Network-based stratification of tumor mutations.

Many forms of cancer have multiple subtypes with different causes and clinical outcomes. Somatic tumor genome sequences provide a rich new source of data for uncovering these subtypes but have proven difficult to compare, as two tumors rarely share the same mutations. Here we introduce network-based stratification (NBS), a method to integrate somatic tumor genomes with gene networks. This approach allows for stratification of cancer into informative subtypes by clustering together patients with mutations in similar network regions. We demonstrate NBS in ovarian, uterine and lung cancer cohorts from The Cancer Genome Atlas. For each tissue, NBS identifies subtypes that are predictive of clinical outcomes such as patient survival, response to therapy or tumor histology. We identify network regions characteristic of each subtype and show how mutation-derived subtypes can be used to train an mRNA expression signature, which provides similar information in the absence of DNA sequence

Linearized self-forces for branes

We compute the regularized force density and renormalized action due to fields of external origin coupled to a brane of arbitrary dimension in a spacetime of any dimension. Specifically, we consider forces generated by gravitational, dilatonic and generalized antisymmetric form-fields. The force density is regularized using a recently developed gradient operator. For the case of a Nambu--Goto brane, we show that the regularization leads to a renormalization of the tension, which is seen to be the same in both approaches. We discuss the specific couplings which lead to cancellation of the self-force in this case.Comment: 15 page

Evolving Sovereignty Relationships Between Affiliated Jurisdictions: Lessons for Native American Jurisdictions

Though sovereignty is principally associated with governance over a territory and freedom to act in the international arena, this article examines sovereignty as empowerment. The study tests the applicability to Native American jurisdictions of the experiences of fifteen case study jurisdictions presently associated with the United Kingdom, the Netherlands, and France in shared sovereign relationships. The focus is on the evolution of those relationships and opportunities for development where jurisdictions do not attain full control over their affairs. The case studies examine the relationships from the perspectives of political, economic, and cultural sovereignty. The article further examines the relationships in three dimensions: evolutionary, frictions, and interwoven governance. It concludes with identifying factors of political cohesion, leadership, and entrepreneurship; conditions of good governance; and structures of consultation that allow for leveraging even limited degrees of sovereignty for political, economic, and cultural advancement

A structural analysis of the AAA+ domains in Saccharomyces cerevisiae cytoplasmic dynein

AbstractDyneins are large protein complexes that act as microtubule based molecular motors. The dynein heavy chain contains a motor domain which is a member of the AAA+ protein family (ATPases Associated with diverse cellular Activities). Proteins of the AAA+ family show a diverse range of functionalities, but share a related core AAA+ domain, which often assembles into hexameric rings. Dynein is unusual because it has all six AAA+ domains linked together, in one long polypeptide. The dynein motor domain generates movement by coupling ATP driven conformational changes in the AAA+ ring to the swing of a motile element called the linker. Dynein binds to its microtubule track via a long antiparallel coiled-coil stalk that emanates from the AAA+ ring. Recently the first high resolution structures of the dynein motor domain were published. Here we provide a detailed structural analysis of the six AAA+ domains using our Saccharomyces cerevisiae crystal structure. We describe how structural similarities in the dynein AAA+ domains suggest they share a common evolutionary origin. We analyse how the different AAA+ domains have diverged from each other. We discuss how this is related to the function of dynein as a motor protein and how the AAA+ domains of dynein compare to those of other AAA+ proteins

Selective Lanthanide Sensing with Gold Nanoparticles and Hydroxypyridinone Chelators.

The octadentate hydroxypyridinone chelator 3,4,3-LI(1,2-HOPO) is a promising therapeutic agent because of its high affinity for f-block elements and noncytotoxicity at medical dosages. The interaction between 3,4,3-LI(1,2-HOPO) and other biomedically relevant metals such as gold, however, has not been explored. Gold nanoparticles functionalized with chelators have demonstrated great potential in theranostics, yet thus far, no protocol that combines 3,4,3-LI(1,2-HOPO) and colloidal gold has been developed. Here, we characterize the solution thermodynamic properties of the complexes formed between 3,4,3-LI(1,2-HOPO) and Au3+ ions and demonstrate how under specific pH conditions the chelator promotes the growth of gold nanoparticles, acting as both reducing and stabilizing agent. 3,4,3-LI(1,2-HOPO) ligands on the nanoparticle surface remain active and selective toward f-block elements, as evidenced by gold nanoparticle selective aggregation. Finally, a new colorimetric assay capable of reaching the detection levels necessary for the quantification of lanthanides in waste from industrial processes is developed based on the inhibition of particle growth by lanthanides

Slowing rates of regional exhumation in the western Himalaya: fission track evidence from the Indus Fan

Weuse apatite fission track ages from sediments recovered by the International Ocean Discovery Program in the Laxmi Basin, Arabian Sea, to constrain exhumation rates in the western Himalaya and Karakoram since 15.5 Ma. With the exception of a Triassic population in the youngest 0.93 Ma samples supplied from western Peninsular India, apatite fission track ages are overwhelmingly Cenozoic, largely <25 Ma, consistent with both a Himalaya–Karakoram source and rapid erosion. Comparison of the minimum cooling age of each sample with depositional age (lag time) indicates an acceleration in exhumation between 7.8 and 7.0 Ma, with lag times shortening from ∼6.0 Myr at 8.5–7.8 Ma to being within error of zero between 7.0 and 5.7 Ma. Sediment supply at 7.0–5.7 Mawas largely from the Karakoram, and to a lesser extent the Himalaya, based on U–Pb zircon ages from the same samples. This time coincides with a period of drying in the Himalayan foreland caused by weaker summermonsoons andWesterly winds. It also correlates with a shift of erosion away from the Karakoram, Kohistan and the Tethyan Himalaya towards more erosion of the Lesser and Greater Himalaya and Nanga Parbat, as shown by zircon U–Pb provenance data, and especially after 5.7 Ma based on Nd isotope data. Samples younger than 5.7 Ma have lag times of ∼4.5 Myr, similar to Holocene Indus delta sediments

Cost effectiveness of a general practice chronic disease management plan for coronary heart disease in Australia

Background. The cost effectiveness of a general practice-based program for managing coronary heart disease (CHD) patients in Australia remains uncertain. We have explored this through an economic model.Methods. A secondary prevention program based on initial clinical assessment and 3 monthly review, optimising of pharmacotherapies and lifestyle modification, supported by a disease registry and financial incentives for quality of care and outcomes achieved was assessed in terms of incremental cost effectiveness ratio (ICER), in Australian dollars per disability adjusted life year (DALY) prevented.Results. Based on 2006 estimates, 263 487 DALYs were attributable to CHD in Australia. The proposed program would add $115 650 000 to the annual national heath expenditure. Using an estimated 15$8081 per DALY prevented. With more conservative estimates of effectiveness and uptake, estimates of up to $38 316 per DALY are observed in sensitivity analysis.Conclusions. Although innovation in CHD management promises improved future patient outcomes, many therapies and strategies proven to reduce morbidity and mortality are available today. A general practice-based program for the optimal application of current therapies is likely to be cost-effective and provide substantial and sustainable benefits to the Australian community.What is known about this topic? Chronic disease management programs are known to provide gains with respect to reductions in death and disability among patients with coronary heart disease. The cost effectiveness of such programs in the Australian context is not known.What does this paper add? This paper suggests that implementing a coronary heart disease program in Australia is highly cost-effective across a broad range of assumptions of uptake and effectiveness.What are the implications for practitioners? These data provide the economic rationale for the implementation of a chronic disease management program with a disease registry and regular review in Australia

Plasma Heating Simulation in the VASIMR System

The paper describes the recent development in the simulation of the ion-cyclotron acceleration of the plasma in the VASIMR experiment. The modeling is done using an improved EMIR code for RF field calculation together with particle trajectory code for plasma transport calculat ion. The simulation results correlate with experimental data on the p lasma loading and predict higher ICRH performance for a higher density plasma target. These simulations assist in optimizing the ICRF anten na so as to achieve higher VASIMR efficiency

Discovery of a meteoritic ejecta layer containing unmelted impactor fragments at the base of Paleocene lavas, Isle of Skye, Scotland

Evidence for meteorite impacts in the geological record may include the presence of shocked minerals, spherule layers, and geochemical anomalies. However, it is highly unusual to nd unmelted crystals from the actual impactor within an ejecta layer. Here we detail the rst recorded occurrence of vanadium-rich osbornite (TiVN) on Earth, from two sites on Skye, northwest Scotland, which are interpreted as part of a meteoritic ejecta layer. TiVN has only previously been reported as dust from comet Wild 2, but on Skye it has been identi ed as an unmelted phase. Both ejecta layer sites also contain niobium-rich osbornite (TiNbN), which has not previously been reported. An extraterrestrial origin for these deposits is strongly supported by the presence of reidite (a high-pressure zircon polymorph), which is only found naturally at sites of meteorite impact. Barringerite [(Fe,Ni)2P], baddeleyite (ZrO2), alabandite (MnS), and carbon-bearing native iron spherules, together with planar deformation features and diaplectic glass in quartz, further support this thesis. We demonstrate through eld relationships and Ar-Ar dating that the meteorite strike occurred during the mid-Paleocene. This is the rst recorded mid-Paleocene impact event in the region and is coincident with the onset of magmatism in the British Palaeogene Igneous Province (BPIP). The Skye ejecta layer deposits provoke important questions regarding their lateral extent at the base of the BPIP and the possibility of their presence elsewhere beneath the much larger North Atlantic Igneous Province