Differential selection pressure exerted on HIV by CTL targeting identical epitopes but restricted by distinct HLA alleles from the same HLA supertype

HLA diversity is seen as a major challenge to CTL vaccines against HIV. One current approach focuses on "promiscuous" epitopes, presented by multiple HLA alleles from within the same HLA supertype. However, the effectiveness of such supertype vaccines depends upon the functional equivalence of CTL targeting a particular epitope, irrespective of the restricting HLA. In this study, we describe the promiscuous HIV-specific CTL epitopes presented by alleles within the B7 supertype. Substantial differences were observed in the ability of CTL to select for escape mutation when targeting the same epitope but restricted by different HLA. This observation was common to all six promiscuous B7 epitopes identified. Moreover, with one exception, there were no significant differences in the frequency, magnitude, or immunodominance of the CTL responses restricted by different HLA alleles to explain these discrepancies. This suggests that the unique peptide/MHC complexes generated by even closely related HLA induce CTL responses that are qualitatively different. This hypothesis is supported by additional differences observed between CTL targeting identical epitopes but restricted by different HLA: first, the occurrence of distinct, HLA-specific escape mutation; second, the recruitment of distinct TCR repertoires by particular peptide/MHC complexes; and, third, significant differences in the functional avidity of CTL. Taken together, these data indicate that significant functional differences exist between CTL targeting identical epitopes but restricted by different, albeit closely related HLA. These findings are of relevance to vaccine approaches that seek to exploit HLA supertypes to overcome the problem of HLA diversity.     

Tricyclic aminopyrimidine histamine H4 receptor antagonists

This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.     

A soluble carotenoid protein involved in phycobilisome-related energy dissipation in cyanobacteria

Photosynthetic organisms have developed multiple protective mechanisms to survive under high-light conditions. In plants, one of these mechanisms is the thermal dissipation of excitation energy in the membrane-bound chlorophyll antenna of photosystem II. The question of whether or not cyanobacteria, the progenitor of the chloroplast, have an equivalent photoprotective mechanism has long been unanswered. Recently, however, evidence was presented for the possible existence of a mechanism dissipating excess absorbed energy in the phycobilisome, the extramembrane antenna of cyanobacteria. Here, we demonstrate that this photoprotective mechanism, characterized by blue light-induced fluorescence quenching, is indeed phycobilisome-related and that a soluble carotenoid binding protein, ORANGE CAROTENOID PROTEIN (OCP), encoded by the slr1963 gene in Synechocystis PCC 6803, plays an essential role in this process. Blue light is unable to quench fluorescence in the absence of phycobilisomes or OCP. The fluorescence quenching is not DeltapH-dependent, and it can be induced in the absence of the reaction center II or the chlorophyll antenna, CP43 and CP47. Our data suggest that OCP, which strongly interacts with the thylakoids, acts as both the photoreceptor and the mediator of the reduction of the amount of energy transferred from the phycobilisomes to the photosystems. These are novel roles for a soluble carotenoid protein.     

Siderophore uptake in bacteria and the battle for iron with the host; a bird’s eye view

Siderophores are biosynthetically produced and secreted by many bacteria, yeasts, fungi and plants, to scavenge for ferric iron (Fe³⁺). They are selective iron-chelators that have an extremely high affinity for binding this trivalent metal ion. The ferric ion is poorly soluble but it is the form of iron that is predominantly found in oxygenated environments. Siderophore uptake in bacteria has been extensively studied and over the last decade, detailed structural information for many of the proteins that are involved in their transport has become available. Specifically, numerous crystal structures for outer membrane siderophore transporters, as well as for soluble periplasmic siderophore-binding proteins, have been reported. Moreover, unique siderophore-binding proteins have recently been serendipitously discovered in humans, and the structures of some of their siderophore-complexes have been characterized. The binding pockets for different ferric-siderophores in these proteins have been described in great molecular detail. In addition to highlighting this structural information, in this review paper we will also briefly discuss the relevant chemical properties of iron, and provide a perspective on our current understanding of the human and bacterial iron uptake pathways. Potential clinical uses of siderophores will also be discussed. The emerging overall picture is that iron metabolism plays an extremely important role during bacterial infections. Because levels of free ferric iron in biological systems are always extremely low, there is serious competition for iron and for ferric-siderophores between pathogenic bacteria and the human or animal host.     

Structure and Function of the Water-Soluble Carotenoid-Binding Proteins of Cyanobacteria

The orange carotenoid protein (OCP) and its derivative, the red carotenoid protein (RCP), appear to play important photoprotective roles in cyanobacteria. Structural and functional characterization is gradually elucidating the specific details of how carotenoid-protein interactions, including the role of six methionine residues oriented toward the pigment, contribute to the spectral and functional properties of these proteins.     

Remotely Monitoring Change in Vegetation Cover on the Montebello Islands,Western Australia,in Response to Introduced Rodent Eradication

The Montebello archipelago consists of 218 islands; 80 km from the north-west coast of Western Australia. Before 1912 the islands had a diverse terrestrial fauna. By 1952 several species were locally extinct. Between 1996 and 2011 rodents and cats were eradicated, and 5 mammal and 2 bird species were translocated to the islands. Monitoring of the broader terrestrial ecosystem over time has been limited. We used 20 dry-season Landsat images from 1988 to 2013 and estimation of green fraction cover in nadir photographs taken at 27 sites within the Montebello islands and six sites on Thevenard Island to assess change in vegetation density over time. Analysis of data averaged across the 26-year period suggests that 719 ha out of 2169 ha have increased in vegetation cover by up to 32%, 955 ha have remained stable and 0.6 ha have declined in vegetation cover. Over 492 ha (22%) had no vegetation cover at any time during the period analysed. Chronological clustering analysis identified two breakpoints in the average vegetation cover data occurring in 1997 and 2003, near the beginning and end of the rodent eradication activities. On many islands vegetation cover was declining prior to 1996 but increased after rodents were eradicated from the islands. Data for North West and Trimouille islands were analysed independently because of the potential confounding effect of native fauna being introduced to these islands. Mala (Lagorchestes hirsutus) and Shark Bay mice (Pseudomys fieldi) both appear to suppress native plant recruitment but not to the same degree as introduced rodents. Future research should assess whether the increase in vegetation cover on the Montebello islands is due to an increase in native or introduced plants.     

Comparison of stem-cell recovery in autoimmune and normal strains

The capacity of NZB stem cells to proliferate in vivo was evaluated in two systems which required repopulation of peripheral organs. In both types of depletion systems, stem-cell repopulation after cyclophosphamide treatment or adoptive transfer repopulation in lethally irradiated hosts, it was found that NZB stem cells were hyperproliferating. The increase in proliferating cells was most pronounced in the spleens of NZB mice treated with high-dose cyclophosphamide and in lethally irradiated F₁ mice reconstituted with NZB T-cell-depleted bone marrow. Thus, upon a stimulus to repopulate, NZB marrow stem cells will hyperproliferate in peripheral organs resulting in an increase in cell number. The abnormality in the marrow cells can be observed in young NZB mice when their marrow cells are in an environment which requires recovery and division.     

The reptilian filarioid genus Foleyella Seurat, 1917 (Onchocercidae: Dirofilariinae) and its relationship to other dirofilariine genera

Summary The type species of Foleyella, i.e. F. candezei (Fraipont, 1882), and F. furcata (Linstow, 1899) are redescribed and an emended diagnosis of the genus is given. Among dirofilariine genera, Foleyella is closest to Pelecitus Railliet & Henry, 1910, which contains numerous parasites of birds and also two species in mammals which appear to have been derived from those in birds. Species in Foleyella and Pelecitus have numerous adult characters in common. Microfilariae of Foleyella species are, however, generally short with a loose sheath, while those of Pelecitus are long with a sheath approximately the same width as the anterior two-thirds of the microfilarial body. ac]19851223     

Discovery of a novel series of selective HCN1 blockers

The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high-throughput VIPR assay led to the identification of a novel series of 2,2-disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1-disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1-yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein.