Dying without Dignity: Homeless Deaths in Los Angeles County: 2000 - 2007

This report is an investigation into 2,815 homeless deaths in Los Angeles County between January, 2000 and May, 2007, based on statistics provided by the Los Angeles County Coroner's office. When a homeless person dies they do not often get the same sense of dying with dignity as a housed person. December 21st has been commemorated as the National Homeless Persons' Memorial Day by the National Coalition for the Homeless in partnership with the National Health Care for the Homeless Council for communities around the nation to commemorate the lives of homeless people that passed away.Local advocates and service providers celebrate the lives of thousands of homeless people in hundreds of cities around the nation with candlelight vigils, a reading of names, and other acts to remember the lives of those lost while living on the streets of our nation.This report is an investigation into homeless deaths in Los Angeles County between January, 2000 and May, 2007, based on statistics from the Los Angeles County Coroner's office. It is our hope that the homeless people who make up the statistics in this report did not die in vain and that policy makers move to implement the recommendations of this report in an effort to provide the dignity they did not find while living on the streets of our community. Equally important, to implement these strategies to help prevent the untimely deaths of homeless people in the future

Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials

A recent joint meeting was held on January 30, 2014, with the US Food and Drug Administration (FDA), National Cancer Institute (NCI), clinical scientists, imaging experts, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocate groups to discuss imaging endpoints for clinical trials in glioblastoma. This workshop developed a set of priorities and action items including the creation of a standardized MRI protocol for multicenter studies. The current document outlines consensus recommendations for a standardized Brain Tumor Imaging Protocol (BTIP), along with the scientific and practical justifications for these recommendations, resulting from a series of discussions between various experts involved in aspects of neuro-oncology neuroimaging for clinical trials. The minimum recommended sequences include: (i) parameter-matched precontrast and postcontrast inversion recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo spin-echo acquired after contrast injection and before postcontrast 3D T1-weighted images to control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted images. Recommended ranges of sequence parameters are provided for both 1.5 T and 3 T MR system

Engineering the Melanocortin-4 Receptor to Control Constitutive and Ligand-Mediated Gs Signaling In Vivo

The molecular and functional diversity of G protein–coupled receptors is essential to many physiological processes. However, this diversity presents a significant challenge to understanding the G protein–mediated signaling events that underlie a specific physiological response. To increase our understanding of these processes, we sought to gain control of the timing and specificity of Gs signaling in vivo. We used naturally occurring human mutations to develop two Gs-coupled engineered receptors that respond solely to a synthetic ligand (RASSLs). Our Gs-coupled RASSLs are based on the melanocortin-4 receptor, a centrally expressed receptor that plays an important role in the regulation of body weight. These RASSLs are not activated by the endogenous hormone α-melanocyte-stimulating hormone but respond potently to a selective synthetic ligand, tetrahydroisoquinoline. The RASSL variants reported here differ in their intrinsic basal activities, allowing the separation of the effects of basal signaling from ligand-mediated activation of the Gs pathway in vivo. These RASSLs can be used to activate Gs signaling in any tissue, but would be particularly useful for analyzing downstream events that mediate body weight regulation in mice. Our study also demonstrates the use of human genetic variation for protein engineering

Low frequency observations of linearly polarized structures in the interstellar medium near the south Galactic pole

This is an author-created, un-copyedited version of an article published in The Astrophysical Journal. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at https://doi.org/10.3847/0004-637X/830/1/38We present deep polarimetric observations at 154 MHz with the Murchison Widefield Array (MWA), covering 625 deg^2 centered on RA=0 h, Dec=-27 deg. The sensitivity available in our deep observations allows an in-band, frequency-dependent analysis of polarized structure for the first time at long wavelengths. Our analysis suggests that the polarized structures are dominated by intrinsic emission but may also have a foreground Faraday screen component. At these wavelengths, the compactness of the MWA baseline distribution provides excellent snapshot sensitivity to large-scale structure. The observations are sensitive to diffuse polarized emission at ~54' resolution with a sensitivity of 5.9 mJy beam^-1 and compact polarized sources at ~2.4' resolution with a sensitivity of 2.3 mJy beam^-1 for a subset (400 deg^2) of this field. The sensitivity allows the effect of ionospheric Faraday rotation to be spatially and temporally measured directly from the diffuse polarized background. Our observations reveal large-scale structures (~1 deg - 8 deg in extent) in linear polarization clearly detectable in ~2 minute snapshots, which would remain undetectable by interferometers with minimum baseline lengths >110 m at 154 MHz. The brightness temperature of these structures is on average 4 K in polarized intensity, peaking at 11 K. Rotation measure synthesis reveals that the structures have Faraday depths ranging from -2 rad m^-2 to 10 rad m^-2 with a large fraction peaking at ~+1 rad m^-2. We estimate a distance of 51+/-20 pc to the polarized emission based on measurements of the in-field pulsar J2330-2005. We detect four extragalactic linearly polarized point sources within the field in our compact source survey. Based on the known polarized source population at 1.4 GHz and non-detections at 154 MHz, we estimate an upper limit on the depolarization ratio of 0.08 from 1.4 GHz to 154 MHz.Peer reviewedFinal Accepted Versio

Behavioral genetics and taste

This review focuses on behavioral genetic studies of sweet, umami, bitter and salt taste responses in mammals. Studies involving mouse inbred strain comparisons and genetic analyses, and their impact on elucidation of taste receptors and transduction mechanisms are discussed. Finally, the effect of genetic variation in taste responsiveness on complex traits such as drug intake is considered. Recent advances in development of genomic resources make behavioral genetics a powerful approach for understanding mechanisms of taste

Multivariate analysis of FcR-mediated NK cell functions identifies unique clustering among humans and rhesus macaques

Rhesus macaques (RMs) are a common pre-clinical model used to test HIV vaccine efficacy and passive immunization strategies. Yet, it remains unclear to what extent the Fc-Fc receptor (FcR) interactions impacting antiviral activities of antibodies in RMs recapitulate those in humans. Here, we evaluated the FcR-related functionality of natural killer cells (NKs) from peripheral blood of uninfected humans and RMs to identify intra- and inter-species variation. NKs were screened for FcγRIIIa (human) and FcγRIII (RM) genotypes (FcγRIII(a)), receptor signaling, and antibody-dependent cellular cytotoxicity (ADCC), the latter mediated by a cocktail of monoclonal IgG1 antibodies with human or RM Fc. FcγRIII(a) genetic polymorphisms alone did not explain differences in NK effector functionality in either species cohort. Using the same parameters, hierarchical clustering separated each species into two clusters. Importantly, in principal components analyses, ADCC magnitude, NK contribution to ADCC, FcγRIII(a) cell-surface expression, and frequency of phosphorylated CD3ζ NK cells all contributed similarly to the first principal component within each species, demonstrating the importance of measuring multiple facets of NK cell function. Although ADCC potency was similar between species, we detected significant differences in frequencies of NK cells and pCD3ζ+ cells, level of cell-surface FcγRIII(a) expression, and NK-mediated ADCC (P<0.001), indicating that a combination of Fc-FcR parameters contribute to overall inter-species functional differences. These data strongly support the importance of multi-parameter analyses of Fc-FcR NK-mediated functions when evaluating efficacy of passive and active immunizations in pre- and clinical trials and identifying correlates of protection. The results also suggest that pre-screening animals for multiple FcR-mediated NK function would ensure even distribution of animals among treatment groups in future preclinical trials

ReproPhylo:An environment for reproducible Phylogenomics

The reproducibility of experiments is key to the scientific process, and particularly necessary for accurate reporting of analyses in data-rich fields such as phylogenomics. We present ReproPhylo, a phylogenomic analysis environment developed to ensure experimental reproducibility, to facilitate the handling of large-scale data, and to assist methodological experimentation. Reproducibility, and instantaneous repeatability, is built in to the ReproPhylo system and does not require user intervention or configuration because it stores the experimental workflow as a single, serialized Python object containing explicit provenance and environment information. This 'single file' approach ensures the persistence of provenance across iterations of the analysis, with changes automatically managed by the version control program Git. This file, along with a Git repository, are the primary reproducibility outputs of the program. In addition, ReproPhylo produces an extensive human-readable report and generates a comprehensive experimental archive file, both of which are suitable for submission with publications. The system facilitates thorough experimental exploration of both parameters and data. ReproPhylo is a platform independent CC0 Python module and is easily installed as a Docker image or a WinPython self-sufficient package, with a Jupyter Notebook GUI, or as a slimmer version in a Galaxy distribution

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival