguin to several lepton flavour violating observables. In particular, and due to the low-scale (TeV) seesaw, the penguin contribution to, for instance, \Br(\mu \to 3e) and $\mu-e$ conversion in nuclei, allows to render some of these observables within future sensitivity reach. Moreover, we show that in this framework, the $Z$-penguin exhibits the same non-decoupling behaviour which had previously been identified in flavour violating Higgs decays in the Minimal Supersymmetric Standard Model.Comment: 29 pages, 9 figures, 4 tables; v2: minor corrections, version to appear in JHE

Cyberbullying in Text Content Detection: An Analytical Review

Technological advancements have resulted in an exponential increase in the use of online social networks (OSNs) worldwide. While online social networks provide a great communication medium, they also increase the user's exposure to life-threatening situations such as suicide, eating disorder, cybercrime, compulsive behavior, anxiety, and depression. To tackle the issue of cyberbullying, most existing literature focuses on developing approaches to identifying factors and understanding the textual factors associated with cyberbullying. While most of these approaches have brought great success in cyberbullying research, data availability needed to develop model detection remains a challenge in the research space. This paper conducts a comprehensive literature review to provide an understanding of cyberbullying detection.Comment: 8 pages. Under revie