Treatment of experimental colitis in mice with LMP-420, an inhibitor of TNF transcription

© 2008 Hale and Cianciolo; licensee BioMed Central Ltd

Immunogenicity and protection conferred by a recombinant Mycobacterium marinum vaccine against Buruli ulcer

AbstractMycobacterium ulcerans (MU) infection causes the disfiguring necrotic skin disease, Buruli ulcer (BU). While vaccination with Mycobacterium bovis BCG provides nominal antigenic cross-reactivity for induction of immunity against experimental MU infection, a mycobacterial species with greater genetic homology to Mycobacterium ulcerans may serve as a richer source of cross-protective immunogens and lack the pathological features of MU-based vaccines. Mycobacterium marinum, a highly homologous genetic relative of MU, could be used to satisfy these criteria and, as such, we have generated a recombinant M. marinum strain expressing the immunodominant, protective MU-Ag85A. The immunogenicity and protection achieved by murine vaccination with this strain are superior to standard BCG vaccination and may serve as a foundation for developing more effective BU vaccines

Expression of CD44 molecules and CD44 ligands during human thymic fetal development: expression of CD44 isoforms is developmentally regulated

It has recently been recognized that CD44 comprises a large family of alternatively spliced forms.In the thymus, CD44 has been postulated to play an important role in immature T cell migration and maturation. In this paper, we have studied the expression of CD44 molecules and two CD44 ligands, hyaluronan (HA) and fibronectin (FN), during human thymic fetal development. We found that mAbs against all CD44 isoforms (A3D8 or A1G3) reacted with both thymic epithelial (TE) cells and thymocytes beginning at the time of initial colonization of the human thymus by hematopoietic stem cells at 8.2 weeks of fetal gestation. However, mAbs specific for splice variants of CD44 containing membrane-proximal inserts (11.24, 11.10 and 11.9) reacted only with terminally differentiated TE cells in and around Hassall's bodies beginning at 16-19 weeks of fetal gestation. Studies of differentiated versus undifferentiated TE cells in vitro confirmed the selective expression of CD44 variant isoforms on terminally differentiated TE cells. Expression of HA and FN was determined by fluorescence microscopy using either biotlnylated-HA binding protein or an anti-FN mAb. We found that whereas FN was present throughout the human fetal thymus beginning at 8.2 weeks, HA was not present until 16 weeks of gestational age. These data demonstrate the differential expression of standard versus variant CD44 isoforms during thymic ontogeny and implicate CD44 interactions with ligands other than HA as important in the earlier stages of humanthymus developmen

Bone Marrow–generated Dendritic Cells Pulsed with Tumor Extracts or Tumor RNA Induce Antitumor Immunity against Central Nervous System Tumors

Recent studies have shown that the brain is not a barrier to successful active immunotherapy that uses gene-modified autologous tumor cell vaccines. In this study, we compared the efficacy of two types of vaccines for the treatment of tumors within the central nervous system (CNS): dendritic cell (DC)-based vaccines pulsed with either tumor extract or tumor RNA, and cytokine gene–modified tumor vaccines. Using the B16/F10 murine melanoma (B16) as a model for CNS tumor, we show that vaccination with bone marrow–generated DCs, pulsed with either B16 cell extract or B16 total RNA, can induce specific cytotoxic T lymphocytes against B16 tumor cells. Both types of DC vaccines were able to protect animals from tumors located in the CNS. DC-based vaccines also led to prolonged survival in mice with tumors placed before the initiation of vaccine therapy. The DC-based vaccines were at least as effective, if not more so, as vaccines containing B16 tumor cells in which the granulocytic macrophage colony-stimulating factor gene had been modified. These data support the use of DC-based vaccines for the treatment of patients with CNS tumors

Connecting urban food plans to the countryside: leveraging Denver's food vision to explore meaningful rural-urban linkages

Includes bibliographical references (pages 14-18).Cities are increasingly turning to food policy plans to support goals related to food access, food security, the environment, and economic development. This paper investigates ways that rural farmers, communities, and economies can both support and be supported by metropolitan food-focused initiatives. Specifically, our research question asked what opportunities and barriers exist to developing food policies that support urban food goals, particularly related to local procurement, as well as rural economic development. To address this question, we described and analyzed a meeting of urban stakeholders and larger-scale rural producers related to Colorado’s Denver Food Vision and Plan. We documented and explored “findings” gleaned from a supply chain diagraming and data compilation process that were then used to inform an event that brought together diverse supply chain partners. Three findings stand out. First, facilitating dialog between urban food policymakers and rural producers to understand potential tensions, mitigate such tensions, and capitalize on opportunities is essential. Second, perceptions and expectations surrounding “good food” are nuanced—a timely finding given the number of preferred procurement programs emerging across the county. Third, critical evaluation is needed across a diverse set of value chain strategies (e.g., conventional and alternative distribution) if food policy intends to support heterogeneous producers, their communities, and urban food policy goals

Microbial nitrogen limitation in the mammalian large intestine

Resource limitation is a fundamental factor governing the composition and function of ecological communities. However, the role of resource supply in structuring the intestinal microbiome has not been established and represents a challenge for mammals that rely on microbial symbionts for digestion: too little supply might starve the microbiome while too much might starve the host. We present evidence that microbiota occupy a habitat that is limited in total nitrogen supply within the large intestines of 30 mammal species. Lowering dietary protein levels in mice reduced their faecal concentrations of bacteria. A gradient of stoichiometry along the length of the gut was consistent with the hypothesis that intestinal nitrogen limitation results from host absorption of dietary nutrients. Nitrogen availability is also likely to be shaped by host-microbe interactions: levels of host-secreted nitrogen were altered in germ-free mice and when bacterial loads were reduced via experimental antibiotic treatment. Single-cell spectrometry revealed that members of the phylum Bacteroidetes consumed nitrogen in the large intestine more readily than other commensal taxa did. Our findings support a model where nitrogen limitation arises from preferential host use of dietary nutrients. We speculate that this resource limitation could enable hosts to regulate microbial communities in the large intestine. Commensal microbiota may have adapted to nitrogen-limited settings, suggesting one reason why excess dietary protein has been associated with degraded gut-microbial ecosystems

Sec61 Inhibitor Apratoxin S4 Potently Inhibits SARS-CoV-2 and Exhibits Broad-Spectrum Antiviral Activity

There is a pressing need for host-directed therapeutics that elicit broad-spectrum antiviral activities to potentially address current and future viral pandemics. Apratoxin S4 (Apra S4) is a potent Sec61 inhibitor that prevents cotranslational translocation of secretory proteins into the endoplasmic reticulum (ER), leading to anticancer and antiangiogenic activity both in vitro and in vivo. Since Sec61 has been shown to be an essential host factor for viral proteostasis, we tested Apra S4 in cellular models of viral infection, including SARS-CoV-2, influenza A virus, and flaviviruses (Zika, West Nile, and Dengue virus). Apra S4 inhibited viral replication in a concentration-dependent manner and had high potency particularly against SARS-CoV-2 and influenza A virus, with subnanomolar activity in human cells. Characterization studies focused on SARS-CoV-2 revealed that Apra S4 impacted a post-entry stage of the viral life-cycle. Transmission electron microscopy revealed that Apra S4 blocked formation of stacked double-membrane vesicles, the sites of viral replication. Apra S4 reduced dsRNA formation and prevented viral protein production and trafficking of secretory proteins, especially the spike protein. Given the potent and broad-spectrum activity of Apra S4, further preclinical evaluation of Apra S4 and other Sec61 inhibitors as antivirals is warranted

Analyzing the building blocks of resilience: Findings from a baseline survey of the Tuungane Population, Health, and Environment Project in western Tanzania

Although the value of population, health, environment (PHE) programs is appreciated by the development community and the conceptual linkages they incorporate are sound, little evidence exists to demonstrate their short- and long-term impacts—particularly the role that the family planning (FP) component of PHE projects plays in building resilience, improving livelihoods, and helping people adapt to climate change. To contribute to filling this gap, the Evidence Project collaborated with Tuungane, a PHE project jointly implemented by The Nature Conservancy and Pathfinder International, to conduct further analysis of their existing data and examine the evidence base around integrated PHE programming, FP, climate change adaptation, and resilience. This paper analyzes data from the Tuungane Project baseline survey to show the pre-project level of knowledge and attitudes among village residents regarding their understanding and use of FP. We hope to use this analysis to inform future efforts that will look more deeply at the relationships among and between: FP and climate change adaptation, FP and resilience, and the pathways through which the FP and other components of PHE projects like Tuungane contribute to building resilience and enhancing the ability to adapt to climate change

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL