Vaccines for papillomavirus infection

Vaccines to prevent PV infection, utilising PV L1 virus like particles (VLPs) to induce neutralising antibody, are in clinical trial and show all the characteristics likely to be associated with success. Results warrant global planning for the deployment of VLP vaccines within a decade, as part of a program to prevent cervical cancer. Vaccines designed to treat existing PV infection by inducing therapeutic cellular immunity targeted to PV proteins are at a much earlier stage of development. The wide choice of potential and proposed antigens, routes and mechanisms of delivery, and possible treatment regimens suggest that, to move the field forward, surrogate markers allowing comparison of the relative efficacy of different vaccine approaches are required. These should be based on reduction in load of virus infection, and need to be validated in animal models or in man. (C) 2002 Published by Elsevier Science B.V.

Blockade of vascular smooth muscle cell proliferation and intimal thickening after balloon injury by the sulfated oligosaccharide PI-88: Phosphomannopentaose sulfate directly binds FGF-2, blocks cellular signaling, and inhibits proliferation

Percutaneous transluminal coronary angioplasty is a frequently used interventional technique to reopen arteries that have narrowed because of atherosclerosis. Restenosis, or renarrowing of the artery shortly after angioplasty, is a major limitation to the success of the procedure and is due mainly to smooth muscle cell accumulation in the artery wall at the site of balloon injury. In the present study, we demonstrate that the antiangiogenic sulfated oligosaccharide, PI-88, inhibits primary vascular smooth muscle cell proliferation and reduces intimal thickening 14 days after balloon angioplasty of rat and rabbit arteries. PI-88 reduced heparan sulfate content in the injured artery wall and prevented change in smooth muscle phenotype. However, the mechanism of PI-88 inhibition was not merely confined to the antiheparanase activity of this compound. PI-88 blocked extracellular signal-regulated kinase-1/2 (ERK1/2) activity within minutes of smooth muscle cell injury. It facilitated FGF-2 release from uninjured smooth muscle cells in vitro, and super-released FGF-2 after injury while inhibiting ERK1/2 activation. PI-88 inhibited the decrease in levels of FGF-2 protein in the rat artery wall within 8 minutes of injury. PI-88 also blocked injury-inducible ERK phosphorylation, without altering the clotting time in these animals. Optical biosensor studies revealed that PI-88 potently inhibited (K-i 10.3 nmol/L) the interaction of FGF-2 with heparan sulfate. These findings show for the first time the capacity of this sulfated oligosaccharide to directly bind FGF-2, block cellular signaling and proliferation in vitro, and inhibit injury-induced smooth muscle cell hyperplasia in two animal models. As such, this study demonstrates a new role for PI-88 as an inhibitor of intimal thickening after balloon angioplasty. The full text of this article is available online at http://www.circresaha.org.

Homomeric ring assemblies of eukaryotic Sm proteins have affinity for both RNA and DNA - Crystal structure of an oligomeric complex of yeast SmF

Sm and Sm-like proteins are key components of small ribonucleoproteins involved in many RNA and DNA processing pathways. In eukaryotes, these complexes contain seven unique Sm or Sm-like (Lsm) proteins assembled as hetero-heptameric rings, whereas in Archaea and bacteria six or seven-membered rings are made from only a single polypeptide chain. Here we show that single Sm and Lsm proteins from yeast also have the capacity to assemble into homo-oligomeric rings. Formation of homo-oligomers by the spliceosomal small nuclear ribonucleoprotein components SmE and SmF preclude hetero-interactions vital to formation of functional small nuclear RNP complexes in vivo. To better understand these unusual complexes, we have determined the crystal structure of the homomeric assembly of the spliceosomal protein SmF. Like its archaeal/bacterial homologs, the SmF complex forms a homomeric ring but in an entirely novel arrangement whereby two heptameric rings form a co-axially stacked dimer via interactions mediated by the variable loops of the individual SmF protein chains. Furthermore, we demonstrate that the homomeric assemblies of yeast Sm and Lsm proteins are capable of binding not only to oligo(U) RNA but, in the case of SmF, also to oligo(dT) single-stranded DNA.

Aspergillicins A-E: five novel depsipeptides from the marine-derived fungus Aspergillus carneus

A search for new antiparasitic agents from a strain of the fungus Aspergillus carneus isolated from an estuarine sediment collected in Tasmania, Australia, yielded the known terrestrial fungal metabolite marcfortine A ( 1) as an exceptionally potent antiparasitic agent. This study also yielded a series of new depsipeptides, aspergillicins A - E ( 2 - 6) and the known terrestrial fungal metabolite acyl aszonalenin ( 7). Marcfortine A ( 1) and acyl aszonalenin ( 7) were identified by spectroscopic analysis, with comparison to literature data. Complete stereostructures were assigned to aspergillicins A - E ( 2 - 6) on the basis of detailed spectroscopic analysis, together with ESIMS analysis of the free amino acids generated by acid hydrolysis, and HPLC analysis of Marfey derivatives prepared from the acid hydrolysate. The peptide amino acid sequence for all aspergillicins was unambiguously assigned by MSn ion-trap ESI mass spectrometry.

Bringing the state to England: Andrew Tooke's translation of Samuel Pufendorf's 'De officio hominis et civis'

Andrew Tooke's 1691 English translation of Samuel Pufendorf's De officio hominis et civis, published as The Whole Duty of Man According to the Law of Nature, brought Pufendorf's manual fo statist natural law into English politics at a moment of temporary equilibrium in the unfinished contest between Crown and Parliament for the rights and powers of sovereignty. Drawing on the authors' re-edition of The Whole Duty of Man, this article describes and analyses a telling instance of how--by translation--the core political terms and concepts of the German natural jurist's 'absolutist' formulary were reshaped for reception in the different political culture of late seventeenth-century England.

A randomized trial comparing hormone replacement therapy (HRT) and HRT plus calcitriol in the treatment of postmenopausal osteoporosis with vertebral fractures: Benefit of the combination on total body and hip density

We report a prospective, randomized, multi-center, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 - 1.25 mg/d +/- medroxyprogesterone acetate (MPA) 2.5 - 5 mg/d,- group HRT/D received HRT plus calcitriol 0.25 mug bd. All with a baseline dietary calcium (Ca) of < I g/d received Ca carbonate 0.6 g nocte. Final data were on 66 - 70 patients. On HRT/D, significant (P < 0.001) BNID increases from baseline by DXA were at total body - head, trochanter, Ward's, total hip, inter-trochanter and femoral shaft (% group mean Delta 4.2, 6.1, 9.3. 3.7. 3.3 and 3.3%, respectively). On HRT, at these significant Deltas were restricted to the trochanter and sites. si Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean Delta at these sites were 1.3, 2.6 and 3.9%. At the following, both groups Improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site - specific benefits of the combination associated with significant suppression of parathyroid hormone-suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This Is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BNID at the hip, the major site of osteoporotic fracture.

Effect of storage of adzuki bean (Vigna angularis) on starch and protein properties

Differential scanning calorimetry was used to evaluate the effect of storage at 10degreesC, 20degreesC and 30degreesC, and 40% and 65% relative humidity (RH) on adzuki bean starch gelatinisation and protein denaturation temperatures. Storage for 6 months at an elevated storage temperature (30degreesC) caused increases in the starch gelatinisation onset temperature (T-o) and gelatinisation peak temperature (T-p) for both Bloodwood and Erimo varieties. Storage at 40% RH resulted in higher T-o and T-p values than storage at 65% RH. The T-o of starch from Bloodwood and Erimo beans stored for up to 1.5 months at 10degreesC and 65% were similar to those of fresh beans. The changes in the salt-soluble protein component were less clear cut than those of the starch. Nonetheless, protein extracted from beans stored at 40% RH exhibited significantly lower T-o and T-p values compared with those stored at 65% RH. This indicates some destabilisation of the protein at the higher RH. These results suggest that detrimental changes occur in starch and, to a lesser extent protein, of adzuki beans stored under unfavourable conditions. On the basis of these results, the best storage conditions to maintain the characteristics of fresh beans are low temperatures (e.g. 10degreesC) and high RH (e.g. 65%). (C) 2003 Swiss Society of Food Science and Technology. Published by Elsevier Science Ltd. All rights reserved.

Extrinsic versus intrinsic factors in the decline and extinction of Australian marsupials

Recent attempts to explain the susceptibility of vertebrates to declines worldwide have largely focused on intrinsic factors such as body size, reproductive potential, ecological specialization, geographical range and phylogenetic longevity. Here, we use a database of 145 Australian marsupial species to test the effects of both intrinsic and extrinsic factors in a multivariate comparative approach. We model five intrinsic (body size, habitat specialization, diet, reproductive rate and range size) and four extrinsic (climate and range overlap with introduced foxes, sheep and rabbits) factors. We use quantitative measures of geographical range contraction as indices of decline. We also develop a new modelling approach of phylogenetically independent contrasts combined with imputation of missing values to deal simultaneously with phylogenetic structuring and missing data. One extrinsic variable-geographical range overlap with sheep-was the only consistent predictor of declines. Habitat specialization was independently but less consistently associated with declines. This suggests that extrinsic factors largely determine interspecific variation in extinction risk among Australian marsupials, and that the intrinsic factors that are consistently associated with extinction risk in other vertebrates are less important in this group. We conclude that recent anthropogenic changes have been profound enough to affect species on a continent-wide scale, regardless of their intrinsic biology.

Ethical preferences for influencing superiors: A 41-society study

With a 41-society sample of 9990 managers and professionals, we used hierarchical linear modeling to investigate the impact of both macro-level and micro-level predictors on subordinate influence ethics. While we found that both macro-level and micro-level predictors contributed to the model definition, we also found global agreement for a subordinate influence ethics hierarchy. Thus our findings provide evidence that developing a global model of subordinate ethics is possible, and should be based upon multiple criteria and multilevel variables. Journal of International Business Studies (2009) 40, 1022-1045. doi:10.1057/jibs.2008.109

Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation

We have identified truncating mutations in the human DLG3 ( neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.

A long-term study in Merino sheep experimentally infected with Mycobacterium avium subsp paratuberculosis: clinical disease, faecal culture and immunological studies

Two longitudinal experiments involving Merino sheep challenged with either bovine or ovine strains of Mycobacterium avium subsp. paratuberculosis (Map) have been conducted over a period of 54 and 35 months, respectively. Blood samples for the interferon-gamma test, the absorbed ELISA and faecal samples for bacteriological culture were taken pre-challenge and monthly post-challenge. Infections were induced with either a bovine or ovine strain of Map in separate experiments with infections being more easily established, in terms of faecal bacterial shedding and clinical disease when the challenge inoculum was prepared from gut mucosal tissue than cultured bacteria. The patterns of response for shedding and clinical disease were similar. Cell-mediated immune responses were proportionally elevated by at least an order of magnitude in all sheep dosed with either a bovine or ovine strain of Map. Conversely, antibody responses were only elevated in a relatively small proportion of infected sheep. Neither of the clinically affected tissue challenged sheep developed an antibody response despite the presence of persistent shedding and the development and decline in cell-mediated immunity. The results indicated that for sheep the interferon-gamma test may be useful for determining if a flock has been exposed to ovine Johne's disease. (C) 2004 Elsevier B.V. All rights reserved.

An Unprecedented Neolignan Skeleton from Chimarrhis turbinata

A lignan with a new skeleton named chimarrhinin (1) was isolated from an extract of the leaves of Chimarrhis turbinata, a Rubiaceae plant species. (13)C NMR spectrometric techniques including 1D and 2D experiments and HRESIMS provided unequivocal structural confirmation of this new C(6).C(3) skeleton type. The relative configuration of 1 was established by 2D (1)H-H analysis and J couplings, while its conformation was evaluated through molecular modeling using the RM1 semiempirical method, with the aid of coupling constants obtained by NMR analysis. The antioxidant activity of the new derivative 1 and two known and previously isolated phenolic derivatives (2 and 3) was investigated. An IC(50) value of 7.50 +/- 0.5 mu mol L(-1) was obtained for the new derivative 1, while 2 and 3 showed IC(50) values of 18.60 +/- 0.4 and 18.50 +/- 0.6 mu mol, respectively.

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.