Biomedical subjects

Björn Albrecht

Publications and source records attributed to Björn Albrecht.

8 recordsLinked to original sources

PubMed2006

Colour perception in ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is associated with unexplained impairments on speeded naming of coloured stimuli. These deficits may reflect hypofunctioning retinal dopaminergic mechanisms impairing particularly blue-yellow colour discrimination. Colour perception and rapid colour naming ability were investigated in 14 children with ADHD and 13 healthy peers matched for age, gender, and IQ, using the Farnsworth-Munsell 100 Hue Test (FMT) and the Stroop-Colour-Word test. Children with ADHD committed more errors on the FMT, particularly on discrimination of colours along the blue-yellow axis, and were slower on Stroop subtests involving colour naming. However, the latter deficit was accounted for similarly by blue-yellow and red-green discrimination abilities. Blue-yellow colour perception problems in ADHD contribute to but do not fully explain the observed slowed colour naming.

Adolescent↗

PubMed2005

Response inhibition deficits in externalizing child psychiatric disorders: an ERP-study with the Stop-task.

BACKGROUND: Evidence from behavioural studies suggests that impaired motor response inhibition may be common to several externalizing child psychiatric disorders, although it has been proposed to be the core-deficit in AD/HD. Since similar overt behaviour may be accompanied by different covert brain activity, the aim of this study was to investigate both brain-electric-activity and performance measures in three groups of children with externalizing child psychiatric disorders and a group of normal controls. METHODS: A Stop-task was used to measure specific aspects of response inhibition in 10 children with attention-deficit hyperactivity disorder (AD/HD), 8 children with oppositional defiant disorder/conduct disorder (ODD/CD), 11 children with comorbid AD/HD+ODD/CD and 11 normal controls. All children were between 8 and 14 years old. Event-related potentials and behavioural responses were recorded. An initial go-signal related microstate, a subsequent Stop-signal related N200, and performance measures were analyzed using ANCOVA with age as covariate. RESULTS: Groups did not differ in accuracy or reaction time to the Go-stimuli. However, all clinical groups displayed reduced map strength in a microstate related to initial processing of the Go-stimulus compared to normal controls, whereas topography did not differ. Concerning motor response inhibition, the AD/HD-only and the ODD/CD-only groups displayed slower Stop-signal reaction times (SSRT) and Stop-failure reaction time compared to normal controls. In children with comorbid AD/HD+ODD/CD, Stop-failure reaction-time was longer than in controls, but their SSRT was not slowed. Moreover, SSRT in AD/HD+ODD/CD was faster than in AD/HD-only or ODD/CD-only. The AD/HD-only and ODD/CD-only groups displayed reduced Stop-N200 mean amplitude over right-frontal electrodes. This effect reached only a trend for comorbid AD/HD+ODD/CD. CONCLUSION: Following similar attenuations in initial processing of the Go-signal in all clinical groups compared to controls, distinct Stop-signal related deficits became evident in the clinical groups. Both children with AD/HD and ODD/CD showed deficits in behavioural response-inhibition accompanied by decreased central conflict signalling or inhibition processes. Neither behavioural nor neural markers of inhibitory deficits as found in AD/HD-only and ODD/CD-only were additive. Instead, children with comorbid AD/HD+ODD/CD showed similar or even less prominent inhibition deficits than the other clinical groups. Hence, the AD/HD+ODD/CD-group may represent a separate clinical entity.

Journal Article↗

PubMed2003

Requirement for CARMA1 in antigen receptor-induced NF-kappa B activation and lymphocyte proliferation.

Ligation of antigen receptors (TCR, BCR) on T and B lymphocytes leads to the activation of new transcriptional programs and cell cycle progression. Antigen receptor-mediated activation of NF-kappa B, required for proliferation of B and T cells, is disrupted in T cells lacking PKC theta and in B and T cells lacking Bcl10, a caspase recruitment domain (CARD)-containing adaptor protein. CARMA1 (also called CARD11 and Bimp3), the only lymphocyte-specific member in a family of membrane-associated guanylate kinase (MAGUK) scaffolding proteins that interact with Bcl10 by way of CARD-CARD interactions, is required for TCR-induced NF-kappa B activation in Jurkat T lymphoma cells. Here we show that T cells from mice lacking CARMA1 expression were defective in recruitment of Bcl10 to clustered TCR complexes and lipid rafts, in activation of NF-kappa B, and in induction of IL-2 production. Development of CD5(+) peritoneal B cells was disrupted in these mice, as was B cell proliferation in response to both BCR and CD40 ligation. Serum immunoglobulin levels were also markedly reduced in the mutant mice. Together, these results show that CARMA1 has a central role in antigen receptor signaling that results in activation and proliferation of both B and T lymphocytes.

Adaptor Proteins, Vesicular Transport↗

PubMed2003

A conserved calcineurin-binding motif in human T lymphotropic virus type 1 p12I functions to modulate nuclear factor of activated T cell activation.

The PXIXIT calcineurin binding motif or highly related sequences are found in a variety of calcineurin-binding proteins in yeast, mammalian cells, and viruses. The accessory protein p12(I) encoded in the HTLV-1 pX ORF I promotes T cell activation during the early stages of HTLV-1 infection by activating nuclear factor of activated T cells (NFAT) through calcium release from the endoplasmic reticulum. We identified in p12(I), a conserved motif, which is highly homologous with the PXIXIT calcineurin-binding motif of NFAT. Both immunoprecipitation and calmodulin agarose bead pull-down assays indicated that wild type p12(I) and mutants of p12(I) that contained the motif-bound calcineurin. In addition, an alanine substitution p12(I) mutant (p12(I) AXAXAA) had greatly reduced binding affinity for calcineurin. We then tested whether p12(I) binding to calcineurin affected NFAT activity. p12(I) competed with NFAT for calcineurin binding in calmodulin bead pull-down experiments. Furthermore, the p12(I) AXAXAA mutant enhanced NFAT nuclear translocation compared with wild type p12(I) and increased NFAT transcriptional activity 2-fold greater than wild type p12(I). Similar to NFAT, endogenous calcineurin phosphatase activity was increased in Jurkat T cells expressing p12(I) independent of its calcineurin binding property. Thus, the reduced binding of p12(I) to calcineurin allows enhanced nuclear translocation and transcription mediated by NFAT. Herein, we are the first to identify a retroviral protein that binds calcineurin. Our data suggest that HTLV-1 p12(I) modulates NFAT activation to promote early virus infection of T lymphocytes, providing a novel mechanism for retrovirus-mediated cell activation.

Active Transport, Cell Nucleus↗

PubMed2002

Protein kinase C-theta;: signaling from the center of the T-cell synapse.

The hypothesis that protein kinase C (PKC)-theta; plays an important role in T-lymphocyte activation, as indicated by numerous studies in cell lines, was recently confirmed in mice deficient in the expression of this enzyme. In response to TCR stimulation, peripheral T cells lacking PKC-theta; failed to activate NF-kappaB and AP-1, and to express IL-2. This revealed a critical function for this PKC family member in linking membrane-proximal activation cascades to transcriptional responses governing T-cell activation. Although the molecular interactions in which PKC-theta; engages have not been fully delineated, insights from a variety of recent studies have permitted new models to be formulated regarding the mechanisms through which it achieves its unique effector functions.

Animals↗

PubMed2002

Human T-cell lymphotropic virus type 1 p12(I) expression increases cytoplasmic calcium to enhance the activation of nuclear factor of activated T cells.

Human T-cell lymphotropic virus type 1 (HTLV-1) establishes persistent infection and is associated with lymphoproliferative or neurodegenerative diseases. As a complex retrovirus, HTLV-1 contains typical structural and enzymatic genes, as well as regulatory and accessory genes encoded in the pX region. The early events necessary for HTLV-1 to establish infection in lymphocytes, its primary target cells, remain unresolved. Recent studies have demonstrated the importance of regulatory and accessory gene products in determining this virus-host interaction. Among these, pX open reading frame I, which encodes two proteins, p12(I) and p27(I), is required for establishing persistent infection in vivo and for infection in quiescent primary lymphocytes. In addition, p12(I) localizes in the endoplasmic reticulum (ER) and cis-Golgi apparatus and associates with a calcium binding protein, calreticulin. We recently reported that p12(I) expression induces the calcium-responsive T-cell transcription factor, nuclear factor of activated T cells (NFAT), in the presence of phorbol ester activation. Based on these studies, we hypothesize that p12(I) may modulate calcium release from the ER. Here, we report that p12(I) expression increases basal cytoplasmic calcium and concurrently diminishes calcium available for release from the ER stores. Overexpression of calreticulin, a calcium buffer protein, blocked p12(I)-mediated NFAT activation independently of its ability to bind p12(I). Chemical inhibition studies using inhibitors of inositol 1,4,5-triphosphate receptor and calcium release-activated calcium channels suggest that inositol 1,4,5-triphosphate receptor in the ER membrane and calcium release-activated calcium channels in the plasma membrane contribute to p12(I)-mediated NFAT activation. Collectively, our results are the first to demonstrate the role of p12(I) in elevating cytoplasmic calcium, an antecedent to T-cell activation, and further support the important role of this accessory protein in the early events of HTLV-1 infection.

Calcium↗

PubMed2002

Activation of nuclear factor of activated T cells by human T-lymphotropic virus type 1 accessory protein p12(I).

Human T-lymphotropic virus type 1 (HTLV-1) is the agent of an aggressive malignancy of CD4(+) T lymphocytes, called adult T-cell lymphoma/leukemia, and is associated with numerous immune-mediated diseases. To establish infection, HTLV-1 must activate targeted T cells during early stages of infection. We recently demonstrated that the HTLV-1 accessory protein p12(I) is critical for persistent infection in vivo and for viral infectivity in quiescent primary lymphocytes, suggesting a role for p12(I) in lymphocyte activation. To test whether p12(I) modulates signaling pathways required for T-lymphocyte activation, we examined AP-1-, NF-kappaB-, and nuclear factor of activated T cells (NFAT)-driven reporter gene activity in p12(I)-expressing Jurkat T cells compared to vector-transfected control cells. HTLV-1 p12(I) specifically induced NFAT-mediated transcription approximately 20-fold in synergy with the Ras/mitogen-activated protein kinase pathway, but did not influence AP-1- or NF-kappaB-dependent gene expression. Inhibition of calcium-dependent signals by cyclosporin A, BAPTA-AM [glycine, N,N'-1,2-ethanediylbis(oxy-2,1-phenylene)-bis-N-2-(acetyloxy)methoxy-2-oxoethyl]-[bis(acetyloxy)methyl ester], and a dominant negative mutant of NFAT2 abolished the p12(I)-mediated activation of NFAT-dependent transcription. In contrast, inhibition of phospholipase C-gamma and LAT (linker for activation of T cells) did not affect p12(I)-induced NFAT activity. Importantly, p12(I) functionally substituted for thapsigargin, which selectively depletes intracellular calcium stores. Our data are the first to demonstrate a role for HTLV-1 p12(I) in calcium-dependent activation of NFAT-mediated transcription in lymphoid cells. We propose a novel mechanism by which HTLV-1, a virus associated with lymphoproliferative disease, dysregulates common T-cell activation pathways critical for the virus to establish persistent infection.

Calcium↗

PubMed2002

Critical role of human T-lymphotropic virus type 1 accessory proteins in viral replication and pathogenesis.

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is associated with a diverse range of lymphoproliferative and neurodegenerative diseases, yet pathogenic mechanisms induced by the virus remain obscure. This complex retrovirus contains typical structural and enzymatic genes but also unique regulatory and accessory genes in four open reading frames (ORFs) of the pX region of the viral genome (pX ORFs I to IV). The regulatory proteins encoded by pX ORFs III and IV, Tax and Rex, respectively, have been extensively characterized. In contrast the contribution of the four accessory proteins p12(I), p27(I), p13(II), and p30(II), encoded by pX ORFs I and II, to viral replication and pathogenesis remained unclear. Proviral clones that are mutated in either pX ORF I or II, while fully competent in cell culture, are severely limited in their replicative capacity in a rabbit model. Emerging evidence indicates that the HTLV-1 accessory proteins are critical for establishment of viral infectivity, enhance T-lymphocyte activation, and potentially alter gene transcription and mitochondrial function. HTLV-1 pX ORF I expression is critical to the viral infectivity in resting primary lymphocytes, suggesting a role for p12(I) in lymphocyte activation. The endoplasmic reticulum and cis-Golgi localizing p12(I), encoded from pX ORF I, activates NFAT, a key T-cell transcription factor, through calcium-mediated signaling pathways and may lower the threshold of lymphocyte activation via the JAK/STAT pathway. In contrast p30(II) localizes to the nucleus and represses viral promoter activity, but may regulate cellular gene expression through p300/CBP or related coactivators of transcription. p13(II) targets mitochondrial proteins, where it alters the organelle morphology and may influence energy metabolism. Collectively, studies of the molecular functions of the HTLV-1 accessory proteins provide insight into strategies used by retroviruses that are associated with lymphoproliferative diseases.

Animals↗