Ethyl 4-{1-[(2,4-dinitro­phen­yl)hydrazono]eth­yl}-5-(2-naphthyl­methoxy­meth­yl)isoxazole-3-carboxyl­ate

The title compound, C26H23N5O8, was prepared and its structure investigated to further develop a working hypothesis for the essential binding pharmacophore for ligands of the System Xc- transporter [Patel et al. (2004 ▶). Neuropharmacology, 46, 273–284]. The hydrazone group displays an E geometry and the isoxazole double bond and C=N group of the hydrazone are in an s-cis relationship. The secondary amino NH group forms an intra­molecular N—H⋯O hydrogen bond to a ring nitro group. There is a dihedral angle of 44.27 (5)° between the isoxazole plane and the hydrazone group plane

Anthracenyl isoxazole amides (AIMs) stabilize quadruplex DNA structures in telomeric and c-MYC promotor sequences

Approximately 23,000 people are affected by malignant brain and CNS tumors in the United States each year and those afflicted have a median survival rate of only 12–15 months due to the limited treatment options available. The anthracenyl isoxazole amides (AIMs) are a novel class of compounds that have been shown to possess significant anti tumor activity in the NCI 60 cell line panel and to inhibit growth of SNB-19 glioblastoma cells at low micromolar and nanomolar concentrations. The goal of our current research is to characterize the mechanism underlying the anti tumor activity of the AIMs. We hypothesize the mechanism of growth inhibition to involve binding and stabilization of a DNA tertiary structure known as a guanine quadruplex. Various regulatory regions of DNA, such the c-MYC oncogene promoter sequence and repeating sequences formed at the end of telomeres, adopt the quadruplex conformation. Stabilization of quadruplex structures by small-molecule binding ligands has been reported to modulate the expression of genes and inhibit telomerase activity. Down-regulation of certain oncogenes or the inhibition of telomerase can cause tumor cells to undergo apoptosis or become unable to efficiently replicate. To establish whether interactions between the AIMs and quadruplex-forming sequences act to stabilize the quadruplex tertiary structure, circular dichroism spectroscopy (CD) was employed. CD is a method that utilizes the differential absorbance of left and right circularly polarized light to examine the chiral structure of molecules. CD thermal melting studies were conducted to determine whether the AIMs would increase the melting temperature of quadruplex forming sequences as an indication of increased stability. Our results demonstrated the AIMs, at two equivalents, increase the melting temperature (Tm) of both the c-MYC promoter and telomeric sequences by approximately 2–3 °C with strong statistical significance and reproducibility. Utilizing CD allows the use of low micromolar concentrations of DNA and this method will be used in the future to rapidly develop additional structure-activity relationships between novel AIMs and quadruplex forming sequences. Our laboratory has also shown chemical shifts in the imino region upon treatment with the AIMs for both the c-MYC promotor and telomeric sequence by NMR, providing additional evidence of the AIMs interaction with quadruplex structures. Interestingly, fluorescence microscopy of SNB-19 cells treated with AIMs show their localization is primarily in the mitochondria, and mitochondrial DNA contains several other important quadruplex forming sequences. Mitochondrial-dependent apoptosis has been suggested for other quadruplex binding ligands and therefore our future work will examine the potential stabilization of mitochondrial quadruplexes by these and other novel AIMs

Seasonal mixed layer depth shapes phytoplankton physiology, viral production, and accumulation in the North Atlantic

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Diaz, B. P., Knowles, B., Johns, C. T., Laber, C. P., Bondoc, K. G. V., Haramaty, L., Natale, F., Harvey, E. L., Kramer, S. J., Bolaños, L. M., Lowenstein, D. P., Fredricks, H. F., Graff, J., Westberry, T. K., Mojica, K. D. A., Haëntjens, N., Baetge, N., Gaube, P., Boss, E., Carlson, C. A., Behrenfeld, M. J., Van Mooy, B. A. S., Bidle, K. D. Seasonal mixed layer depth shapes phytoplankton physiology, viral production, and accumulation in the North Atlantic. Nature Communications, 12(1), (2021): 6634, https://doi.org/10.1038/s41467-021-26836-1.Seasonal shifts in phytoplankton accumulation and loss largely follow changes in mixed layer depth, but the impact of mixed layer depth on cell physiology remains unexplored. Here, we investigate the physiological state of phytoplankton populations associated with distinct bloom phases and mixing regimes in the North Atlantic. Stratification and deep mixing alter community physiology and viral production, effectively shaping accumulation rates. Communities in relatively deep, early-spring mixed layers are characterized by low levels of stress and high accumulation rates, while those in the recently shallowed mixed layers in late-spring have high levels of oxidative stress. Prolonged stratification into early autumn manifests in negative accumulation rates, along with pronounced signatures of compromised membranes, death-related protease activity, virus production, nutrient drawdown, and lipid markers indicative of nutrient stress. Positive accumulation renews during mixed layer deepening with transition into winter, concomitant with enhanced nutrient supply and lessened viral pressure.This work was made possible by NASA’s Earth Science Program in support of the North Atlantic Aerosol and Marine Ecosystem Study (15-RRNES15-0011 and 0NSSC18K1563 to K.D.B.; NNX15AF30G to M.J.B.), as well as with support from the National Science Foundation (OIA-2021032 to K.D.B., OCE-157943 to C.A.C., and OCE-1756254 to B.A.S.V.M.), the Gordon and Betty Moore Foundation (Award# 3789 to K.G.V.B.), and NASA’s Future Investigators in Space Science and Technology program (FINESST; grant #826380 to K.D.B.; graduate support to BD)

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan

This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Juxtaposing BTE and ATE – on the role of the European insurance industry in funding civil litigation

One of the ways in which legal services are financed, and indeed shaped, is through private insurance arrangement. Two contrasting types of legal expenses insurance contracts (LEI) seem to dominate in Europe: before the event (BTE) and after the event (ATE) legal expenses insurance. Notwithstanding institutional differences between different legal systems, BTE and ATE insurance arrangements may be instrumental if government policy is geared towards strengthening a market-oriented system of financing access to justice for individuals and business. At the same time, emphasizing the role of a private industry as a keeper of the gates to justice raises issues of accountability and transparency, not readily reconcilable with demands of competition. Moreover, multiple actors (clients, lawyers, courts, insurers) are involved, causing behavioural dynamics which are not easily predicted or influenced. Against this background, this paper looks into BTE and ATE arrangements by analysing the particularities of BTE and ATE arrangements currently available in some European jurisdictions and by painting a picture of their respective markets and legal contexts. This allows for some reflection on the performance of BTE and ATE providers as both financiers and keepers. Two issues emerge from the analysis that are worthy of some further reflection. Firstly, there is the problematic long-term sustainability of some ATE products. Secondly, the challenges faced by policymakers that would like to nudge consumers into voluntarily taking out BTE LEI