Plasmodium falciparum glutamate dehydrogenase a is dispensable and not a drug target during erythrocytic development

<p>Background: Plasmodium falciparum contains three genes encoding potential glutamate dehydrogenases. The protein encoded by gdha has previously been biochemically and structurally characterized. It was suggested that it is important for the supply of reducing equivalents during intra-erythrocytic development of Plasmodium and, therefore, a suitable drug target.</p> <p>Methods: The gene encoding the NADP(H)-dependent GDHa has been disrupted by reverse genetics in P. falciparum and the effect on the antioxidant and metabolic capacities of the resulting mutant parasites was investigated.</p> <p>Results: No growth defect under low and elevated oxygen tension, no up-or down-regulation of a number of antioxidant and NADP(H)-generating proteins or mRNAs and no increased levels of GSH were detected in the D10(Delta gdha) parasite lines. Further, the fate of the carbon skeleton of [(13)C] labelled glutamine was assessed by metabolomic studies, revealing no differences in the labelling of a-ketoglutarate and other TCA pathway intermediates between wild type and mutant parasites.</p> <p>Conclusions: First, the data support the conclusion that D10(Delta gdha) parasites are not experiencing enhanced oxidative stress and that GDHa function may not be the provision of NADP(H) for reductive reactions. Second, the results imply that the cytosolic, NADP(H)-dependent GDHa protein is not involved in the oxidative deamination of glutamate but that the protein may play a role in ammonia assimilation as has been described for other NADP(H)dependent GDH from plants and fungi. The lack of an obvious phenotype in the absence of GDHa may point to a regulatory role of the protein providing glutamate (as nitrogen storage molecule) in situations where the parasites experience a limiting supply of carbon sources and, therefore, under in vitro conditions the enzyme is unlikely to be of significant importance. The data imply that the protein is not a suitable target for future drug development against intra-erythrocytic parasite development.</p&gt

Atmospheric parameters of Cepheids from flux ratios with ATHOS: I. The temperature scale

Context: The effective temperature is a key parameter governing the properties of a star. For stellar chemistry, it has the strongest impact on the accuracy of the abundances derived. Since Cepheids are pulsating stars, determining their effective temperature is more complicated that in the case of non-variable stars. Aims: We want to provide a new temperature scale for classical Cepheids, with a high precision and full control of the systematics. Methods: Using a data-driven machine learning technique employing observed spectra, and taking great care to accurately phase single-epoch observations, we have tied flux ratios to (label) temperatures derived using the infrared surface brightness method. Results: We identified 143 flux ratios that allow us to determine the effective temperature with a precision of a few K and an accuracy better than 150 K, which is in line with the most accurate temperature measures available to date. The method does not require a normalization of the input spectra and provides homogeneous temperatures for low- and high-resolution spectra, even at the lowest signal-to-noise ratios. Due to the lack of a dataset of sufficient sample size for Small Magellanic Cloud Cepheids, the temperature scale does not extend to Cepheids with [Fe/H] < -0.6 dex but nevertheless provides an exquisite, homogeneous means of characterizing Galactic and Large Magellanic Cloud Cepheids. Conclusions: The temperature scale will be extremely useful in the context of spectroscopic surveys for Milky Way archaeology with the WEAVE and 4MOST spectrographs. It paves the way for highly accurate and precise metallicity estimates, which will allow us to assess the possible metallicity dependence of Cepheids' period-luminosity relations and, in turn, to improve our measurement of the Hubble constant H0.Comment: 16 pages, 13 figures, accepted in A&

CARMA Large Area Star Formation Survey: Observational Analysis of Filaments in the Serpens South Molecular Cloud

We present the N2H+(J=1-0) map of the Serpens South molecular cloud obtained as part of the CARMA Large Area Star Formation Survey (CLASSy). The observations cover 250 square arcminutes and fully sample structures from 3000 AU to 3 pc with a velocity resolution of 0.16 km/s, and they can be used to constrain the origin and evolution of molecular cloud filaments. The spatial distribution of the N2H+ emission is characterized by long filaments that resemble those observed in the dust continuum emission by Herschel. However, the gas filaments are typically narrower such that, in some cases, two or three quasi-parallel N2H+ filaments comprise a single observed dust continuum filament. The difference between the dust and gas filament widths casts doubt on Herschel ability to resolve the Serpens South filaments. Some molecular filaments show velocity gradients along their major axis, and two are characterized by a steep velocity gradient in the direction perpendicular to the filament axis. The observed velocity gradient along one of these filaments was previously postulated as evidence for mass infall toward the central cluster, but these kind of gradients can be interpreted as projection of large-scale turbulence.Comment: 12 pages, 4 figures, published in ApJL (July 2014

Холотропное дыхание как метод реализации потенциала личности сотрудника

На сегодняшний день в организациях существует множество проблем, из-за которых возникают сложности как в управлении предприятием, так и в эффективной работе сотрудников. Для любого управляющего компанией важно, чтобы сотрудник был уверенным, умеющим нестандартно мыслить, инициативным, целеустремленным, но в большинстве случаев на предприятии такие сотрудники отсутствуют или их количество ограниченно. В любом сотруднике кроется творческая личность, которая не всегда может быть реализована на практике или же просто подавлена. Для того чтобы предприятие могло эффективно функционировать, важно, чтобы каждый сотрудник мог разобраться в своих проблемах и обрести внутреннюю гармонию, которая позволит ему настроиться на работу и выполнять ее эффективно. Методика холотропного дыхания может помочь личности реализовать свой скрытый потенциал. Цель работы: определить значимость методики холотропного дыхания в организации и выявить, какое влияние она оказывает как на сотрудников, так и на предприятие в целом. Методы исследования: анализ литера- туры по данной проблематике, аналитический метод. Результаты: выводы, полученные в данном исследовании, способствуют определению действенности методики холотропного дыхания и значимости ее применения в организации. Today there are many problems in organizations which lead to difficulties in the management of an enterpriseand in the effective work of the staff. For any company manager it is important that the employee wasconfident, able to think outside the box, initiative, committed, but in most cases such employees are absent ortheir number is limited. There is creative personality in any employee which can’t always be revealed or issimply suppressed. In order for a company to operate effectively, it is important that every employee couldunderstand their problems and find inner harmony, which will allow them to tune into work and perform itefficiently. The technique of holotropic breathwork can help the person to realize their hidden potential. Objective:to determine the significance of the technique of holotropic breathwork in the organization and itsimpact on the employees and the enterprise as a whole. Methods: review of the literature on this subject,data analysis. Results. The findings of this study help to identify the effective methods of holotropic breathworkand the importance of its application in the organization

Universal Algebraic Relaxation of Velocity and Phase in Pulled Fronts generating Periodic or Chaotic States

We investigate the asymptotic relaxation of so-called pulled fronts propagating into an unstable state. The ``leading edge representation'' of the equation of motion reveals the universal nature of their propagation mechanism and allows us to generalize the universal algebraic velocity relaxation of uniformly translating fronts to fronts, that generate periodic or even chaotic states. Such fronts in addition exhibit a universal algebraic phase relaxation. We numerically verify our analytical predictions for the Swift-Hohenberg and the Complex Ginzburg Landau equation.Comment: 4 pages Revtex, 2 figures, submitted to Phys. Rev. Let

Quantum transport through a DNA wire in a dissipative environment

Electronic transport through DNA wires in the presence of a strong dissipative environment is investigated. We show that new bath-induced electronic states are formed within the bandgap. These states show up in the linear conductance spectrum as a temperature dependent background and lead to a crossover from tunneling to thermal activated behavior with increasing temperature. Depending on the strength of the electron-bath coupling, the conductance at the Fermi level can show a weak exponential or even an algebraic length dependence. Our results suggest a new environmental-induced transport mechanism. This might be relevant for the understanding of molecular conduction experiments in liquid solution, like those recently performed on poly(GC) oligomers in a water buffer (B. Xu et al., Nano Lett 4, 1105 (2004)).Comment: 5 pages, 3 figure

Structural phase transitions in yttrium up to 183 GPa

Angle-dispersive x-ray powder diffraction experiments have been performed on yttrium metal up to 183 GPa.We find that the recently discoveredoF16 structure observed in the high-Ztrivalent lanthanides is also adoptedby yttrium above 106 GPa, pressures where it has a superconducting temperature of∼20 K. We have also refinedboth tetragonal and rhombohedral structures against the diffraction data from the preceding “distorted-fcc” phaseand we are unable to state categorically which of these is the true structure of this phase. Finally, analysis ofyttrium’s equation of state reveals a marked change in the compressibility upon adoption of theoF16 structure,after which the compression is that of a “regular” metal. Electronic structure calculations ofoF16-Y confirm itsstability overoF8 structure seen in Nd and Sm, and provide insight into the nature of the shift of orbital characterfromstodunder compression

CARMA Large Area Star Formation Survey: Project Overview with Analysis of Dense Gas Structure and Kinematics in Barnard 1

We present details of the CARMA Large Area Star Formation Survey (CLASSy), while focusing on observations of Barnard 1. CLASSy is a CARMA Key Project that spectrally imaged N2H+, HCO+, and HCN (J=1-0 transitions) across over 800 square arcminutes of the Perseus and Serpens Molecular Clouds. The observations have angular resolution near 7" and spectral resolution near 0.16 km/s. We imaged ~150 square arcminutes of Barnard 1, focusing on the main core, and the B1 Ridge and clumps to its southwest. N2H+ shows the strongest emission, with morphology similar to cool dust in the region, while HCO+ and HCN trace several molecular outflows from a collection of protostars in the main core. We identify a range of kinematic complexity, with N2H+ velocity dispersions ranging from ~0.05-0.50 km/s across the field. Simultaneous continuum mapping at 3 mm reveals six compact object detections, three of which are new detections. A new non-binary dendrogram algorithm is used to analyze dense gas structures in the N2H+ position-position-velocity (PPV) cube. The projected sizes of dendrogram-identified structures range from about 0.01-0.34 pc. Size-linewidth relations using those structures show that non-thermal line-of-sight velocity dispersion varies weakly with projected size, while rms variation in the centroid velocity rises steeply with projected size. Comparing these relations, we propose that all dense gas structures in Barnard 1 have comparable depths into the sky, around 0.1-0.2 pc; this suggests that over-dense, parsec-scale regions within molecular clouds are better described as flattened structures rather than spherical collections of gas. Science-ready PPV cubes for Barnard 1 molecular emission are available for download.Comment: Accepted to The Astrophysical Journal (ApJ), 51 pages, 27 figures (some with reduced resolution in this preprint); Project website is at http://carma.astro.umd.edu/class

Biodegradable Poly(2-Dimethylamino Ethylamino)Phosphazene for In Vivo Gene Delivery to Tumor Cells. Effect of Polymer Molecular Weight

Purpose. Previously, we have shown that complexes of plasmid DNA with the biodegradable polymer poly(2-dimethylamino ethylamino)phosphazene (p(DMAEA)-ppz) mediated tumor selective gene expression after intravenous administration in mice. In this study, we investigated the effect of p(DMAEA)-ppz molecular weight on both in vitro and in vivo tumor transfection, as well as on complex induced toxicity. Materials and Methods. p(DMAEA)-ppz with a broad molar mass distribution was fractionated by preparative size exclusion chromatography. Polyplexes consisting of plasmid DNA and the collected polymer fractions were tested for biophysical properties, (cyto)toxicity and transfection activity. Results. Four p(DMAEA)-ppz fractions were collected with weight average molecular weights ranging from 130 to 950 kDa, and with narrow molecular mass distributions (Mw/Mn from 1.1 to 1.3). At polymer-to-DNA (N/P) ratios above 6, polyplexes based on these polymers were all positively charged (zeta potential 25–29 mV), and had a size of 80–90 nm. The in vitro cytotoxicity of the polyplexes positively correlated with polymer molecular weight. The in vitro transfection activity of the different polyplexes depended on their N/P ratio, and was affected by the degree of cytotoxicity, as well as the colloidal stability of the different polyplexes. Intravenous administration of polyplexes based on the high molecular weight polymers led to apparent toxicity, as a result of polyplex-induced erythrocyte aggregation. On the other hand, administration of polyplexes based on low molecular weight p(DMAEA)-ppz_s (Mw130 kDa) did not show signs of toxicity and resulted in tumor selective gene expression. Conclusion. Polymer molecular weight fractionation enabled us to optimize the transfection efficiency/ toxicity ratio of p(DMAEA)-ppz polyplexes for in vitro and in vivo tumor transfection. KEY WORDS: biodegradable; cationic polymer; DNA; molecular weight; tumor gene delivery