Superior infectivity for mosquito vectors contributes to competitive displacement among strains of dengue virus

<p>Abstract</p> <p>Background</p> <p>Competitive displacement of a weakly virulent pathogen strain by a more virulent strain is one route to disease emergence. However the mechanisms by which pathogens compete for access to hosts are poorly understood. Among vector-borne pathogens, variation in the ability to infect vectors may effect displacement. The current study focused on competitive displacement in dengue virus serotype 3 (DENV3), a mosquito-borne pathogen of humans. In Sri Lanka in the 1980's, a native DENV3 strain associated with relatively mild dengue disease was displaced by an invasive DENV3 strain associated with the most severe disease manifestations, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), resulting in an outbreak of DHF/DSS. Here we tested the hypothesis that differences between the invasive and native strain in their infectivity for <it>Aedes aegypti </it>mosquitoes, the primary vector of DENV, contributed to the competitive success of the invasive strain</p> <p>Results</p> <p>To be transmitted by a mosquito, DENV must infect and replicate in the midgut, disseminate into the hemocoel, infect the salivary glands, and be released into the saliva. The ability of the native and invasive DENV3 strains to complete the first three steps of this process in <it>Aedes aegypti </it>mosquitoes was measured <it>in vivo</it>. The invasive strain infected a similar proportion of mosquitoes as the native strain but replicated to significantly higher titers in the midgut and disseminated with significantly greater efficiency than the native strain. In contrast, the native and invasive strain showed no significant difference in replication in cultured mosquito, monkey or human cells.</p> <p>Conclusion</p> <p>The invasive DENV3 strain infects and disseminates in <it>Ae. aegypti </it>more efficiently than the displaced native DENV3 strain, suggesting that the invasive strain is transmitted more efficiently. Replication in cultured cells did not adequately characterize the known phenotypic differences between native and invasive DENV3 strains. Infection dynamics within the vector may have a significant impact on the spread and replacement of dengue virus lineages.</p

A Potent and Effective Suicidal Listeria Vaccine Platform.

Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection

Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading?

<p>Abstract</p> <p>Background</p> <p>Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels <150 mg/dL or ≥150 mg/dL.</p> <p>Results</p> <p>Both treatments significantly reduced LDL-C (and the cholesterol content of most LDL subfractions [LDL_1-4]) apolipoprotein B, non-HDL-C levels, but did not reduce the proportion of smaller, more dense LDL particles; in fact, the proportion of Pattern B was numerically increased. Results were generally similar in patients with triglyceride levels <150 or ≥150 mg/dL.</p> <p>Conclusions</p> <p>When assessing the effects of escalating cholesterol-lowering therapy, effects upon Pattern B alone to assess coronary heart disease risk may be misleading when interpreted without considerations of other lipid effects, such as reductions in LDL-C, atherogenic lipoprotein particle concentration, and non-HDL-C levels.</p> <p>Trial Registration</p> <p>(Registered at clinicaltrials.gov: Clinical trial # NCT00276484)</p

Effect on Fasting Serum Glucose Levels of Adding Ezetimibe to Statins in Patients With Nondiabetic Hypercholesterolemia

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Discovery of an intermediate-luminosity red transient in M51 and its likely dust-obscured, infrared-variable progenitor

We present the discovery of an optical transient (OT) in Messier 51, designated M51 OT2019-1 (also ZTF19aadyppr, AT 2019abn, ATLAS19bzl), by the Zwicky Transient Facility (ZTF). The OT rose over 15 days to an observed luminosity of $M_r=-13$ (${\nu}L_{\nu}=9\times10^6~L_{\odot}$), in the luminosity gap between novae and typical supernovae (SNe). Spectra during the outburst show a red continuum, Balmer emission with a velocity width of $\approx400$ km s$^{-1}$, Ca II and [Ca II] emission, and absorption features characteristic of an F-type supergiant. The spectra and multiband light curves are similar to the so-called "SN impostors" and intermediate-luminosity red transients (ILRTs). We directly identify the likely progenitor in archival Spitzer Space Telescope imaging with a $4.5~\mu$m luminosity of $M_{[4.5]}\approx-12.2$ and a $[3.6]-[4.5]$ color redder than 0.74 mag, similar to those of the prototype ILRTs SN 2008S and NGC 300 OT2008-1. Intensive monitoring of M51 with Spitzer further reveals evidence for variability of the progenitor candidate at [4.5] in the years before the OT. The progenitor is not detected in pre-outburst Hubble Space Telescope optical and near-IR images. The optical colors during outburst combined with spectroscopic temperature constraints imply a higher reddening of $E(B-V)\approx0.7$ mag and higher intrinsic luminosity of $M_r\approx-14.9$ (${\nu}L_{\nu}=5.3\times10^7~L_{\odot}$) near peak than seen in previous ILRT candidates. Moreover, the extinction estimate is higher on the rise than on the plateau, suggestive of an extended phase of circumstellar dust destruction. These results, enabled by the early discovery of M51 OT2019-1 and extensive pre-outburst archival coverage, offer new clues about the debated origins of ILRTs and may challenge the hypothesis that they arise from the electron-capture induced collapse of extreme asymptotic giant branch stars.Comment: 21 pages, 5 figures, published in ApJ

Evaluation of Life History Diversity, Habitat Connectivity, and Survival Benefits Associated with Habitat Restoration Actions in the Lower Columbia River and Estuary, Annual Report 2010

This report describes the 2010 research conducted under the U.S. Army Corps of Engineers (USACE) project EST-P-09-1, titled Evaluation of Life History Diversity, Habitat Connectivity, and Survival Benefits Associated with Habitat Restoration Actions in the Lower Columbia River and Estuary, and known as the 'Salmon Benefits' study. The primary goal of the study is to establish scientific methods to quantify habitat restoration benefits to listed salmon and trout in the lower Columbia River and estuary (LCRE) in three required areas: habitat connectivity, early life history diversity, and survival (Figure ES.1). The general study approach was to first evaluate the state of the science regarding the ability to quantify benefits to listed salmon and trout from habitat restoration actions in the LCRE in the 2009 project year, and then, if feasible, in subsequent project years to develop quantitative indices of habitat connectivity, early life history diversity, and survival. Based on the 2009 literature review, the following definitions are used in this study. Habitat connectivity is defined as a landscape descriptor concerning the ability of organisms to move among habitat patches, including the spatial arrangement of habitats (structural connectivity) and how the perception and behavior of salmon affect the potential for movement among habitats (functional connectivity). Life history is defined as the combination of traits exhibited by an organism throughout its life cycle, and for the purposes of this investigation, a life history strategy refers to the body size and temporal patterns of estuarine usage exhibited by migrating juvenile salmon. Survival is defined as the probability of fish remaining alive over a defined amount of space and/or time. The objectives of the 4-year study are as follows: (1) develop and test a quantitative index of juvenile salmon habitat connectivity in the LCRE incorporating structural, functional, and hydrologic components; (2) develop and test a quantitative index of the early life history diversity of juvenile salmon in the LCRE; (3) assess and, if feasible, develop and test a quantitative index of the survival benefits of tidal wetland habitat restoration (hydrologic reconnection) in the LCRE; and (4) synthesize the results of investigations into the indices for habitat connectivity, early life history diversity, and survival benefits

Can understanding reward help illuminate anhedonia?

Purpose of review: The goal of this paper is to examine how reward processing might help us understand the symptom of anhedonia. Recent findings: There are extensive reviews exploring the relationship between responses to rewarding stimuli and depression. These often include a discussion on anhedonia and how this might be underpinned in particular by dysfunctional reward processing. However, there is no specific consensus on whether studies to date have adequately examined the various sub-components of reward processing or how these might relate in turn to various aspects of anhedonia symptoms. Summary: The approach to understanding the symptom of anhedonia should be to examine all the sub-components of reward processing at the subjective and objective behavioural and neural level, with well validated tasks that can be replicated. Investigating real life experiences of anhedonia and how theses might be predicted by objective lab measures is also needed in future research

Cytotoxic T Lymphocyte Trafficking and Survival in an Augmented Fibrin Matrix Carrier

Cell-based therapies have intriguing potential for the treatment of a variety of neurological disorders. One such example is genetically engineered cytotoxic T lymphocytes (CTLs) that are being investigated in brain tumor clinical trials. The development of methods for CTL delivery is critical to their use in the laboratory and clinical setting. In our study, we determined whether CTLs can migrate through fibrin matrices and if their migration, survival, and function could be modulated by adding chemokines to the matrix. Our results indicated that CTLs can freely migrate through fibrin matrices. As expected, the addition of the monocyte chemotactic protein-1 (MCP-1), also known as chemokine C-C motif ligand 2 (CCL2), to the surrounding media increased egress of the CTLs out of the fibrin clot. Interleukin (IL) -2 and/or IL-15 embedded in the matrix enhanced T cell survival and further promoted T cell migration. The interleukin-13 receptor alpha 2 specific (IL-13R alpha2) T cells that traveled out of the fibrin clot retained the capacity to kill U251 glioma cells. In summary, CTLs can survive and migrate robustly in fibrin matrices. These processes can be influenced by modification of matrix constituents. We conclude that fibrin matrices may be suitable T cell carriers and can be used to facilitate understanding of T cell interaction with the surrounding microenvironment

G protein-coupled receptor-mediated calcium signaling in astrocytes

Astrocytes express a large variety of G~protein-coupled receptors (GPCRs) which mediate the transduction of extracellular signals into intracellular calcium responses. This transduction is provided by a complex network of biochemical reactions which mobilizes a wealth of possible calcium-mobilizing second messenger molecules. Inositol 1,4,5-trisphosphate is probably the best known of these molecules whose enzymes for its production and degradation are nonetheless calcium-dependent. We present a biophysical modeling approach based on the assumption of Michaelis-Menten enzyme kinetics, to effectively describe GPCR-mediated astrocytic calcium signals. Our model is then used to study different mechanisms at play in stimulus encoding by shape and frequency of calcium oscillations in astrocytes.Comment: 35 pages, 6 figures, 1 table, 3 appendices (book chapter