Time-resolved pharmacological studies using automated, on-line monitoring of five parallel suspension cultures

Early stage pharmacological studies rely on in vitro methodologies for screening and testing compounds. Conventional assays based on endpoint measurements provide limited information because the lack in temporal resolution may not determine the pharmacological effect at its maximum. We developed an on-line, automated system for near real-time monitoring of extracellular content from five parallel suspension cultures, combining cell density measurements with a high-resolution separations every 12 minutes for 4 days. Selector and switching valves provide the fluidic control required to sample from one culture during the analysis of the previous sample from another culture, a time-saving measure that is fundamental to the throughput of the presented system. The system was applied to study the metabolic effects of the drugs rotenone, β-lapachone and clioquinol using lactate as metabolic indicator. For each drug, 96 assays were executed on the extracellular matrix at three concentrations with two controls in parallel, consuming only 5.78 mL of media from each culture over four days, less than 60 μL per analysis. The automated system provides high sample throughput, good temporal resolution and low sample consumption combined with a rugged analytical method with adequate sensitivity, providing a promising new platform for pharmacological and biotechnological studies

Spinorial geometry and Killing spinor equations of 6-D supergravity

We solve the Killing spinor equations of 6-dimensional (1,0)-supergravity coupled to any number of tensor, vector and scalar multiplets in all cases. The isotropy groups of Killing spinors are Sp(1)\cdot Sp(1)\ltimes \bH (1), U(1)\cdot Sp(1)\ltimes \bH (2), Sp(1)\ltimes \bH (3,4), $Sp(1) (2)$, $U(1) (4)$ and $\{1\} (8)$, where in parenthesis is the number of supersymmetries preserved in each case. If the isotropy group is non-compact, the spacetime admits a parallel null 1-form with respect to a connection with torsion the 3-form field strength of the gravitational multiplet. The associated vector field is Killing and the 3-form is determined in terms of the geometry of spacetime. The Sp(1)\ltimes \bH case admits a descendant solution preserving 3 out of 4 supersymmetries due to the hyperini Killing spinor equation. If the isotropy group is compact, the spacetime admits a natural frame constructed from 1-form spinor bi-linears. In the $Sp(1)$ and U(1) cases, the spacetime admits 3 and 4 parallel 1-forms with respect to the connection with torsion, respectively. The associated vector fields are Killing and under some additional restrictions the spacetime is a principal bundle with fibre a Lorentzian Lie group. The conditions imposed by the Killing spinor equations on all other fields are also determined.Comment: 34 pages, Minor change

Generalized holonomy of M-theory vacua

The number of M-theory vacuum supersymmetries, 0 <= n <= 32, is given by the number of singlets appearing in the decomposition of the 32 of SL(32,R) under H \subset SL(32,R) where H is the holonomy group of the generalized connection which incorporates non-vanishing 4-form. Here we compute this generalized holonomy for the n=16 examples of the M2-brane, M5-brane, M-wave, M-monopole, for a variety of their n=8 intersections and also for the n>16 pp waves.Comment: 24 pages, LaTe

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage.

A defective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome

p-p' Branes in PP-wave Background

We present several supergravity solutions corresponding to both Dp, as well as Dp-Dp' systems, in NS-NS and R-R PP-wave background originating from AdS_3 times S^3 times R^4. The Dp brane solutions, p=1,..,5 are fully localized, whereas Dp-Dp' are localized along common transverse directions. We also discuss the supersymmetry properties of these solutions and the worldsheet construction for the p-p' system.Comment: 17 pages, v5: supergrav. solns. corrected, v6: more results added: now includes p-p' branes in both NS-NS and R-R PP-wave background, some restructuring of the tex

On Type IIA String Theory on the PP-wave Background

We study type IIA superstring theory on a PP-wave background with 24 supercharges. This model can exactly be solved and then quantized. The open string in this PP-wave background is also studied. We observe that the theory has supersymmetric Dp-branes for p=2,4,6,8.Comment: 19 pages, latex. v2: references adde

On BPS preons, generalized holonomies and D=11 supergravities

We develop the BPS preon conjecture to analyze the supersymmetric solutions of D=11 supergravity. By relating the notions of Killing spinors and BPS preons, we develop a moving G-frame method (G=GL(32,R), SL(32,R) or Sp(32,R)) to analyze their associated generalized holonomies. As a first application we derive here the equations determining the generalized holonomies of k/32 supersymmetric solutions and, in particular, those solving the necessary conditions for the existence of BPS preonic (31/32) solutions of the standard D=11 supergravity. We also show that there exist elementary preonic solutions, i.e. solutions preserving 31 out of 32 supersymmetries in a Chern--Simons type supergravity. We present as well a family of worldvolume actions describing the motion of pointlike and extended BPS preons in the background of a D'Auria-Fre type OSp(1|32)-related supergravity model. We discuss the possible implications for M-theory.Comment: 11 pages, RevTeX Typos corrected, a short note and references adde

Quotients of AdS_{p+1} x S^q: causally well-behaved spaces and black holes

Starting from the recent classification of quotients of Freund--Rubin backgrounds in string theory of the type AdS_{p+1} x S^q by one-parameter subgroups of isometries, we investigate the physical interpretation of the associated quotients by discrete cyclic subgroups. We establish which quotients have well-behaved causal structures, and of those containing closed timelike curves, which have interpretations as black holes. We explain the relation to previous investigations of quotients of asymptotically flat spacetimes and plane waves, of black holes in AdS and of Godel-type universes.Comment: 48 pages; v2: minor typos correcte

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation