The D153del mutation in GNB3 gene causes tissue specific signalling patterns and an abnormal renal morphology in rge chickens

Background The GNB3 gene is expressed in cone but not rod photoreceptors of vertebrates, where it acts as the β transducin subunit in the colour visual transduction process. A naturally occurring mutation ‘D153del’ in the GNB3 gene causes the recessively inherited blinding phenotype retinopathy globe enlarged (rge) disease in chickens. GNB3 is however also expressed in most other vertebrate tissues suggesting that the D153del mutation may exert pathological effects that outlie from eye. Principal Findings Recombinant studies in COS-7 cells that were transfected with normal and mutant recombinant GNB3 constructs and subjected to cycloheximide chase showed that the mutant GNB3d protein had a much shorter half life compared to normal GNB3. GNB3 codes for the Gβ3 protein subunit that, together with different Gγ and Gα subunits, activates and regulates phosphorylation cascades in different tissues. As expected, the relative levels of cGMP and cAMP secondary messengers and their activated kinases such as MAPK, AKT and GRK2 were also found to be altered significantly in a tissue specific manner in rge chickens. Histochemical analysis on kidney tissue sections, from rge homozygous affected chickens, showed the chickens had enlargement of the glomerular capsule, causing glomerulomegaly and tubulointerstitial inflammation whereas other tissues (brain, heart, liver, pancreas) were unaffected. Significance These findings confirm that the D153del mutation in GNB3 gene targets GNB3 protein to early degradation. Lack of GNB3 signalling causes reduced phosphorylation activity of ERK2 and AKT leading to severe pathological phenotypes such as blindness and renal abnormalities in rge chickens

Ares V and Future Very Large Launch Vehicles to Enable Major Astronomical Missions

The current NASA architecture intended to return humans to the lunar surface includes the Ares V cargo launch vehicle, which is planned to be available within a decade. The capabilities designed for Ares V would permit an 8.8-m diameter, 55 mT payload to be carried to Sun-Earth L1,2 locations. That is, this vehicle could launch very large optical systems to achieve major scientific goals that would otherwise be very difficult. For example, an 8-m monolith UV/visual/IR telescope appears able to be launched to a Sun-Earth L2 location. Even larger apertures that are deployed or assembled seem possible. Alternatively, multiple elements of a spatial array or two or three astronomical observatories might be launched simultaneously. Over the years, scientists and engineers have been evaluating concepts for astronomical observatories that use future large launch vehicles. In this presentation, we report on results of a recent workshop held at NASA Ames Research Center that have improved understanding of the science goals that can be achieved using Ares V. While such a vehicle uniquely enables few of the observatory concepts considered at the workshop, most have a baseline mission that can be flown on existing or near-future vehicles. However, the performance of the Ares V permits design concepts (e.g., large monolithic mirrors) that reduce complexity and risk

Does the Constellation Program Offer Opportunities to Achieve Space Science Goals in Space?

Future space science missions developed to achieve the most ambitious goals are likely to be complex, large, publicly and professionally very important, and at the limit of affordability. Consequently, it may be valuable if such missions can be upgraded, repaired, and/or deployed in space, either with robots or with astronauts. In response to a Request for Information from the US National Research Council panel on Science Opportunities Enabled by NASA's Constellation System, we developed a concept for astronaut-based in-space servicing at the Earth-Moon L1,2 locations that may be implemented by using elements of NASA's Constellation architecture. This libration point jobsite could be of great value for major heliospheric and astronomy missions operating at Earth-Sun Lagrange points. We explored five alternative servicing options that plausibly would be available within about a decade. We highlight one that we believe is both the least costly and most efficiently uses Constellation hardware that appears to be available by mid-next decade: the Ares I launch vehicle, Orion/Crew Exploration Vehicle, Centaur vehicle, and an airlock/servicing node developed for lunar surface operations. Our concept may be considered similar to the Apollo 8 mission: a valuable exercise before descent by astronauts to the lunar surface

Supersymmetric particle mass measurement with the boost-corrected contransverse mass

A modification to the contransverse mass (MCT) technique for measuring the masses of pair-produced semi-invisibly decaying heavy particles is proposed in which MCT is corrected for non-zero boosts of the centre-of-momentum (CoM) frame of the heavy states in the laboratory transverse plane. Lack of knowledge of the mass of the CoM frame prevents exact correction for this boost, however it is shown that a conservative correction can nevertheless be derived which always generates an MCT value which is less than or equal to the true value of MCT in the CoM frame. The new technique is demonstrated with case studies of mass measurement with fully leptonic ttbar events and with SUSY events possessing a similar final state.Comment: 33 pages, 33 .eps figures, JHEP3 styl

Constraining Dark Matter in the MSSM at the LHC

In the event that R-Parity conserving supersymmetry (SUSY) is discovered at the LHC, a key issue which will need to be addressed will be the consistency of that signal with astrophysical and non-accelerator constraints on SUSY Dark Matter. This issue is studied for the SPA benchmark model based on measurements of end-points and thresholds in the invariant mass spectra of various combinations of leptons and jets. These measurements are used to constrain the soft SUSY breaking parameters at the electroweak scale in a general MSSM model. Based on these constraints, we assess the accuracy with which the Dark Matter relic density can be measured.Comment: 21 pages, 12 figure

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

American Society of Clinical Oncology/College ofAmerican Pathologists guideline recommendations forimmunohistochemical testing of estrogen andprogesterone receptors in breast cancer

Purpose: To develop a guideline to improve theaccuracy of immunohistochemical (IHC) estrogen receptor(ER) and progesterone receptor (PgR) testing in breastcancer and the utility of these receptors as predictivemarkers.Methods: The American Society of Clinical Oncologyand the College of American Pathologists convened aninternational Expert Panel that conducted a systematicreview and evaluation of the literature in partnership withCancer Care Ontario and developed recommendations foroptimal IHC ER/PgR testing performance.Results: Up to 20% of current IHC determinations ofER and PgR testing worldwide may be inaccurate (falsenegative or false positive). Most of the issues with testinghave occurred because of variation in preanalyticvariables, thresholds for positivity, and interpretationcriteria.Recommendations: The Panel recommends that ER andPgR status be determined on all invasive breast cancers andbreast cancer recurrences. A testing algorithm that relieson accurate, reproducible assay performance is proposed.Elements to reliably reduce assay variation are specified. It is recommended that ER and PgR assays be consideredpositive if there are at least 1% positive tumor nuclei in the sample on testing in the presence of expected reactivity of internal (normal epithelial elements) and external controls. The absence of benefit from endocrine therapy for women with ER-negative invasive breast cancers has been confirmed in large overviews of randomized clinical trials.(Arch Pathol Lab Med. 2010;134:907–922

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations