Analog peptides of type II collagen can suppress arthritis in HLA-DR4 (DRB1*0401) transgenic mice

Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in diarthrodial joints. We have previously established that mice transgenic for the human DR genes associated with RA are susceptible to collagen-induced arthritis (CIA) and we have identified a determinant of type II collagen (CII(263–270)) that triggers T-cell immune responses in these mice. We have also determined that an analog of CII(263–270 )would suppress disease in DR1 transgenic mice. Because the immunodominant determinant is the same for both DR1 transgenic and DR4 transgenic mice, we attempted to determine whether the analog peptide that was suppressive in DR1 transgenic mice would also be effective in suppressing CIA in DR4 transgenic mice. We treated DR4 transgenic mice with two analog peptides of CII that contained substitutions in the core of the immunodominant determinant: CII(256–276 )(F263N, E266D) and CII(256–270 )(F263N, E266A). Mice were observed for CIA, and T-cell proliferative responses were determined. Either peptide administered at the time of immunization with CII significantly downregulated arthritis. Binding studies demonstrated that replacement of the phenylalanine residue in position 263 of the CII peptide with asparagine significantly decreased the affinity of the peptide for the DR4 molecule. In contrast, replacement of the glutamic acid residue in position 266 with aspartic acid or with alanine had differing results. Aspartic acid reduced the affinity (35-fold) whereas alanine did not. Both peptides were capable of suppressing CIA. With the use of either peptide, CII(256–276 )(F263N, E266D) or CII(256–270 )(F263N, E266A), the modulation of CIA was associated with an increase in T-cell secretion of IL-4 together with a decrease in IFN-γ. We have identified two analog peptides that are potent suppressors of CIA in DR4 transgenic mice. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of HLA-DR4 that can suppress autoimmune arthritis

Dynamics of earthquake nucleation process represented by the Burridge-Knopoff model

Dynamics of earthquake nucleation process is studied on the basis of the one-dimensional Burridge-Knopoff (BK) model obeying the rate- and state-dependent friction (RSF) law. We investigate the properties of the model at each stage of the nucleation process, including the quasi-static initial phase, the unstable acceleration phase and the high-speed rupture phase or a mainshock. Two kinds of nucleation lengths L_sc and L_c are identified and investigated. The nucleation length L_sc and the initial phase exist only for a weak frictional instability regime, while the nucleation length L_c and the acceleration phase exist for both weak and strong instability regimes. Both L_sc and L_c are found to be determined by the model parameters, the frictional weakening parameter and the elastic stiffness parameter, hardly dependent on the size of an ensuing mainshock. The sliding velocity is extremely slow in the initial phase up to L_sc, of order the pulling speed of the plate, while it reaches a detectable level at a certain stage of the acceleration phase. The continuum limits of the results are discussed. The continuum limit of the BK model lies in the weak frictional instability regime so that a mature homogeneous fault under the RSF law always accompanies the quasi-static nucleation process. Duration times of each stage of the nucleation process are examined. The relation to the elastic continuum model and implications to real seismicity are discussed.Comment: Title changed. Changes mainly in abstract and in section 1. To appear in European Physical Journal

Precision Physics at LEP

1 - Introduction 2 - Small-Angle Bhabha Scattering and the Luminosity Measurement 3 - Z^0 Physics 4 - Fits to Precision Data 5 - Physics at LEP2 6 - ConclusionsComment: Review paper to appear in the RIVISTA DEL NUOVO CIMENTO; 160 pages, LateX, 70 eps figures include

Climate Influence on Deep Sea Populations

Dynamics of biological processes on the deep-sea floor are traditionally thought to be controlled by vertical sinking of particles from the euphotic zone at a seasonal scale. However, little is known about the influence of lateral particle transport from continental margins to deep-sea ecosystems. To address this question, we report here how the formation of dense shelf waters and their subsequent downslope cascade, a climate induced phenomenon, affects the population of the deep-sea shrimp Aristeus antennatus. We found evidence that strong currents associated with intense cascading events correlates with the disappearance of this species from its fishing grounds, producing a temporary fishery collapse. Despite this initial negative effect, landings increase between 3 and 5 years after these major events, preceded by an increase of juveniles. The transport of particulate organic matter associated with cascading appears to enhance the recruitment of this deep-sea living resource, apparently mitigating the general trend of overexploitation. Because cascade of dense water from continental shelves is a global phenomenon, we anticipate that its influence on deep-sea ecosystems and fisheries worldwide should be larger than previously thought

The in vitro effect of gefitinib ('Iressa') alone and in combination with cytotoxic chemotherapy on human solid tumours

BACKGROUND: Activation of the epidermal growth factor receptor (EGFR) triggers downstream signaling pathways that regulate many cellular processes involved in tumour survival and growth. Gefitinib ('Iressa') is an orally active tyrosine kinase inhibitor (TKI) targeted to the ATP-binding domain of EGFR (HER1; erbB1). METHODS: In this study we have used a standardised ATP-based tumour chemosensitivity assay (ATP-TCA) to measure the activity of gefitinib alone or in combination with different cytotoxic drugs (cisplatin, gemcitabine, oxaliplatin and treosulfan) against a variety of solid tumours (n = 86), including breast, colorectal, oesophageal and ovarian cancer, carcinoma of unknown primary site, cutaneous and uveal melanoma, non-small cell lung cancer (NSCLC) and sarcoma. The IC50 and IC90 were calculated for each single agent or combination. To allow comparison between samples the Index(SUM )was calculated based on the percentage tumour growth inhibition (TGI) at each test drug concentration (TDC). Gefitinib was tested at concentrations ranging from 0.0625–2 microM (TDC = 0.446 microg/ml). This study represents the first use of a TKI in the assay. RESULTS: There was heterogeneity in the degree of TGI observed when tumours were tested against single agent gefitinib. 7% (6/86) of tumours exhibited considerable inhibition, but most showed a more modest response resulting in a low TGI. The median IC50 value for single agent gefitinib in all tumours tested was 3.98 microM. Interestingly, gefitinib had both positive and negative effects when used in combination with different cytotoxics. In 59% (45/76) of tumours tested, the addition of gefitinib appeared to potentiate the effect of the cytotoxic agent or combination (of these, 11% (5/45) had a >50% decrease in their Index(SUM)). In 38% of tumours (29/76), the TGI was decreased when the combination of gefitinib + cytotoxic was used in comparison to the cytotoxic alone. In the remaining 3% (2/76) there was no change observed. CONCLUSION: The in vitro model suggests that gefitinib may have differential effects in response to concomitant cytotoxic chemotherapy with the agents tested during this study. The mechanism involved may relate to the effect of TKIs on growth rate versus their effect on the ability of the cell to survive the stimulus to apoptosis produced by chemotherapy

Sun protection and sunbathing practices among at-risk family members of patients with melanoma

<p>Abstract</p> <p>Background</p> <p>Despite the increased level of familial risk, research indicates that family members of patients with melanoma engage in relatively low levels of sun protection and high levels of sun exposure. The goal of this study was to evaluate a broad range of demographic, medical, psychological, knowledge, and social influence correlates of sun protection and sunbathing practices among first-degree relatives (FDRs) of melanoma patients and to determine if correlates of sun protection and sunbathing were unique.</p> <p>Methods</p> <p>We evaluated correlates of sun protection and sunbathing among FDRs of melanoma patients who were at increased disease risk due to low compliance with sun protection and skin surveillance behaviors. Participants (<it>N </it>= 545) completed a phone survey.</p> <p>Results</p> <p>FDRs who reported higher sun protection had a higher education level, lower benefits of sunbathing, greater sunscreen self-efficacy, greater concerns about photo-aging and greater sun protection norms. FDRs who reported higher sunbathing were younger, more likely to be female, endorsed fewer sunscreen barriers, perceived more benefits of sunbathing, had lower image norms for tanness, and endorsed higher sunbathing norms.</p> <p>Conclusion</p> <p>Interventions for family members at risk for melanoma might benefit from improving sun protection self-efficacy, reducing perceived sunbathing benefits, and targeting normative influences to sunbathe.</p

A Genomewide Functional Network for the Laboratory Mouse

Establishing a functional network is invaluable to our understanding of gene function, pathways, and systems-level properties of an organism and can be a powerful resource in directing targeted experiments. In this study, we present a functional network for the laboratory mouse based on a Bayesian integration of diverse genetic and functional genomic data. The resulting network includes probabilistic functional linkages among 20,581 protein-coding genes. We show that this network can accurately predict novel functional assignments and network components and present experimental evidence for predictions related to Nanog homeobox (Nanog), a critical gene in mouse embryonic stem cell pluripotency. An analysis of the global topology of the mouse functional network reveals multiple biologically relevant systems-level features of the mouse proteome. Specifically, we identify the clustering coefficient as a critical characteristic of central modulators that affect diverse pathways as well as genes associated with different phenotype traits and diseases. In addition, a cross-species comparison of functional interactomes on a genomic scale revealed distinct functional characteristics of conserved neighborhoods as compared to subnetworks specific to higher organisms. Thus, our global functional network for the laboratory mouse provides the community with a key resource for discovering protein functions and novel pathway components as well as a tool for exploring systems-level topological and evolutionary features of cellular interactomes. To facilitate exploration of this network by the biomedical research community, we illustrate its application in function and disease gene discovery through an interactive, Web-based, publicly available interface at http://mouseNET.princeton.edu

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types