Efficient discovery of immune response targets by cyclical refinement of QSAR models of peptide binding

Peptides that induce and recall T-cell responses are called T-cell epitopes. T-cell epitopes may be useful in a subunit vaccine against malaria. Computer models that simulate peptide binding to MHC are useful for selecting candidate T-cell epitopes since they minimize the number of experiments required for their identification. We applied a combination of computational and immunological strategies to select candidate T-cell epitopes. A total of 86 experimental binding assays were performed in three rounds of identification of HLA-All binding peptides from the six preerythrocytic malaria antigens. Thirty-six peptides were experimentally confirmed as binders. We show that the cyclical refinement of the ANN models results in a significant improvement of the efficiency of identifying potential T-cell epitopes. (C) 2001 by Elsevier Science Inc.

Clinical and molecular genetics of myoclonic-astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome)

The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEF(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI. (C) 2001 Elsevier Science B.V. All rights reserved.

No association between the deficit syndrome in psychosis and summer birth in the Southern Hemisphere

Recent studies have shown that individuals with schizophrenia who are born in summer have an increased odds of have deficit syndrome versus nondeficit syndrome. This study extends this work to examiningthis issue in patients from the Southern Hemisphere. Data which included OPCRITrSCAN items and demographic information was obtained for Australian-born cases from the Australian National Mental Health Survey. Followingpreviously published methods, cases were assigned to the deficit group Žns153.or non-deficit groupŽns228.. A logistic regression analysis was used to ascertain whether beingborn in summer ŽDecember, January, February.in the Southern Hemisphere altered the odds of havingdeficit syndrome. There was no association between summer birth and odds of havingdeficit versus non-deficit schizophrenia ŽOdds Ratios0.75, 95% CI 0.49–1.16.. Based on our previous work showingthat the size of the winterrspringbirth excess in schizophrenia is reduced in the Southern Hemisphere, we speculate that factors that influence the association between summer birth and non-deficit syndrome may also vary across geography andror latitude. The Stanley Foundation supported this project.

A coiled-coil region of an insect immune suppressor protein is involved in binding and uptake by hemocytes

Polydnaviruses are associated with certain parasitoid wasps and are introduced into the body cavity of the host caterpillar during oviposition. Some of the viral genes are expressed in host tissues and corresponding proteins are secreted into the hemocoel causing suppression of the host immune system. The Cotesia rubecula polydnavirus gene product, CrV1, effectively inactivates hemocytes by mediating cytoskeleton break-down. A precondition for the CrV1 function is the incorporation of the extracellular protein by hemocytes. Here, we show that a coiled-coil domain containing a putative leucine zipper is required for CrV1 function, since removal of this domain abolishes binding and uptake of the CrV1 protein by hemocytes. (C) 2002 Elsevier Science Ltd. All rights reserved.

Nonoxynol-9 spermicide for prevention of vaginally acquired HIV and other sexually transmitted infections: systematic review and meta-analysis of randomised controlled trials including more than 5000 women

We aimed to determine the effectiveness of the vaginally administered spermicide nonoxynol-9 (N-9) among women for the prevention of HIV and other sexually transmitted infections (STIs), We did a systematic review of randomised controlled trials, Nine such trials including 5096 women, predominantly sex workers, comparing N-9 with placebo or no treatment, were included. Primary outcomes were new HIV infection, new episodes of various STIs, and genital lesions. Five trials included HIV and nine included STI outcomes, and all but one (2% of the data) contributed to the meta-analysis. Overall, relative risks of HIV infection (1.12, 95% confidence interval 0.88-1.42), gonorrhoea (0.91, 0.67-1.24), chlamyclia (0.88, 0.77-1.01), cervical infection (1.01, 0.84-1-22), trichomoniasis (0.84, 0.69-1.02), bacterial vaginosis (0.88, 0.74-1.04) and candidiasis (0.97, 0.84-1.12) were not significantly different in the N-9 and placebo or no treatment groups. Genital lesions were more common in the N-9 group (1.18, 1.02-1.36). Our review has found no statistically significant reduction in risk of HIV and STIs, and the confidence intervals indicate that any protection that may exist is likely to be very small. There is some evidence of harm through genital lesions. N-9 cannot be recommended for HIV and STI prevention.

Characterization of a novel protein with homology to C-type lectins expressed by the Cotesia rubecula bracovirus in larvae of the lepidopteran host, Pieris rapae

Polydnaviruses are essential for the survival of many Ichneumonoid endoparasitoids, providing active immune suppression of the host in which parasitoid larvae develop. The Cotesia rubecula bracovirus is unique among polydnaviruses in that only four major genes are detected in parasitized host ( Pieris rapae) tissues, and gene expression is transient. Here we describe a novel C. rubecula bracovirus gene (CrV3) encoding a lectin monomer composed of 159 amino acids, which has conserved residues consistent with invertebrate and mammalian C-type lectins. Bacterially expressed CrV3 agglutinated sheep red blood cells in a divalent ion-dependent but Ca2+-independent manner. Agglutination was inhibited by EDTA but not by biological concentrations of any saccharides tested. Two monomers of similar to14 and similar to17 kDa in size were identified on SDS-PAGE in parasitized P. rapae larvae. The 17-kDa monomer was found to be an N-glyscosylated form of the 14-kDa monomer. CrV3 is produced in infected hemocytes and fat body cells and subsequently secreted into hemolymph. We propose that CrV3 is a novel lectin, the first characterized from an invertebrate virus. CrV3 shows over 60% homology with hypothetical proteins isolated from polydnaviruses in two other Cotesia wasps, indicating that these proteins may also be C-type lectins and that a novel polydnavirus lectin family exists in Cotesia-associated bracoviruses. CrV3 is probably interacting with components in host hemolymph, resulting in suppression of the Pieris immune response. The high similarity of CrV3 with invertebrate lectins, as opposed to those from viruses, may indicate that some bracovirus functions were acquired from their hosts.

Examining the influence of biological and psychological factors on cognitive performance in chronic fatigue syndrome: A randomized, double-blind, placebo-controlled, crossover study

The pathophysiology of chronic fatigue syndrome (CFS) remains unclear; however, both biological and psychological factors have been implicated in establishing or maintaining this condition. People with CFS report significant and disabling cognitive difficulties such as impaired concentration that in some cases are exacerbated by exposure to chemical triggers. The aim of this study was to determine if neuropsychological deficits in CFS are triggered by exposure to chemicals, or perceptions about the properties of these substances. Participants were 36 people with a primary diagnosis of CFS, defined according to Centers for Disease Control (CDC) criteria. A randomized, double-blind, placebo-controlled, crossover design was used, with objective assessment of neuropsychological function and participant rating of substance type, before and after exposure to placebo or chemical trigger. Results showed decrements in neuropsychological tests scores on three out of four outcome measures when participants rated the substance they had been exposed to as chemical. No change in performance was found based on actual substance type. These results suggest that cognitive attributions about exposure substances in people with CFS may be associated with worse performance on neuropsychological tasks. In addition, these findings suggest that psychological interventions aimed at modifying substance-related cognitions may reduce some symptoms of CFS.

Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and gamma delta T cells

Few studies have demonstrated that innate lymphocytes play a major role in preventing spontaneous tumor formation. We evaluated the development of spontaneous tumors in mice lacking beta-2 microglobulin (beta2m; and thus MHC class I, CD1d, and CD16) and/or perform, since these tumor cells would be expected to activate innate effector cells. Approximately half the cohort of perform gene-targeted mice succumbed to spontaneous disseminated B cell lymphomas and in mice that also lacked beta2m, the lymphomas developed earlier (by more than 100 d) and with greater incidence (84%). B cell lymphomas from perforin/beta2m gene-targeted mice effectively primed cell-mediated cytotoxicity and perform, but not IFN-gamma, IL-12, or IL-18, was absolutely essential for tumor rejection. Activated NK1.1(+) and gammadeltaTCR(+) T cells were abundant at the tumor site, and transplanted tumors were strongly rejected by either, or both, of these cell types. Blockade of a number of different known costimulatory pathways failed to prevent tumor rejection. These results reflect a critical role for NK cells and gammadeltaTCP(+) T cells in innate immune surveillance of B cell lymphomas, mediated by as yet undetermined pathway(s) of tumor recognition.

Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development

A dendritic cell (DC) imbalance with a marked deficiency in CD4(-)8(+) DC occurs in non-obese diabetic (NOD) mice, a model of human autoimmune diabetes mellitus. Using a NOD congenic mouse strain, we find that this CD4(-)8(+) DC deficiency is associated with a gene segment on chromosome 4, which also encompasses non-MHC diabetes susceptibility loci. Treatment of NOD mice with fms-like tyrosine kinase 3 ligand (FL) enhances the level of CD4(-)8(+) DC, temporarily reversing the DC subtype imbalance. At the same time, fms-like tryosine kinase 3 ligand treatment blocks early stages of the diabetogenic process and with appropriately timed administration can completely prevent diabetes development. This points to a possible clinical use of FL to prevent autoimmune disease.