What role does common ground play in the production of utterances? We outline and test two models. One model assumes that common ground is involved in initial utterance planning, while the other ...model assumes that it only plays a role in monitoring. To compare these models, we focus on common ground as evidenced in physical co-presence. We had speakers describe objects for listeners in a modified version of the referential communication task. While descriptions under no time constraints appeared to incorporate common ground with the listener, common ground was not used when the speakers were under time pressure. These results suggest that speakers do not engage in audience design in the initial planning of utterances; instead, they monitor those plans for violations of common ground.
Fibroblast growth factor receptor 3 (FGFR3) is a major negative regulator of bone growth that inhibits the proliferation and differentiation of growth plate chondrocytes. Activating mutations of its ...c isoform cause dwarfism in humans; somatic mutations can drive oncogenic transformation in multiple myeloma and bladder cancer. How these distinct activities arise is not clear. FGFR3 was previously shown to undergo proteolytic cleavage in the bovine rib growth plate, but this was not explored further. Here, we show that FGF1 induces regulated intramembrane proteolysis (RIP) of FGFR3. The ectodomain is proteolytically cleaved (S1) in response to ligand-induced receptor activation, but unlike most RIP target proteins, it requires endocytosis and does not involve a metalloproteinase. S1 cleavage generates a C-terminal domain fragment that initially remains anchored in the membrane, is phosphorylated, and is spatially distinct from the intact receptor. Ectodomain cleavage is followed by intramembrane cleavage (S2) to generate a soluble intracellular domain that is released into the cytosol and can translocate to the nucleus. We identify the S1 cleavage site and show that γ-secretase mediates the S2 cleavage event. In this way we demonstrate a mechanism for the nuclear localization of FGFR3 in response to ligand activation, which may occur in both development and disease.
On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious
mutation (germline and/or somatic)-associated ...advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDx
test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious
and/or
mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with
mutation-associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% 57/106; 95% confidence interval (CI), 44-64, and median duration of response was 9.2 months (95% CI, 6.6-11.7). The approved companion diagnostic verified tumor
mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval.
.
New approaches to blending geoscience, planetary science, microbiology-geobiology/ecology, geoinformatics and cyberinfrastructure technology disciplines in a holistic effort can be transformative to ...astrobiology explorations. Over the last two decades, overwhelming orbital evidence has confirmed the abundance of authigenic (
, formed in place) minerals on Mars. On Earth, environments where authigenic minerals form provide a substrate for the preservation of microbial life. Similarly, extraterrestrial life is likely to be preserved where crustal minerals can record and preserve the biochemical mechanisms (i.e., biosignatures). The search for astrobiological evidence on Mars has focused on identifying past or present habitable environments - places that could support some semblance of life. Thus, authigenic minerals represent a promising habitable environment where extraterrestrial life could be recorded and potentially preserved over geologic time scales. Astrobiology research necessarily takes place over vastly different scales; from molecules to viruses and microbes to those of satellites and solar system exploration, but the differing scales of analyses are rarely connected quantitatively. The mismatch between the scales of these observations- from the macro- satellite mineralogical observations to the micro- microbial observations- limits the applicability of our astrobiological understanding as we search for records of life beyond Earth. Each-scale observation requires knowledge of the geologic context and the environmental parameters important for assessing habitability. Exploration efforts to search for extraterrestrial life should attempt to quantify both the geospatial context and the temporal/spatial relationships between microbial abundance and diversity within authigenic minerals at multiple scales, while assimilating resolutions from satellite observations to field measurements to microscopic analyses. Statistical measures, computer vision, and the geospatial synergy of Geographic Information Systems (GIS), can allow analyses of objective data-driven methods to locate, map, and predict where the "sweet spots" of habitable environments occur at multiple scales. This approach of science information architecture or an "Astrobiology Information System" can provide the necessary maps to guide researchers to discoveries via testing, visualizing, documenting, and collaborating on significant data relationships that will advance explorations for evidence of life in our solar system and beyond.
ATP-Citrate Lyase Deficiency in the Mouse Beigneux, Anne P.; Kosinski, Cynthia; Gavino, Bryant ...
Journal of biological chemistry/The Journal of biological chemistry,
03/2004, Volume:
279, Issue:
10
Journal Article
Peer reviewed
Open access
ATP-citrate lyase (Acly) is one of two cytosolic enzymes that synthesize acetyl-coenzyme A (CoA). Because acetyl-CoA is an essential building block for cholesterol and triglycerides, Acly has been ...considered a therapeutic target for hyperlipidemias and obesity. To define the phenotype of Acly-deficient mice, we created Acly knockout mice in which a β-galactosidase marker is expressed from Acly regulatory sequences. We also sought to define the cell type-specific expression patterns of Acly to further elucidate the in vivo roles of the enzyme. Homozygous Acly knockout mice died early in development. Heterozygous mice were healthy, fertile, and normolipidemic on both chow and high fat diets, despite expressing half-normal amounts of Acly mRNA and protein. Fibroblasts and hepatocytes from heterozygous Acly mice contained half-normal amounts of Acly mRNA and protein, but this did not perturb triglyceride and cholesterol synthesis or the expression of lipid biosynthetic genes regulated by sterol regulatory element-binding proteins. The expression of acetyl-CoA synthetase 1, another cytosolic enzyme for producing acetyl-CoA, was not up-regulated. As judged by β-galactosidase staining, Acly was expressed ubiquitously but was expressed particularly highly in tissues with high levels of lipogenesis, such as in the livers of mice fed a high-carbohydrate diet. β-Galactosidase staining was intense in the developing brain, in keeping with the high levels of de novo lipogenesis of the tissue. In the adult brain, β-galactosidase staining was in general much lower, consistent with reduced levels of lipogenesis; however, β-galactosidase expression remained very high in cholinergic neurons, likely reflecting the importance of Acly in generating acetyl-CoA for acetylcholine synthesis. The Acly knockout allele is useful for identifying cell types with a high demand for acetyl-CoA synthesis.
Glycated hemoglobin (HbA1c), a standard measure of chronic glycemia for managing diabetes, has been proposed to diagnose diabetes and identify people at risk. The Diabetes Prevention Program (DPP) ...was a 3.2-year randomized clinical trial of preventing type 2 diabetes with a 10-year follow-up study, the DPP Outcomes Study (DPPOS). We evaluated baseline HbA1c as a predictor of diabetes and determined the effects of treatments on diabetes defined by an HbA1c ≥6.5% (48 mmol/mol).
We randomized 3,234 nondiabetic adults at high risk of diabetes to placebo, metformin, or intensive lifestyle intervention and followed them for the development of diabetes as diagnosed by fasting plasma glucose (FPG) and 2-h postload glucose (2hPG) concentrations (1997 American Diabetes Association ADA criteria). HbA1c was measured but not used for study eligibility or outcomes. We now evaluate treatment effects in the 2,765 participants who did not have diabetes at baseline according to FPG, 2hPG, or HbA1c (2010 ADA criteria).
Baseline HbA1c predicted incident diabetes in all treatment groups. Diabetes incidence defined by HbA1c ≥6.5% was reduced by 44% by metformin and 49% by lifestyle during the DPP and by 38% by metformin and 29% by lifestyle throughout follow-up. Unlike the primary DPP and DPPOS findings based on glucose criteria, metformin and lifestyle were similarly effective in preventing diabetes defined by HbA1c.
HbA1c predicted incident diabetes. In contrast to the superiority of the lifestyle intervention on glucose-defined diabetes, metformin and lifestyle interventions had similar effects in preventing HbA1c-defined diabetes. The long-term implications for other health outcomes remain to be determined.
Lifestyle interventions have been shown to improve physical function over the short term; however, whether these benefits are sustainable is unknown. The long-term effects of an intensive lifestyle ...intervention (ILI) on physical function were assessed using a randomized post-test design in the Look AHEAD trial.
Overweight and obese (body mass index ≥ 25 kg/m2) middle-aged and older adults (aged 45-76 years at enrollment) with type 2 diabetes enrolled in Look AHEAD, a trial evaluating an ILI designed to achieve weight loss through caloric restriction and increased physical activity compared to diabetes support and education (DSE), underwent standardized assessments of performance-based physical function including a 4- and 400-m walk, lower extremity physical performance (expanded Short Physical Performance Battery, SPPBexp), and grip strength approximately 11 years postrandomization and 1.5 years after the intervention was stopped (n = 3,783).
Individuals randomized to ILI had lower odds of slow gait speed (<0.8 m/s) compared to those randomized to DSE (adjusted OR 95% CI: 0.84 0.71 to 0.99). Individuals randomized to ILI also had faster gait speed over 4- and 400-m (adjusted mean difference 95% CI: 0.019 0.007 to 0.031 m/s, p = .002, and 0.023 0.012 to 0.034 m/sec, p < .0001, respectively) and higher SPPBexp scores (0.037 0.011 to 0.063, p = .005) compared to those randomized to DSE. The intervention effect was slightly larger for SPPBexp scores among older versus younger participants (0.081 0.038 to 0.124 vs 0.013 -0.021 to 0.047, p = .01).
An intensive lifestyle intervention has modest but significant long-term benefits on physical function in overweight and obese middle-aged and older adults with type 2 diabetes.
NCT00017953.
Fibroblast growth factor receptor 3 (FGFR3) is a key regulator of growth and differentiation, whose aberrant activation causes a number of genetic diseases including achondroplasia and cancer. Hsp90 ...is a specialized molecular chaperone involved in stabilizing a select set of proteins termed clients. Here, we delineate the relationship of Hsp90 and co-chaperone Cdc37 with FGFR3 and the FGFR family. FGFR3 strongly associates with these chaperone complexes and depends on them for stability and function. Inhibition of Hsp90 function using the geldanamycin analog 17-AAG induces the ubiquitination and degradation of FGFR3 and reduces the signaling capacity of FGFR3. Other FGFRs weakly interact with these chaperones and are differentially influenced by Hsp90 inhibition. The Hsp90-related ubiquitin ligase CHIP is able to interact and destabilize FGFR3. Our results establish FGFR3 as a strong Hsp90 client and suggest that modulating Hsp90 chaperone complexes may beneficially influence the stability and function of FGFR3 in disease.
PDF
