J. L. Austin and literal meaning

Alice Crary has recently developed a radical reading of J. L. Austin's philosophy of language. The central contention of Crary's reading is that Austin gives convincing reasons to reject the idea that sentences have context-invariant literal meaning. While I am in sympathy with Crary about the continuing importance of Austin's work, and I think Crary's reading is deep and interesting, I do not think literal sentence meaning is one of Austin's targets, and the arguments that Crary attributes to Austin or finds Austinian in spirit do not provide convincing reasons to reject literal sentence meaning. In this paper, I challenge Crary's reading of Austin and defend the idea of literal sentence meaning

Yucca Mountain licensing support network archive assistant.

This report describes the Licensing Support Network (LSN) Assistant--a set of tools for categorizing e-mail messages and documents, and investigating and correcting existing archives of categorized e-mail messages and documents. The two main tools in the LSN Assistant are the LSN Archive Assistant (LSNAA) tool for recategorizing manually labeled e-mail messages and documents and the LSN Realtime Assistant (LSNRA) tool for categorizing new e-mail messages and documents. This report focuses on the LSNAA tool. There are two main components of the LSNAA tool. The first is the Sandia Categorization Framework, which is responsible for providing categorizations for documents in an archive and storing them in an appropriate Categorization Database. The second is the actual user interface, which primarily interacts with the Categorization Database, providing a way for finding and correcting categorizations errors in the database. A procedure for applying the LSNAA tool and an example use case of the LSNAA tool applied to a set of e-mail messages are provided. Performance results of the categorization model designed for this example use case are presented

Improving human effectiveness for extreme-scale problem solving : final report (assessing the effectiveness of electronic brainstorming in an industrial setting).

An experiment was conducted comparing the effectiveness of individual versus group electronic brainstorming in order to address difficult, real world challenges. While industrial reliance on electronic communications has become ubiquitous, empirical and theoretical understanding of the bounds of its effectiveness have been limited. Previous research using short-term, laboratory experiments have engaged small groups of students in answering questions irrelevant to an industrial setting. The current experiment extends current findings beyond the laboratory to larger groups of real-world employees addressing organization-relevant challenges over the course of four days. Findings are twofold. First, the data demonstrate that (for this design) individuals perform at least as well as groups in producing quantity of electronic ideas, regardless of brainstorming duration. However, when judged with respect to quality along three dimensions (originality, feasibility, and effectiveness), the individuals significantly (p<0.05) out performed the group working together. The theoretical and applied (e.g., cost effectiveness) implications of this finding are discussed. Second, the current experiment yielded several viable solutions to the wickedly difficult problem that was posed

Wnt signaling exerts an antiproliferative effect on adult cardiac progenitor cells through IGFBP3.

RATIONALE: Recent work in animal models and humans has demonstrated the presence of organ-specific progenitor cells required for the regenerative capacity of the adult heart. In response to tissue injury, progenitor cells differentiate into specialized cells, while their numbers are maintained through mechanisms of self-renewal. The molecular cues that dictate the self-renewal of adult progenitor cells in the heart, however, remain unclear. OBJECTIVE: We investigate the role of canonical Wnt signaling on adult cardiac side population (CSP) cells under physiological and disease conditions. METHODS AND RESULTS: CSP cells isolated from C57BL/6J mice were used to study the effects of canonical Wnt signaling on their proliferative capacity. The proliferative capacity of CSP cells was also tested after injection of recombinant Wnt3a protein (r-Wnt3a) in the left ventricular free wall. Wnt signaling was found to decrease the proliferation of adult CSP cells, both in vitro and in vivo, through suppression of cell cycle progression. Wnt stimulation exerted its antiproliferative effects through a previously unappreciated activation of insulin-like growth factor binding protein 3 (IGFBP3), which requires intact IGF binding site for its action. Moreover, injection of r-Wnt3a after myocardial infarction in mice showed that Wnt signaling limits CSP cell renewal, blocks endogenous cardiac regeneration and impairs cardiac performance, highlighting the importance of progenitor cells in maintaining tissue function after injury. CONCLUSIONS: Our study identifies canonical Wnt signaling and the novel downstream mediator, IGFBP3, as key regulators of adult cardiac progenitor self-renewal in physiological and pathological states

Knowledge Discovery and Data Mining (KDDM) survey report.

The large number of government and industry activities supporting the Unit of Action (UA), with attendant documents, reports and briefings, can overwhelm decision-makers with an overabundance of information that hampers the ability to make quick decisions often resulting in a form of gridlock. In particular, the large and rapidly increasing amounts of data and data formats stored on UA Advanced Collaborative Environment (ACE) servers has led to the realization that it has become impractical and even impossible to perform manual analysis leading to timely decisions. UA Program Management (PM UA) has recognized the need to implement a Decision Support System (DSS) on UA ACE. The objective of this document is to research the commercial Knowledge Discovery and Data Mining (KDDM) market and publish the results in a survey. Furthermore, a ranking mechanism based on UA ACE-specific criteria has been developed and applied to a representative set of commercially available KDDM solutions. In addition, an overview of four R&D areas identified as critical to the implementation of DSS on ACE is provided. Finally, a comprehensive database containing detailed information on surveyed KDDM tools has been developed and is available upon customer request

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Decreased Neutrophil Apoptosis in Quiescent ANCA-Associated Systemic Vasculitis

Background: ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues. Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV. less thanbrgreater than less thanbrgreater thanMethods: Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS. Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA. Expression of pro/anti-apoptotic factors, transcription factors C/EBP-alpha, C/EBP-beta and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR. less thanbrgreater than less thanbrgreater thanResults: AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50 +/- 14% vs. HBD 64 +/- 11%, p andlt; 0.0001). In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1. AASV patients had normal levels of G-CSF, GM-CSF and IL-3. Both C/EBP-alpha, C/EBP-beta were significantly higher in neutrophils from AASV patients than HBD. Levels of sFAS were significantly higher in AASV compared to HBD. less thanbrgreater than less thanbrgreater thanConclusion: Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ. Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV. Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.Funding Agencies|Swedish Research Council|71X-15152|Crafoord Foundation||</p

Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in over 140,000 European Descendants

Genome-wide association study–identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 × 10−6, a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 × 10−6 after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. SIGNIFICANCE: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer

Use of Zebrafish to Probe the Divergent Virulence Potentials and Toxin Requirements of Extraintestinal Pathogenic Escherichia coli

Extraintestinal pathogenic E. coli (ExPEC) cause an array of diseases, including sepsis, neonatal meningitis, and urinary tract infections. Many putative virulence factors that might modulate ExPEC pathogenesis have been identified through sequencing efforts, epidemiology, and gene expression profiling, but few of these genes have been assigned clearly defined functional roles during infection. Using zebrafish embryos as surrogate hosts, we have developed a model system with the ability to resolve diverse virulence phenotypes and niche-specific restrictions among closely related ExPEC isolates during either localized or systemic infections. In side-by-side comparisons of prototypic ExPEC isolates, we observed an unexpectedly high degree of phenotypic diversity that is not readily apparent using more traditional animal hosts. In particular, the capacity of different ExPEC isolates to persist and multiply within the zebrafish host and cause disease was shown to be variably dependent upon two secreted toxins, α-hemolysin and cytotoxic necrotizing factor. Both of these toxins appear to function primarily in the neutralization of phagocytes, which are recruited in high numbers to sites of infection where they act as an essential host defense against ExPEC as well as less virulent E. coli strains. These results establish zebrafish as a valuable tool for the elucidation and functional analysis of both ExPEC virulence factors and host defense mechanisms

Antimicrobial proteins and polypeptides in pulmonary innate defence

Inspired air contains a myriad of potential pathogens, pollutants and inflammatory stimuli. In the normal lung, these pathogens are rarely problematic. This is because the epithelial lining fluid in the lung is rich in many innate immunity proteins and peptides that provide a powerful anti-microbial screen. These defensive proteins have anti-bacterial, anti- viral and in some cases, even anti-fungal properties. Their antimicrobial effects are as diverse as inhibition of biofilm formation and prevention of viral replication. The innate immunity proteins and peptides also play key immunomodulatory roles. They are involved in many key processes such as opsonisation facilitating phagocytosis of bacteria and viruses by macrophages and monocytes. They act as important mediators in inflammatory pathways and are capable of binding bacterial endotoxins and CPG motifs. They can also influence expression of adhesion molecules as well as acting as powerful anti-oxidants and anti-proteases. Exciting new antimicrobial and immunomodulatory functions are being elucidated for existing proteins that were previously thought to be of lesser importance. The potential therapeutic applications of these proteins and peptides in combating infection and preventing inflammation are the subject of ongoing research that holds much promise for the future