MRNIP is a replication fork protection factor

The remodeling of stalled replication forks to form four-way DNA junctions is an important component of the replication stress response. Nascent DNA at the regressed arms of these reversed forks is protected by RAD51 and the tumor suppressors BRCA1/2, and when this function is compromised, stalled forks undergo pathological MRE11-dependent degradation, leading to chromosomal instability. However, the mechanisms regulating MRE11 functions at reversed forks are currently unclear. Here, we identify the MRE11-binding protein MRNIP as a novel fork protection factor that directly binds to MRE11 and specifically represses its exonuclease activity. The loss of MRNIP results in impaired replication fork progression, MRE11 exonuclease–dependent degradation of reversed forks, persistence of underreplicated genomic regions, chemosensitivity, and chromosome instability. Our findings identify MRNIP as a novel regulator of MRE11 at reversed forks and provide evidence that regulation of specific MRE11 nuclease activities ensures protection of nascent DNA and thereby genome integrity

Penrose Limits, Deformed pp-Waves and the String Duals of N=1 Large n Gauge Theory

A certain conformally invariant N=1 supersymmetric SU(n) gauge theory has a description as an infra-red fixed point obtained by deforming the N=4 supersymmetric Yang-Mills theory by giving a mass to one of its N=1 chiral multiplets. We study the Penrose limit of the supergravity dual of the large n limit of this N=1 gauge theory. The limit gives a pp-wave with R-R five-form flux and both R-R and NS-NS three-form flux. We discover that this new solution preserves twenty supercharges and that, in the light-cone gauge, string theory on this background is exactly solvable. Correspondingly, this latter is the stringy dual of a particular large charge limit of the large n gauge theory. We are able to identify which operators in the field theory survive the limit to form the string's ground state and some of the spacetime excitations. The full string model, which we exhibit, contains a family of non-trivial predictions for the properties of the gauge theory operators which survive the limit.Comment: 39 pages, Late

From D-Dbar Pairs to Branes in Motion

We investigate various supersymmetric brane intersections. Motivated by the recent results on supertubes, we investigate general constraints in which parallel brane-antibrane configurations are supersymmetric. Dual descriptions of these configurations involve systems of branes in relative motion. In particular, we find new supersymmetric configurations which are not related to a static brane intersection by a boost. In these new configurations, the intersection point moves at the speed of light. These systems provide interesting time dependent backgrounds for open strings.Comment: 28+1 pages, 8 figures, uses JHEP3.cl

'Education, education, education' : legal, moral and clinical

This article brings together Professor Donald Nicolson's intellectual interest in professional legal ethics and his long-standing involvement with law clinics both as an advisor at the University of Cape Town and Director of the University of Bristol Law Clinic and the University of Strathclyde Law Clinic. In this article he looks at how legal education may help start this process of character development, arguing that the best means is through student involvement in voluntary law clinics. And here he builds upon his recent article which argues for voluntary, community service oriented law clinics over those which emphasise the education of students

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Deformations of Holographic Duals to Non-Relativistic CFTs

We construct the non-relativistic counterparts of some well-known supergravity solutions dual to relevant and marginal deformations of N=4 super Yang-Mills. The main tool we use is the null Melvin twist and we apply it to the N=1 and N=2* Pilch-Warner RG flow solutions as well as the Lunin-Maldacena solution dual to beta-deformations of N=4 super Yang-Mills. We also obtain a family of supergravity solutions with Schrodinger symmetry interpolating between the non-relativistic version of the N=1 Pilch-Warner and Klebanov-Witten fixed points. A generic feature of these non-relativistic backgrounds is the presence of non-vanishing internal fluxes. We also find the most general, three-parameter, null Melvin twist of the AdS_5xS^5 black hole. We briefly comment on the field theories dual to these supergravity solutions.Comment: 34 pages, 1 figure, LaTe

Balancing end-to-end budgets of the Georges Bank ecosystem

Author Posting. © Elsevier, 2007. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Progress In Oceanography 74 (2007): 423-448, doi:10.1016/j.pocean.2007.05.003.Oceanographic regimes on the continental shelf display a great range in the time scales of physical exchange, biochemical processes and trophic transfers. The close surface-to-seabed physical coupling at intermediate scales of weeks to months means that the open ocean simplification to a purely pelagic food web is inadequate. Top-down trophic depictions, starting from the fish populations, are insufficient to constrain a system involving extensive nutrient recycling at lower trophic levels and subject to physical forcing as well as fishing. These pelagic-benthic interactions are found on all continental shelves but are particularly important on the relatively shallow Georges Bank in the northwest Atlantic. We have generated budgets for the lower food web for three physical regimes (well mixed, transitional and stratified) and for three seasons (spring, summer and fall/winter). The calculations show that vertical mixing and lateral exchange between the three regimes are important for zooplankton production as well as for nutrient input. Benthic suspension feeders are an additional critical pathway for transfers to higher trophic levels. Estimates of production by mesozooplankton, benthic suspension feeders and deposit feeders, derived primarily from data collected during the GLOBEC years of 1995-1999, provide input to an upper food web. Diets of commercial fish populations are used to calculate food requirements in three fish categories, planktivores, benthivores and piscivores, for four decades, 1963-2002, between which there were major changes in the fish communities. Comparisons of inputs from the lower web with fish energetic requirements for plankton and benthos indicate that we obtained reasonable agreement for the last three decades, 1973 to 2002. However, for the first decade, the fish food requirements were significantly less than the inputs. This decade, 1963-1972, corresponds to a period characterized by a strong Labrador Current and lower nitrate levels at the shelf edge, demonstrating how strong bottom-up physical forcing may determine overall fish yields.The research was done under the aegis of the U.S.-GLOBEC Northwest Atlantic Georges Bank Study, a program sponsored jointly by the U.S. National Science Foundation and the U.S. National Oceanic and Atmospheric Administration. We acknowledge NOAA-CICOR award NA17RJ1233 (J.H. Steele), NSF awards OCE0217399 (D.J. Gifford), OCE0217122 (J.J. Bisagni) and OCE0217257 (M.E. Sieracki). W.T. Stockhausen was supported by the NOAA Sponsored Coastal Ocean Research Program

A Review of Magnetic Phenomena in Probe-Brane Holographic Matter

Gauge/gravity duality is a useful and efficient tool for addressing and studying questions related to strongly interacting systems described by a gauge theory. In this manuscript we will review a number of interesting phenomena that occur in such systems when a background magnetic field is turned on. Specifically, we will discuss holographic models for systems that include matter fields in the fundamental representation of the gauge group, which are incorporated by adding probe branes into the gravitational background dual to the gauge theory. We include three models in this review: the D3-D7 and D4-D8 models, that describe four-dimensional systems, and the D3-D7' model, that describes three-dimensional fermions interacting with a four-dimensional gauge field.Comment: 35 pages, 27 figures, to appear in Lect. Notes Phys. "Strongly interacting matter in magnetic fields" (Springer), edited by D. Kharzeev, K. Landsteiner, A. Schmitt, H.-U. Yee; references adde

Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of l