Extremely Metal-Poor Stars. VII. The Most Metal-Poor Dwarf, CS 22876-032

We report high-resolution, high-signal-to-noise, observations of the extremely metal-poor double-lined spectroscopic binary CS 22876-032. The system has a long period : P = 424.7 $\pm$ 0.6 days. It comprises two main sequence stars having effective temperatures 6300 K and 5600 K, with a ratio of secondary to primary mass of 0.89 $\pm$ 0.04. The metallicity of the system is [Fe/H] = -3.71 $\pm$ 0.11 $\pm$ 0.12 (random and systematic errors) -- somewhat higher than previous estimates. We find [Mg/Fe] = 0.50, typical of values of less extreme halo material. [Si/Fe], [Ca/Fe], and [Ti/Fe], however, all have significantly lower values, ~ 0.0-0.1, suggesting that the heavier elements might have been underproduced relative to Mg in the material from which this object formed. In the context of the hypothesis that the abundance patterns of extremely metal-poor stars are driven by individual enrichment events and the models of Woosley and Weaver (1995), the data for CS 22876-032 are consistent with its having been enriched by a zero-metallicity supernova of mass 30 M$_{\odot}$. As the most metal-poor near-main-sequence-turnoff star currently known, the primary of the system has the potential to strongly constrain the primordial lithium abundance. We find A(Li) (= log(N(Li)/N(H)) + 12.00) = 2.03 $\pm$ 0.07, which is consistent with the finding of Ryan et al. (1999) that for stars of extremely low metallicity A(Li) is a function of [Fe/H].Comment: 27 pages, 9 figures, accepted for publication in The Astrophysical Journal, Sept. 1, 2000 issu

Neuroantigen-specific, tolerogenic vaccines: GM-CSF is a fusion partner that facilitates tolerance rather than immunity to dominant self-epitopes of myelin in murine models of experimental autoimmune encephalomyelitis (EAE)

<p>Abstract</p> <p>Background</p> <p>Vaccination strategies that elicit antigen-specific tolerance are needed as therapies for autoimmune disease. This study focused on whether cytokine-neuroantigen (NAg) fusion proteins could inhibit disease in chronic murine models of experimental autoimmune encephalomyelitis (EAE) and thus serve as potential therapeutic modalities for multiple sclerosis.</p> <p>Results</p> <p>A fusion protein comprised of murine GM-CSF as the N-terminal domain and the encephalitogenic MOG35-55 peptide as the C-terminal domain was tested as a tolerogenic, therapeutic vaccine (TTV) in the C57BL/6 model of EAE. Administration of GMCSF-MOG before active induction of EAE, or alternatively, at the onset of EAE blocked the development and progression of EAE. Covalent linkage of the GM-CSF and MOG35-55 domains was required for tolerogenic activity. Likewise, a TTV comprised of GM-CSF and PLP139-151 was a tolerogen in the SJL model of EAE.</p> <p>Conclusion</p> <p>These data indicated that fusion proteins containing GM-CSF coupled to myelin auto-antigens elicit tolerance rather than immunity.</p

Oncogenic PI3K Mutations Lead to NF- B-Dependent Cytokine Expression following Growth Factor Deprivation

The PI3K pathway is one of the most commonly misregulated signaling pathways in human cancers, but its impact on the tumor microenvironment has not been considered as deeply as its autonomous impact on tumor cells. In this study we demonstrate that NF-κB is activated by the two most common PI3K mutations, PIK3CA E545K and H1047R. We found that markers of NF-κB are most strongly upregulated under conditions of growth factor deprivation. Gene expression analysis performed on cells deprived of growth factors identified the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, subtypes frequently exhibiting constitutive PI3K/Akt activity. An NF-κB-dependent subset of genes driven by oncogenic PI3K mutations was also identified that encoded primarily secreted proteins, suggesting a paracrine role for this gene set. Interestingly, while NF-κB activated by oncogenes such as Ras and EGFR leads to cell-autonomous effects, abrogating NF-κB in PI3K-transformed cells did not decrease proliferation or induce apoptosis. However, conditioned media from PI3K mutant-expressing cells led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-κB and IL-6-dependent manner. Together, our findings describe a PI3K-driven, NF-κB-dependent transcriptional profile which may play a critical role in promoting a microenvironment amenable to tumor progression. These data also indicate that NF-κB plays diverse roles downstream from different oncogenic signaling pathways

Preclinical assessment of viral vectored and protein vaccines targeting the Duffy-binding protein region II of Plasmodium vivax

Malaria vaccine development has largely focused on Plasmodium falciparum; however, a reawakening to the importance of Plasmodium vivax has spurred efforts to develop vaccines against this difficult to treat and at times severe form of relapsing malaria, which constitutes a significant proportion of human malaria cases worldwide. The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII) with the human Duffy antigen receptor for chemokines (DARC) makes this antigen an attractive vaccine candidate against blood-stage P. vivax. Here, we generated both preclinical and clinically compatible adenoviral and poxviral vectored vaccine candidates expressing the Salvador I allele of PvDBP_RII – including human adenovirus serotype 5 (HAdV5), chimpanzee adenovirus serotype 63 (ChAd63), and modified vaccinia virus Ankara (MVA) vectors. We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime or in “mixed-modality” adenovirus prime – protein-in-­adjuvant boost regimes (using a recombinant PvDBP_RII protein antigen formulated in Montanide®ISA720 or Abisco®100 adjuvants). Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay. In recent years, recombinant ChAd63 and MVA vectors have been quickly translated into human clinical trials for numerous antigens from P. falciparum as well as a growing number of other pathogens. The vectors reported here are immunogenic in small animals, elicit antibodies against PvDBP_RII, and have recently entered clinical trials, which will provide the first assessment of the safety and immunogenicity of the PvDBP_RII antigen in humans

Survey of coherent ∼1 Hz waves in Mercury's inner magnetosphere from MESSENGER observations

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95559/1/jgra22073.pd

Incorporating New Technologies Into Toxicity Testing and Risk Assessment: Moving From 21st Century Vision to a Data-Driven Framework

Based on existing data and previous work, a series of studies is proposed as a basis toward a pragmatic early step in transforming toxicity testing. These studies were assembled into a data-driven framework that invokes successive tiers of testing with margin of exposure (MOE) as the primary metric. The first tier of the framework integrates data from high-throughput in vitro assays, in vitro-to-in vivo extrapolation (IVIVE) pharmacokinetic modeling, and exposure modeling. The in vitro assays are used to separate chemicals based on their relative selectivity in interacting with biological targets and identify the concentration at which these interactions occur. The IVIVE modeling converts in vitro concentrations into external dose for calculation of the point of departure (POD) and comparisons to human exposure estimates to yield a MOE. The second tier involves short-term in vivo studies, expanded pharmacokinetic evaluations, and refined human exposure estimates. The results from the second tier studies provide more accurate estimates of the POD and the MOE. The third tier contains the traditional animal studies currently used to assess chemical safety. In each tier, the POD for selective chemicals is based primarily on endpoints associated with a proposed mode of action, whereas the POD for nonselective chemicals is based on potential biological perturbation. Based on the MOE, a significant percentage of chemicals evaluated in the first 2 tiers could be eliminated from further testing. The framework provides a risk-based and animal-sparing approach to evaluate chemical safety, drawing broadly from previous experience but incorporating technological advances to increase efficiency

Citizen science can improve conservation science, natural resource management, and environmental protection

Citizen science has advanced science for hundreds of years, contributed to many peer-reviewed articles, and informed land management decisions and policies across the United States. Over the last 10 years, citizen science has grown immensely in the United States and many other countries. Here, we show how citizen science is a powerful tool for tackling many of the challenges faced in the field of conservation biology. We describe the two interwoven paths bywhich citizen science can improve conservation efforts, natural resource management, and environmental protection. The first path includes building scientific knowledge, while the other path involves informing policy and encouraging public action. We explore how citizen science is currently used and describe the investments needed to create a citizen science program. We find that: 1. Citizen science already contributes substantially to many domains of science, including conservation, natural resource, and environmental science. Citizen science informs natural resource management, environmental protection, and policymaking and fosters public input and engagement. 2. Many types of projects can benefit fromcitizen science, but one must be careful tomatch the needs for science and public involvement with the right type of citizen science project and the right method of public participation. 3. Citizen science is a rigorous process of scientific discovery, indistinguishable from conventional science apart from the participation of volunteers.When properly designed, carried out, and evaluated, citizen science can provide sound science, efficiently generate high-quality data, and help solve problems