Potential strategies utilised by papillomavirus to evade host immunity

The co-evolution of papillomaviruses (PV) and their mammalian hosts has produced mechanisms by which PV might avoid specific and non-specific host immune responses. Low level expression of PV proteins in infected basal epithelial cells, together with an absence of inflammation and of virus-induced cell lysis, restricts the opportunity for effective PV protein presentation to immunocytes by dendritic cells. Additionally, PV early proteins, by a range of mechanisms, may restrict the efficacy of antigen presentation by these cells. Should an immune response be induced to PV antigens, resting keratinocytes (KC) appear resistant to interferon-gamma-enhanced mechanisms of cytotoxic T-lymphocyte (CTL)-mediated lysis, and expression of PV antigens by resting KC can tolerise PV-specific CTL. Thus, KC, in the absence of inflammation, may represent an immunologically privileged site for PV infection. Together, these mechanisms play a parr in allowing persistence of PV-induced proliferative skin lesions for months to years, even in immunocompetent hosts.

Structure-activity relationships of omega-conotoxins MVIIA, MVIIC and 14 loop splice hybrids at N and P/Q-type calcium channels

The omega-conotoxins are a set of structurally related, four-loop, six cysteine containing peptides, that have a range of selectivities for different subtypes of the voltage-sensitive calcium channel (VSCC). To investigate the basis of the selectivity displayed by these peptides, we have studied the binding affinities of two naturally occurring omega-conotoxins, MVIIA and MVIIC and a series of 14 MVIIA/MVIIC loop hybrids using radioligand binding assays for N and P/Q-type Ca2+ channels in rat brain tissue. A selectivity profile was developed from the ratio of relative potencies at N-type VSCCs (using [I-125]GVIA radioligand binding assays) and P/Q-type VSCCs (using [I-125]MVIIC radioligand binding assays). in these peptides, loops 2 and 4 make the greatest contribution to VSCC subtype selectivity, while the effects of loops 1 and 3 are negligible. Peptides with homogenous combinations of loop 2 and 4 display clear selectivity preferences, while those with heterogeneous combinations of loops 2 and 4 are less discriminatory. H-1 NMR spectroscopy revealed that the global folds of MVIIA, MVIIC and the 14 loop hybrid peptides were similar; however, several differences in local structure were identified. Based on the binding data and the 3D structures of MVIIA, GVIA and MVIIC, we have developed a preliminary pharmacophore based on the omega-conotoxin residues most Likely to interact with the N-type VSCC. (C) 1999 Academic Press.

Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes

omega -Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new omega -conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other omega -conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, omega -conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha (1B-d)) and peripheral (alpha (1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta (3) in Xenopus oocytes, However, the potency of CVID and MVIIA increased when alpha (1B-d) and alpha (1B-b) were expressed in the absence of rat beta (3), an effect most pronounced for CVID at alpha (1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha (1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. H-1 NMR studies reveal that CMD possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined.

History of vegetation and habitat change in the Austral-Asian region

Over 1000 marine and terrestrial pollen diagrams and Some hundreds of vertebrate faunal sequences have been studied in the Austral-Asian region bisected by the PEPII transect, from the Russian arctic extending south through east Asia, Indochina, southern Asia, insular Southeast Asia (Sunda), Melanesia, Australasia (Sahul) and the western south Pacific. The majority of these records are Holocene but sufficient data exist to allow the reconstruction of the changing biomes over at least the past 200,000 years. The PEPII transect is free of the effects of large northern ice caps yet exhibits vegetational change in glacial cycles of a similar scale to North America. Major processes that can be discerned are the response of tropical forests in both lowlands and uplands to glacial cycles, the expansion of humid vegetation at the Pleistocene-Holocene transition and the change in faunal and vegetational controls as humans occupy the region. There is evidence for major changes in the intensity of monsoon and El Nino-Southern oscillation variability both on glacial-interglacial and longer time scales with much of the region experiencing a long-term trend towards more variable and/or drier climatic conditions. Temperature variation is most marked in high latitudes and high altitudes with precipitation providing the major climate control in lower latitude, lowland areas. At least some boundary shifts may be the response of vegetation to changing CO2 levels in the atmosphere. Numerous questions of detail remain, however, and current resolution is too coarse to examine the degree of synchroneity of millennial scale change along the transect. (C) 2003 Elsevier Ltd and INQUA. All rights reserved.

Presentation of the HPV16E7 protein by skin grafts is insufficient to allow graft rejection in an E7-primed animal

The E7 transforming protein of Human Papillomavirus type 16 (HPV16) is expressed in the skin of a line of RIB mice transgenic for the E6 and E7 open reading frames of HPV16 driven from the alpha A crystallin promoter (FVB alpha AcryHPV16E6E7). We have transferred skin from FVB alpha AcryHPV16E6E7 mice to naive or E7-primed syngeneic NE recipients to assess whether the E7 protein of HPV16 can function as a minor transplantation antigen (MTA) and promote skin graft rejection. FVB mice did not reject E7 expressing tail or flank skin grafts. E7 immunized FVB x C57BL/6J mice recipients of FVB alpha AcryHPV16E6E7 x C57BL/6J skin generated humoral and DTH responses to E7 in vivo and E7-specific CTL precursors in the spleen, but failed to reject 57 expressing tail skin grafts by 100 days posttransfer. Thus although HPV16 E7 + ve mesenchymal and endodermal tumors can be eliminated by an E7-specific immune response, the same protein is unable to act as a MTA and promote graft rejection when expressed in skin cells. Lack of rejection of grafts expressing MTAs such as E7 may be relevant to the immunology of epithelial tumors expressing tumor-specific antigens and to our understanding of the immunology of diseases of the skin. (C) 1997 Academic Press.

Management of acute psychostimulant toxicity

Psychostimulants produce a broad range of effects. Adverse effects can exist on a spectrum of severity from minor symptoms to life threatening toxicity. Although regular use or use of high doses increases risk of adverse events, many adverse events requiring emergency intervention may occur even in the naïve user.