Preclinical correction of human Fanconi anemia complementation group A bone marrow cells using a safety-modified lentiviral vector.

One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P<0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P<0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA

Probing Density Fluctuations using the FIRST Radio Survey

We use results of angular clustering measurements in 3000 sq. deg's of the FIRST radio survey to infer information on spatial clustering. Measurements are compared with CDM-model predictions. Clustering of FIRST sources with optical ID's in the APM catalog are also investigated. Finally, we outline a preliminary search for a weak lensing signal in the survey.Comment: 6 pages latex, 2 figures, to appear in Cosmology with the New Radio Surveys (Kluwer

Determination of Pericardial Adipose Tissue Increases the Prognostic Accuracy of Coronary Artery Calcification for Future Cardiovascular Events

Objectives: Pericardial adipose tissue (PAT) is associated with coronary artery plaque accumulation and the incidence of coronary heart disease. We evaluated the possible incremental prognostic value of PAT for future cardiovascular events. Methods: 145 patients (94 males, age 60 10 years) with stable coronary artery disease underwent coronary artery calcification (CAC) scanning in a multislice CT scanner, and the volume of pericardial fat was measured. Mean observation time was 5.4 years. Results: 34 patients experienced a severe cardiac event. They had a significantly higher CAC score (1,708 +/- 2,269 vs. 538 +/- 1,150, p 400, 3.5 (1.9-5.4; p = 0.007) for scores > 800 and 5.9 (3.7-7.8; p = 0.005) for scores > 1,600. When additionally a PAT volume > 200 cm(3) was determined, there was a significant increase in the event rate and relative risk. We calculated a relative risk of 2.9 (1.9-4.2; p = 0.01) for scores > 400, 4.0 (2.1-5.0; p = 0.006) for scores > 800 and 7.1 (4.1-10.2; p = 0.005) for scores > 1,600. Conclusions:The additional determination of PAT increases the predictive power of CAC for future cardiovascular events. PAT might therefore be used as a further parameter for risk stratification. Copyright (C) 2012 S. Karger AG, Base

Non-thermal emission processes in massive binaries

In this paper, I present a general discussion of several astrophysical processes likely to play a role in the production of non-thermal emission in massive stars, with emphasis on massive binaries. Even though the discussion will start in the radio domain where the non-thermal emission was first detected, the census of physical processes involved in the non-thermal emission from massive stars shows that many spectral domains are concerned, from the radio to the very high energies. First, the theoretical aspects of the non-thermal emission from early-type stars will be addressed. The main topics that will be discussed are respectively the physics of individual stellar winds and their interaction in binary systems, the acceleration of relativistic electrons, the magnetic field of massive stars, and finally the non-thermal emission processes relevant to the case of massive stars. Second, this general qualitative discussion will be followed by a more quantitative one, devoted to the most probable scenario where non-thermal radio emitters are massive binaries. I will show how several stellar, wind and orbital parameters can be combined in order to make some semi-quantitative predictions on the high-energy counterpart to the non-thermal emission detected in the radio domain. These theoretical considerations will be followed by a census of results obtained so far, and related to this topic... (see paper for full abstract)Comment: 47 pages, 5 postscript figures, accepted for publication in Astronomy and Astrophysics Review. Astronomy and Astrophysics Review, in pres

Phylogenetically Driven Sequencing of Extremely Halophilic Archaea Reveals Strategies for Static and Dynamic Osmo-response

© 2014. Organisms across the tree of life use a variety of mechanisms to respond to stress-inducing fluctuations in osmotic conditions. Cellular response mechanisms and phenotypes associated with osmoadaptation also play important roles in bacterial virulence, human health, agricultural production and many other biological systems. To improve understanding of osmoadaptive strategies, we have generated 59 high-quality draft genomes for the haloarchaea (a euryarchaeal clade whose members thrive in hypersaline environments and routinely experience drastic changes in environmental salinity) and analyzed these new genomes in combination with those from 21 previously sequenced haloarchaeal isolates. We propose a generalized model for haloarchaeal management of cytoplasmic osmolarity in response to osmotic shifts, where potassium accumulation and sodium expulsion during osmotic upshock are accomplished via secondary transport using the proton gradient as an energy source, and potassium loss during downshock is via a combination of secondary transport and non-specific ion loss through mechanosensitive channels. We also propose new mechanisms for magnesium and chloride accumulation. We describe the expansion and differentiation of haloarchaeal general transcription factor families, including two novel expansions of the TATA-binding protein family, and discuss their potential for enabling rapid adaptation to environmental fluxes. We challenge a recent high-profile proposal regarding the evolutionary origins of the haloarchaea by showing that inclusion of additional genomes significantly reduces support for a proposed large-scale horizontal gene transfer into the ancestral haloarchaeon from the bacterial domain. The combination of broad (17 genera) and deep (≥5 species in four genera) sampling of a phenotypically unified clade has enabled us to uncover both highly conserved and specialized features of osmoadaptation. Finally, we demonstrate the broad utility of such datasets, for metagenomics, improvements to automated gene annotation and investigations of evolutionary processes

Connexin 43 is overexpressed in human fetal membrane defects after fetoscopic surgery

This project was funded by the RoseTrees Trust (M400, TTC), the QMUL Life Sciences Initiative, Institutional Strategic Support Fund from the Wellcome Trust (105626/Z/14/Z, TTC) and supported by researchers at the National Institute for Health Research, University College London Hospitals Biomedical Research Centre (ALD)

D-brane anomaly inflow revisited

Axial and gravitational anomaly of field theories, when embedded in string theory, must be accompanied by canceling inflow. We give a self-contained overview for various world-volume theories, and clarify the role of smeared magnetic sources in I-brane/D-brane cases. The proper anomaly descent of the source, as demanded by regularity of RR field strengths H's, turns out to be an essential ingredient. We show how this allows correct inflow to be generated for all such theories, including self-dual cases, and also that the mechanism is now insensitive to the choice between the two related but inequivalent forms of D-brane Chern-Simons couplings. In particular, SO(6)_R axial anomaly of d=4 maximal SYM is canceled by the inflow onto D3-branes via the standard minimal coupling to C_4. We also propose how, for the anomaly cancelation, the four types of Orientifold planes should be coupled to the spacetime curvatures, of which conflicting claims existed previously.Comment: 41 pages, references updated; version to appear in JHE

Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function

Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition

Sabotage in Contests: A Survey

A contest is a situation in which individuals expend irretrievable resources to win valuable prize(s). ‘Sabotage’ is a deliberate and costly act of damaging a rival’s' likelihood of winning the contest. Sabotage can be observed in, e.g., sports, war, promotion tournaments, political or marketing campaigns. In this article, we provide a model and various perspectives on such sabotage activities and review the economics literature analyzing the act of sabotage in contests. We discuss the theories and evidence highlighting the means of sabotage, why sabotage occurs, and the effects of sabotage on individual players and on overall welfare, along with possible mechanisms to reduce sabotage. We note that most sabotage activities are aimed at the ablest player, the possibility of sabotage reduces productive effort exerted by the players, and sabotage may lessen the effectiveness of public policies, such as affirmative action, or information revelation in contests. We discuss various policies that a designer may employ to counteract sabotage activities. We conclude by pointing out some areas of future research

Transit Timing and Duration Variations for the Discovery and Characterization of Exoplanets

Transiting exoplanets in multi-planet systems have non-Keplerian orbits which can cause the times and durations of transits to vary. The theory and observations of transit timing variations (TTV) and transit duration variations (TDV) are reviewed. Since the last review, the Kepler spacecraft has detected several hundred perturbed planets. In a few cases, these data have been used to discover additional planets, similar to the historical discovery of Neptune in our own Solar System. However, the more impactful aspect of TTV and TDV studies has been characterization of planetary systems in which multiple planets transit. After addressing the equations of motion and parameter scalings, the main dynamical mechanisms for TTV and TDV are described, with citations to the observational literature for real examples. We describe parameter constraints, particularly the origin of the mass/eccentricity degeneracy and how it is overcome by the high-frequency component of the signal. On the observational side, derivation of timing precision and introduction to the timing diagram are given. Science results are reviewed, with an emphasis on mass measurements of transiting sub-Neptunes and super-Earths, from which bulk compositions may be inferred.Comment: Revised version. Invited review submitted to 'Handbook of Exoplanets,' Exoplanet Discovery Methods section, Springer Reference Works, Juan Antonio Belmonte and Hans Deeg, Eds. TeX and figures may be found at https://github.com/ericagol/TTV_revie