Amphotericin B Serum Concentrations During Therapy

Therapeutic outcome of patients being treated for systemic mycoses with amphotericin B is possibly related to the serum concentrations of this drug that are produced in these patients. Because current data are conflicting, the magnitude of these concentrations was restudied by using a bioassay which gave precise and accurate results. The highest of 155 serum concentrations was 2.01 mug/ml. Mean concentrations were 1.21, 0.62, and 0.32 mug/ml, at 1, 18, and 42 hr, respectively, after intravenous infusion of amphotericin B. This drug was detected in serum 7 weeks after completion of treatment, but it could not be detected 13 weeks after treatment. Drug levels did not appreciably decrease in serum stored for 8 to 9 months at - 10 C. Unequal serum content in assay tubes and measurement of assay turbidity by visual inspection may explain previously reported amphotericin B levels of 3.0 to 12.5 mug/ml.     

Local and systemic inhibition of lung tumor growth after nanoparticle-mediated mda-7/IL-24 gene delivery

The human melanoma differentiation associated gene-7 (mda-7), also known as interleukin-24 (IL-24), is a novel gene with tumor suppressor, antiangiogenic, and cytokine properties. In vitro adenovirus-mediated gene transfer of the human mda-7/IL-24 gene (Ad-mda-7) results in ubiquitous growth suppression of human cancer cells with minimal toxicity to normal cells. Intratumoral administration of Ad-mda-7 to lung tumor xenografts results in growth suppression via induction of apoptosis and antiangiogenic mechanisms. Although these results are encouraging, one limitation of this approach is that its locoregional clinical application-systemic delivery of adenoviruses for treatment of disseminated cancer is not feasible at the present time. An alternative approach that is suitable for systemic application is non-viral gene delivery. We recently demonstrated that DOTAP:cholesterol (DOTAP:Chol) nanoparticles effectively deliver tumor suppressor genes to primary and disseminated lung tumors. In the present study, therefore, we evaluated nanoparticle-mediated delivery of the human mda-7/IL-24 gene to primary and disseminated lung tumors in vivo. We demonstrate that DOTAP:Chol efficiently delivers the mda-7/IL-24 gene to human lung tumor xenografts, resulting in suppression of tumor growth. Growth-inhibitory effects were observed in both primary (P=0.001) and metastatic lung tumors (P=0.02). Furthermore, tumor vascularization was reduced in mda-7/IL-24-treated tumors. Finally, growth was also inhibited in murine syngenic tumors treated with DOTAP:Chol-mda-7 nanoparticles (P=0.01). This is the first report demonstrating (1) systemic therapeutic effects of mda-7/IL-24 in lung cancer, and (2) antitumor effects of human mda-7 in syngeneic cancer models. Our findings are important for the development of mda-7/IL-24 treatments for primary and disseminated cancers.     

基于CSSL的水稻抽穗期QTL定位及遗传分析

抽穗期是水稻（Oryza sativa）品种的重要农艺性状之一,适宜的抽穗期是获得理想产量的前提。鉴定和定位水稻抽穗期基因/QTL,分析其遗传效应对改良水稻抽穗期至关重要。以籼稻品种9311（Oryzasativa ssp.indica‘Yangdao 6’）为受体,粳稻品种日本晴（Oryza sativa ssp.japonica‘Nipponbare’）为供体构建的94个染色体片段置换系群体为材料,以P≤0.01为阈值,对置换片段上的抽穗期QTL进行了鉴定。采用代换作图法共定位了4个控制水稻抽穗期的QTL,分别位于第3、第4、第5和第8染色体;QTL的加性效应值变化范围为–6.4––2.7,加性效应百分率变化范围为–6.4%––2.7%;qHD-3和qHD-8加性效应值较大,表现主效基因特征。为了进一步定位qHD-3和qHD-8,在目标区域加密16对SSR引物,qHD-3和qHD-8分别被界定在第3染色体RM3166–RM16206之间及第8染色体RM4085–RM8271之间,其遗传距离分别为13.9cM和6.4cM。研究结果为利用分子标记辅助选择改良水稻抽穗期奠定了基础。     

Synthesis of Dideoxymycobactin Antigens Presented by CD1a Reveals T Cell Fine Specificity for Natural Lipopeptide Structures

Mycobacterium tuberculosis survival in cells requires mycobactin siderophores. Recently, the search for lipid antigens presented by the CD1a antigen-presenting protein led to the discovery of a mycobactin-like compound, dideoxymycobactin (DDM). Here we synthesize DDMs using solution phase and solid phase peptide synthesis chemistry. Comparison of synthetic standards to natural mycobacterial mycobactins by nuclear magnetic resonance and mass spectrometry allowed identification of an unexpected α-methyl serine unit in natural DDM. This finding further distinguishes these pre-siderophores as foreign compounds distinct from conventional peptides, and we provide evidence that this chemical variation influences the T cell response. One synthetic DDM recapitulated natural structures and potently stimulated T cells, making it suitable for patient studies of CD1a in infectious disease. DDM analogs differing in the stereochemistry of their butyrate or oxazoline moieties were not recognized by human T cells. Therefore, we conclude that T cells show precise specificity for both arms of the peptide, which are predicted to lie at the CD1a-T cell receptor interface.Pathogens are detected by the host when antigenic molecules directly contact immune receptors during the early stages of infection. The strategy of intracellular infection allows viruses, certain bacteria and protozoa to partially cloak themselves from the immune response by physically encapsulating their antigens within host cells. Intracellular residence also takes advantage of immune tolerance mechanisms that prevent autoimmune destruction of self. T cells play a central role in immunity to intracellular pathogens because they can respond to antigens that are generated inside cells and then transported to the surface of infected cells after binding to antigen-presenting molecules. The antigen-presenting molecules encoded in the major histocompatibility complex are widely known for presenting peptide fragments of proteins (1). More recently, human and mouse members of the CD1 (cluster of differentiation 1) system have been shown to present small amphipathic molecules, including a variety of membrane lipids, glycolipids, and lipopeptides, greatly expanding the molecular structures recognized by the cellular immune system (2, 3).Among human CD1 proteins (CD1a, CD1b, CD1c, CD1d, and CD1e), each CD1 isoform is expressed on a different spectrum of antigen-presenting cells. Human CD1a proteins are distinguished from other CD1 proteins by high expression levels on the surface of intradermal Langerhans cells, which play a role in barrier immune function (4). Human T cell clones have been shown to directly recognize CD1a proteins in the presence of exogenous foreign antigens (5) or in the presence of sulfatide and other self lipids (6, 7), suggesting a role for CD1a in T cell activation. In addition, mycobacteria and other intracellular pathogens have been shown to increase CD1a expression in lesions found in leprosy and tuberculosis patients, implying a possible role for CD1a in the response to infection, especially at mucosal or skin sites (8–10). Analysis of the molecular target recognized by CD1a-restricted T cell clone (CD8-2) allowed the identification of a foreign antigen presented by CD1a as dideoxymycobactin (DDM) (11).²Mycobactin binds iron to promote Mycobacterium tuberculosis survival. DDM was initially isolated (11) from antigenic lipid extracts of M. tuberculosis, a pathogen that kills ∼1.7 million humans annually on a worldwide basis (12). The determination of DDM structure was based on mass spectrometric and NMR studies of limiting amounts of natural material derived from the pathogenic organisms, so that not all elements of its chemical structure could be formally determined. Instead, its assigned structure was facilitated by obvious parallels of dideoxymycobactin with mycobactin, a lipopeptide siderophore (13, 14). Iron is required for reduction-oxidation reactions involving respiration and other basic metabolic pathways in bacterial pathogens (13). Environmental mycobacteria have at least two iron uptake pathways, but mycobactin and the related molecule carboxymycobactin represent the only known dedicated iron uptake pathway for pathogenic species like M. tuberculosis (15, 16). Highlighting the physiological importance of the mycobactin pathway, deletion of mycobactin synthase B limits M. tuberculosis survival in cells (13, 14). Also, mammalian innate immune systems produce siderocalin, a 20-kDa lipocalin that binds both ferric and apo siderophores, preventing their uptake and subsequent iron delivery to microbes (17–20). The small available yields of natural material highlighted the need for a straightforward method to synthesize DDM for studies of its role in mycobacterial iron acquisition and testing T cell responses in human populations, as well as to provide authentic standards to investigate unknown aspects of natural DDM stereochemistry. Here we report two syntheses for production of DDM in solution phase and solid phase. Comparison of synthetic and natural DDMs gives unexpected insight into the stereochemical structures of the methylserine, oxazoline, and butyrate moieties of DDM and provides direct evidence that the T cell response is highly specific for a unique aspect of DDM structure that protrudes from the surface of the CD1a-DDM complexes.     

Marine fisheries as ecological experiments

There are many examples of ecological theory informing fishery management. Yet fisheries also provide tremendous opportunities to test ecological theory through large-scale, repeated, and well-documented perturbations of natural systems. Although treating fisheries as experiments presents several challenges, few comparable tests exist at the ecosystem scale. Experimental manipulations of fish populations in lakes have been widely used to develop and test ecological theory. Controlled manipulation of fish populations in open marine systems is rarely possible, but fisheries data provide a valuable substitute for such manipulations. To highlight the value of marine fisheries data, we review leading ecological theories that have been empirically tested using such data. For example, density dependence has been examined through meta-analysis of spawning stock and recruitment data to show that compensation (higher population growth) occurs commonly when populations are reduced to low levels, while depensation (the Allee effect) is rare. As populations decline, spatial changes typically involve populations contracting into high-density core habitats while abandoning less productive habitats. Fishing down predators may result in trophic cascades, possibly shifting entire ecosystems into alternate stable states, although alternate states can be maintained by both ecological processes and continued fishing pressure. Conversely, depleting low trophic level groups may affect central-place foragers, although these bottom–up effects rarely appear to impact fish—perhaps because many fish populations have been reduced to the point that they are no longer prey limited. Fisheries provide empirical tests for diversity–stability relations: catch data suggest that more diverse systems recover faster and provide more stable returns than less diverse systems. Fisheries have also provided examples of the tragedy of the commons, as well as counter-examples where common property resources have been managed successfully. We also address two barriers to use of fisheries data to answer ecological questions: differences in terminology for similar concepts and misuse of records of fishery landings (catch data) as a proxy for biomass trends.     

Patterns of Root Colonization in Epacridaceous Plants Collected from Different Sites

Root colonization was studied in ten species of the Epacridaceaeat three sites in Victoria by morphological and cross-inoculationexperiments. The sites and genera chosen were Cranbourne [Epacrisimpressa Labill. andLeucopogon ericoides(Smith) R. Br.] andRye [L. parviflorus(Andrews) Lindley] on the Mornington Peninsula,and the Grampians[Astroloma conostephioides(Sond.) Benth.,A.humifusum(Cav.) R. Br.,A pinifolium(R. Br.) Benth,Brachylomadaphnoides(Smith) Benth.,E. impressa, E. impressavar.grandifloraBenth.andStyphelia adscendensR. Br.] in western Victoria. For morphologicalstudies, samples of roots from each species at each site werecleared and stained and examined microscopically. For cross-inoculationstudies, cuttings from each site were struck in potting mediuminoculated with soil from the same and other sites. The ericoidmycorrhizae in the roots of plants found at or grown in Cranbourneand Rye soils were similar. Both were significantly differentfrom the internal hyphae found in the roots of plants foundat or grown in Grampians soils, which were three times largerin diameter and formed dense coils which filled the host celland invaded adjacent epidermal cells. This suggests that morethan one fungus is involved in the relationships, that the MorningtonPeninsula sites had a different fungus from the Grampians siteand that host specificity is low. Vesicular structures werealso found commonly on plants at the Grampians site, in contrastwith other sites. Epacridaceae; root; fungus; mycorrhiza; morphology; inoculation     

Length–weight relationships for 85 fish species from Guam

Length–weight relationships (LWRs) were developed for 85 reef and bottom‐fish species from Guam. These are the first published LWRs for Guam, and include new LWRs for nine species lacking these relationships in FishBase.     

The influence of bioturbation by the sandprawn Callianassa kraussi on feeding and survival of the bivalve Eumarcia paupercula and the gastropod Nassarius kraussianus

Field observations and experimental evidence have shown that bioturbation by the southern African sandprawn Callianassa kraussi may significantly influence the abundance and distribution of the filter-feeding bivalve Eumarcia paupercula and the grazing gastropod Nassarius kraussianus. It was hypothesized that (1) sediment reworking by C. kraussi negatively affects microalgal growth on the sediment surface, leading to a reduction in food intake by N. kraussianus, (2) sediment deposited by C. kraussi will also diminish the food uptake of E. paupercula by interfering with its filtration mechanism. To test these hypotheses, manipulative field and laboratory experiments were undertaken in which N. kraussianus and E. paupercula were added to treatments with and without C. kraussi, and their survival and gut chlorophyll-a content measured. The effects of C. kraussi on sediment erodability and on condition of E. paupercula (tissue mass/shell length) were determined in a second experiment. In the presence of C. kraussi, (1) microalgal consumption by both N. kraussianus and E. paupercula was halved; (2) condition and survival of E. paupercula were significantly reduced but survival of N. kraussianus was unaffected; and (3) sediment erodability was increased. A significant negative relationship was established between sediment erodability and condition of E. paupercula. Evidently C. kraussi exerts a strongly negative influence on the feeding of E. paupercula and N. kraussianus, and this may explain the scarcity of these organisms in areas containing high densities of C. kraussi.     

Overcoming Obstacles to Evolution Education: Why Bother Teaching Evolution in High School?

Evolution is a foundational organizing principle of the life sciences, and yet people still argue that it should be taught only in college, urging that it’s not necessary, too controversial, or too difficult to teach evolution in high school. Faced with such arguments, teachers and administrators need to have responses. Moreover, they need to teach evolution so that the coverage of evolution in the K-12 curriculum reflects its central place in biology.