Immune responses to isolated human cytomegalovirus envelope proteins.

A group of envelope proteins of human cytomegalovirus, gA protein (L. Pereira, M. Hoffman, M. Tatsuno, and D. Dondero, Virology 139:73-86, 1984; L. Pereira, p. 383-404, in B. Roizman, ed., The herpesviruses, vol. 3, 1985), and two protein mixtures (58,000-molecular-weight [58K]-66K and 130K-66K), separated by serial columns prepared with anti-gA immunoglobulin G from sera of immunized guinea pigs, induced neutralizing antibodies and a cellular immune response in the animals. The gA is a disulfide-linked protein complex consisting of high-molecular-weight (greater than 200K), 130K-150K, and 55K-58K proteins.     

Isolation and properties of the soluble c-type cytochromes of the dinoflagellate Peridinium cinctum

Four soluble cytochromes of the c type were isolated from the freshwater dinoflagellate Peridinium cinctum collected from Lake Kinneret, Israel. Cytochrome c with alpha-band maximum at 550 nm in the reduced state had a molecular mass of 10,200 Da, pI 7.4, and Em of 278 m V. This cytochrome was active in the respiratory chain of beef heart Keilin-Hartree particles. Cytochrome c-553 had a molecular mass of 13,200 Da, pI 4.9, and Em of 384 m V, and was active in light induced electron transport of Euglena gracilis chloroplast fragments. Cytochrome c-554 had a molecular mass of 13,500 Da, pI 4.4, and Em of 326 m V. This cytochrome was inactive in light induced electron transport but competed with cytochrome c-552 of Euglena in the assay. The acidic cytochrome c-557 was present in very small quantities. The properties of the soluble c-type cytochromes of P. cinctum are compatible with the classification of dinoflagellates as primitive eucaryotes.     

Human cytomegalovirus stimulates host cell RNA synthesis.

Human cytomegalovirus infection of human fibroblast cells (WI-38) induced cellular RNA synthesis. The RNA synthesis in infected cultures preceded the synthesis of viral DNA and progeny virus by approximately 24 h. RNA species synthesized in infected cells included ribosomal 28S and 18S; and 4S transfer RNA; all were markedly increased in comparison to uninfected cells. This induction of host cell RNA synthesis was dependent upon a protein(s) that was synthesized during the early stages of infection.     

Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV

A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.     

Beyond trophic morphology: stable isotopes reveal ubiquitous versatility in marine turtle trophic ecology

The idea that interspecific variation in trophic morphology among closely related species effectively permits resource partitioning has driven research on ecological radiation since Darwin first described variation in beak morphology among Geospiza. Marine turtles comprise an ecological radiation in which interspecific differences in trophic morphology have similarly been implicated as a pathway to ecopartition the marine realm, in both extant and extinct species. Because marine turtles are charismatic flagship species of conservation concern, their trophic ecology has been studied intensively using stable isotope analyses to gain insights into habitat use and diet, principally to inform conservation management. This legion of studies provides an unparalleled opportunity to examine ecological partitioning across numerous hierarchical levels that heretofore has not been applied to any other ecological radiation. Our contribution aims to provide a quantitative analysis of interspecific variation and a comprehensive review of intraspecific variation in trophic ecology across different hierarchical levels marshalling insights about realised trophic ecology derived from stable isotopes. We reviewed 113 stable isotope studies, mostly involving single species, and conducted a meta‐analysis of data from adults to elucidate differences in trophic ecology among species. Our study reveals a more intricate hierarchy of ecopartitioning by marine turtles than previously recognised based on trophic morphology and dietary analyses. We found strong statistical support for interspecific partitioning, as well as a continuum of intraspecific trophic sub‐specialisation in most species across several hierarchical levels. This ubiquity of trophic specialisation across many hierarchical levels exposes a far more complex view of trophic ecology and resource‐axis exploitation than suggested by species diversity alone. Not only do species segregate along many widely understood axes such as body size, macrohabitat, and trophic morphology but the general pattern revealed by isotopic studies is one of microhabitat segregation and variation in foraging behaviour within species, within populations, and among individuals. These findings are highly relevant to conservation management because they imply ecological non‐exchangeability, which introduces a new dimension beyond that of genetic stocks which drives current conservation planning. Perhaps the most remarkable finding from our data synthesis is that four of six marine turtle species forage across several trophic levels. This pattern is unlike that seen in other large marine predators, which forage at a single trophic level according to stable isotopes. This finding affirms suggestions that marine turtles are robust sentinels of ocean health and likely stabilise marine food webs. This insight has broader significance for studies of marine food webs and trophic ecology of large marine predators. Beyond insights concerning marine turtle ecology and conservation, our findings also have broader implications for the study of ecological radiations. Particularly, the unrecognised complexity of ecopartitioning beyond that predicted by trophic morphology suggests that this dominant approach in adaptive radiation research likely underestimates the degree of resource overlap and that interspecific disparities in trophic morphology may often over‐predict the degree of realised ecopartitioning. Hence, our findings suggest that stable isotopes can profitably be applied to study other ecological radiations and may reveal trophic variation beyond that reflected by trophic morphology.     

Postscript relating to new allegations made by Edward Hooper at The Royal Society Discussion Meeting on 11 September 2000

At The Royal Society Discussion Meeting, Origins of HIV and the AIDS epidemic, which this issue records, Edward Hooper added two new 'smoking guns' to the accusations published previously in The river. These were proposed as conclusive evidence for the hypothesis that simian immunodeficiency virus-contaminated CHAT polio vaccine caused the HIV-1 group M epidemic. We have investigated the facts in relation to these 'smoking guns'.     

Tumor-Targeted Human T Cells Expressing CD28-Based Chimeric Antigen Receptors Circumvent CTLA-4 Inhibition

Adoptive T cell therapy represents a promising treatment for cancer. Human T cells engineered to express a chimeric antigen receptor (CAR) recognize and kill tumor cells in a MHC-unrestricted manner and persist in vivo when the CAR includes a CD28 costimulatory domain. However, the intensity of the CAR-mediated CD28 activation signal and its regulation by the CTLA-4 checkpoint are unknown. We investigated whether T cells expressing an anti-CD19, CD3 zeta and CD28-based CAR (19-28z) displayed the same proliferation and anti-tumor abilities than T cells expressing a CD3 zeta-based CAR (19z1) costimulated through the CD80/CD28, ligand/receptor pathway. Repeated in vitro antigen-specific stimulations indicated that 19-28z⁺ T cells secreted higher levels of Th1 cytokines and showed enhanced proliferation compared to those of 19z1⁺ or 19z1-CD80⁺ T cells. In an aggressive pre-B cell leukemia model, mice treated with 19-28z⁺ T cells had 10-fold reduced tumor progression compared to those treated with 19z1⁺ or 19z1-CD80⁺ T cells. shRNA-mediated CTLA-4 down-regulation in 19z1-CD80⁺ T cells significantly increased their in vivo expansion and anti-tumor properties, but had no effect in 19-28z⁺ T cells. Our results establish that CTLA-4 down-regulation may benefit human adoptive T cell therapy and demonstrate that CAR design can elude negative checkpoints to better sustain T cell function.