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Stephen Brooks

Publications and source records attributed to Stephen Brooks.

11 recordsLinked to original sources
PubMed2026

Type I Interferon Signature is Associated With Lung Disease, Drug-Associated Immune Reactions, and Genetic Variation in Interferon-Linked Pathways in Still Disease.

OBJECTIVE: To evaluate the relationship across type I interferon (IFN-I)-stimulated gene (ISG) expression, Still disease, and the development of lung disease (LD) and drug-associated immune reactions (DAIR) to interleukin-1 (IL-1) and/or IL-6 inhibitors. METHODS: Whole blood ISG expression was quantified by NanoString array. ISG-28 scores were calculated in consecutive patients with Still or Still-like disease. Exome sequencing with family-based variant prioritization identified candidate genes harboring rare candidate causative variants. Lists of candidate genes were subjected to functional enrichment analysis. RESULTS: Among 57 patients (32 children, 25 adults), 16 had elevated ISG-28 scores. This group exhibited higher prevalence of LD (0.44 vs 0.1, P = 0.007) and DAIR (0.63 vs 0.17, P = 0.003) and lower IL-6 inhibitor use (0 vs 0.25, P = 0.048) compared to others. No significant differences were found in the rates of macrophage activation syndrome, active disease, elevated IL-18, or current IL-1 inhibition. The combination of HLA-DRB1*15 with high ISG-28 scores is associated with LD and DAIR with high specificity, whereas absence of both biomarkers had high negative predictive value. Candidate genes from high ISG-28 individuals were enriched in IFN-related pathways, including autophagy, IFN-I production, toll-like receptor signaling, macrophage activation, cytoskeletal organization, and responses to stress. CONCLUSION: High IFN-I expression correlates with LD and DAIR in Still disease, linked to rare genetic variation in immune pathways. Combining high ISG-28 with HLA-DRB1*15 significantly improves post hoc stratification of patients for these complications. If prospectively validated, these findings may guide molecular risk assessment and targeted therapies, including IFN-I directed treatments in Still disease with IFN-I signature.

Humans↗
PubMed2006

Human Immunodeficiency Virus-Type 1 LTR DNA contains an intrinsic gene producing antisense RNA and protein products.

BACKGROUND: While viruses have long been shown to capitalize on their limited genomic size by utilizing both strands of DNA or complementary DNA/RNA intermediates to code for viral proteins, it has been assumed that human retroviruses have all their major proteins translated only from the plus or sense strand of RNA, despite their requirement for a dsDNA proviral intermediate. Several studies, however, have suggested the presence of antisense transcription for both HIV-1 and HTLV-1. More recently an antisense transcript responsible for the HTLV-1 bZIP factor (HBZ) protein has been described. In this study we investigated the possibility of an antisense gene contained within the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). RESULTS: Inspection of published sequences revealed a potential transcription initiator element (INR) situated downstream of, and in reverse orientation to, the usual HIV-1 promoter and transcription start site. This antisense initiator (HIVaINR) suggested the possibility of an antisense gene responsible for RNA and protein production. We show that antisense transcripts are generated, in vitro and in vivo, originating from the TAR DNA of the HIV-1 LTR. To test the possibility that protein(s) could be translated from this novel HIV-1 antisense RNA, recombinant HIV antisense gene-FLAG vectors were designed. Recombinant protein(s) were produced and isolated utilizing carboxy-terminal FLAG epitope (DYKDDDDK) sequences. In addition, affinity-purified antisera to an internal peptide derived from the HIV antisense protein (HAP) sequences identified HAPs from HIV+ human peripheral blood lymphocytes. CONCLUSION: HIV-1 contains an antisense gene in the U3-R regions of the LTR responsible for both an antisense RNA transcript and proteins. This antisense transcript has tremendous potential for intrinsic RNA regulation because of its overlap with the beginning of all HIV-1 sense RNA transcripts by 25 nucleotides. The novel HAPs are encoded in a region of the LTR that has already been shown to be deleted in some HIV-infected long-term survivors and represent new potential targets for vaccine development.

Base Sequence↗
PubMed2006

Development of autoimmunity in IL-14alpha-transgenic mice.

Multiple genetic loci contribute to the development of systemic lupus erythematosus (SLE). In murine models for SLE, various genes on chromosome four have been implicated. IL-14 is a cytokine originally identified as a B cell growth factor. The il14 gene is located on chromosome 4. IL-14alpha is a cytokine encoded by the plus strand of the IL-14 gene using exons 3-10. The expression of IL-14alpha is increased in (NZB x NZW)F1 mice. In this study, we produced IL-14alpha-transgenic mice to study the role of IL-14alpha in the development of autoimmunity. At age 3-9 mo, IL-14alpha-transgenic mice demonstrate increased numbers of B1 cells in the peritoneum, increased serum IgM, IgG, and IgG 2a and show enhanced responses to T-dependent and T-independent Ags compared with littermate controls. At age 9-17 mo, IL-14alpha-transgenic mice develop autoantibodies, sialadenitis, as in Sjögren's syndrome, and immune complex-mediated nephritis, as in World Health Organization class II SLE nephritis. Between the ages 14-18 mo, 95% of IL-14alpha-transgenic mice developed CD5+ B cell lymphomas, consistent with the lymphomas seen in elderly patients with Sjögren's syndrome and SLE. These data support a role for IL-14alpha in the development of both autoimmunity and lymphomagenesis. These studies may provide a genetic link between these often related disorders.

Age Factors↗
PubMed2005

Alkalosis and the plasma catecholamine response to high-intensity exercise in man.

PURPOSE: The aims of this study were to examine the plasma dopamine response to a controlled bout of short-duration high-intensity exercise and investigate the magnitude of the plasma dopamine (DA), norepinephrine (NE), and epinephrine (EPI) responses to this exercise after induced alkalosis. METHODS: Eight male subjects were given in randomized order either; PLAC 0.3 g.kg(-1) body mass CaCO3 + 1 g NaCl, 0.3CIT 0.3 g.kg(-1) or 0.5CIT 0.5 g.kg(-1) body mass tri-sodium citrate in 500 mL water. One hour after ingestion subjects performed a 2-min cycle test at a workload calculated to elicit 110% VO(2max). Plasma catecholamines were measured using high performance liquid chromatography with electrochemical detection. RESULTS: Antecubital venous blood pH and blood base excess (BBE) were significantly increased after ingestion of sodium citrate compared with placebo (P < 0.05). All postexercise sodium citrate blood pH and BBE values were significantly greater than placebo (P < 0.05). High-intensity exercise did not affect resting plasma DA concentrations. Peak plasma NE and EPI concentrations occurred immediately postexercise [NE PLAC 4.6 +/- 2.1 ES = 1.2, 0.3CIT 4.2 +/- 1.8 ES = 1.5, 0.5CIT 4.6 +/- 2.2 nmol.L(-1) ES = 1.2; EPI PLAC 0.6 +/- 0.3 ES = 1.3, 0.3CIT 0.5 +/- 0.2 ES = 1.3, 0.5CIT 0.5 +/- 0.3 nmol.L(-1) ES = 0.8] and were still elevated 5 min postexercise (P < 0.05). The magnitude of the plasma dopamine, norepinephrine and epinephrine response to exercise was unaltered with either 0.3CIT or 0.5CIT. CONCLUSION: This study has demonstrated that performance of a controlled bout of high-intensity exercise did not alter the plasma dopamine concentration. In addition, alterations in blood alkalosis did not influence the magnitude of the plasma dopamine, norepinephrine or epinephrine responses to exercise.

Acid-Base Equilibrium↗
PubMed2004

B cell signaling is regulated by induced palmitoylation of CD81.

Signaling through the B cell antigen receptor (BCR) is amplified and prolonged by coligation of the BCR to the CD19/CD21/CD81 coreceptor complex. Coligation is induced during immune responses by the simultaneous binding of complement-tagged antigens to the complement receptor, CD21, and to the BCR. Enhanced signaling is due in part to the ability of the CD19/CD21/CD81 complex to stabilize the BCR in sphingolipid- and cholesterol-rich membrane microdomains termed lipid rafts. The tetraspanin CD81 is essential for the raft-stabilizing function of the coreceptor. Here we show that coligation of the BCR and the CD19/CD21/CD81 complex leads to selective, rapid, and reversible palmitoylation of CD81 and that palmitoylation is necessary for the raft stabilizing function of the CD19/CD21/CD81 complex. Inducible palmitoylation may represent a novel mechanism by which tetraspanins function to facilitate lipid raft-dependent receptor signaling.

Antibodies, Monoclonal↗
PubMed2004

The tetraspanin CD81 is necessary for partitioning of coligated CD19/CD21-B cell antigen receptor complexes into signaling-active lipid rafts.

Tetraspanins have been hypothesized to facilitate the organization of functional multimolecular membrane complexes. In B cells the tetraspanin CD81 is a component of the CD19/CD21 complex. When coligated to the B cell Ag receptor (BCR), the CD19/CD21 complex significantly enhances BCR signaling in part by prolonging the association of the BCR with signaling-active lipid rafts. In this study CD81 is shown to associate with lipid rafts upon coligation of the BCR and the CD19/CD21 complex. Using B cells from CD81-deficient mice we demonstrate that in the absence of CD81, coligated BCR and CD19/CD21 complexes fail to partition into lipid rafts and enhance BCR signaling from rafts. Furthermore, a chimeric CD19 protein that associates only weakly if at all with CD81 fails to promote the association of coligated BCR with lipid rafts. The requirement for CD81 to promote lipid raft association may define a novel mechanism by which tetraspanins function as molecular facilitators of signaling receptors.

Adjuvants, Immunologic↗
PubMed2002

Behavioral parasomnias.

Sleep is not a static state. During the sleep period, physiologic changes occur throughout the body and brain. This complex, dynamic process can, at times, result in episodes of unusual or undesirable behaviors. These phenomena are called parasomnias. The accurate diagnosis of this group of treatable disorders is important, because they can have a negative impact on sleep, health, and social function. In addition, some of the parasomnias may provide clues to the presence of other underlying pathologic conditions. The parasomnias may be categorized in more than one way, but any attempt to classify such a diverse collection of entities is likely to be somewhat arbitrary. This article discusses the parasomnias according to the classification of the International Classification of Sleep Disorders, with emphasis on those characterized by observable behavior. As the understanding of these disorders (and sleep, in general) continues to deepen, new entities and schemes of classification may emerge.

Brain↗
PubMed2002

Role of CD19 signal transduction in B cell biology.

Knockout studies have established an important role for the B lymphocyte surface protein CD19 in physiology. Previous studies by us and others have examined how CD19 might function at the biochemical level, with focus on the cytoplasmic tyrosines. We have mapped multiple different molecular associations with these tyrosines. However, the major question in CD19 signaling is, how do these tyrosines relate to what happens in vivo? To address this issue, we created mice expressing only mutant forms of CD19. Our initial studies have found that most CD19 function in vivo is dependent on two of these cytoplasmic tyrosines, Y482 and Y513. However, the signaling defects in cells expressing this mutation are subtle. They demonstrate that how CD19 signals depends on how it is ligated, and that CD19 signals by more than one mechanism. These observations in primary cells give insights into how CD19 functions at the molecular level and likely explain some of the differences in CD19 function that have been reported in vivo.

Animals↗
PubMed2002

Novel therapies for narcolepsy.

Narcolepsy is a primary neurological disorder, which often produces disabling symptoms, including excessive daytime sleepiness and cataplexy. Although the precise aetiology of narcolepsy has not been determined, our understanding of the pathophysiology of this complex disorder has grown dramatically during the past several years, especially as it relates to the newly discovered hypocretin system. While symptomatic treatment of narcolepsy is available, the commonly used pharmacological agents are often not completely effective and may be poorly tolerated. The need for new therapeutic tools is, therefore, apparent. This paper explores some exciting new approaches to the treatment of narcolepsy. It is important to emphasise that, although narcolepsy is not a common disorder, new agents for its treatment will undoubtedly find more extensive use in other conditions.

Adrenergic Agents↗
PubMedDate not supplied

Image-based stained glass.

We present a method of restyling an image so that it approximates the visual appearance of a work of stained glass. To this end, we develop a novel approach which involves image warping, segmentation, querying, and colorization along with texture synthesis. In our method, a given input image is first segmented. Each segment is subsequently transformed to match real segments of stained glass queried from a database of image exemplars. By using real sources of stained glass, our method produces high quality results in this nascent area of nonphotorealistic rendering. The generation of the stained glass requires only modest amounts of user interaction. This interaction is facilitated with a unique region-merging tool.

Algorithms↗