Polymorphisms in the bradykinin B2 receptor gene and childhood asthma

Bradykinin has been suggested as one of the key mediators of bronchial asthma. Polymorphisms with a potential functional relevance have been described in the B2 bradykinin receptor gene. Study of these polymorphisms in 77 children with asthma and 73 controls revealed no association. However, when comparing the asthmatics according to their age at onset (before and after age 4), the exon 1 allele BE1-2G was significantly associated with late-onset asthma (p <0.05). Since BE1-2G has previously been shown to lead to a higher transcription rate of the B2 receptor, this result warrants further investigation of the role of bradykinin in conferring susceptibility to pediatric asthma

Arbeitsfreude und Tanzwut im (Post-)Fordismus

Black dances became popular in Europe and the United States not be-cause they were exotic or different, but because they enabled a critical attitude towards (self-)exploitation under modern regimes of mass labor. While the capacity of bodies to communicate and cooperate freely was increasingly supervised and instrumentalized on the shopfloor by disciplinary arrangements and racist discourses, people reappropriated it on the dancefloor in radically experimental and non-instrumentalist ways. The aesthetics and techniques of black diaspora dances constituted a vast repertoire of polemical movements and attitudes questioning the idea of self-liberation through work. Today, this history offers new perspectives on post-Fordist subjectivities and their work ethics. By assembling a diverse body of sources from early cinema to the 1980s Hollywood dance movies, from picture postcards to popular scientific publications and caricatures, the article shows that dancing was not the "other" of work in modern times

Cryo-electron microscopic studies of RNA polymerase complexes

Related RNA polymerases (RNAPs) carry out gene transcription all three domains of life. This thesis deals with the structure determination of RNAPs and their functional complexes from different species. Protein complexes were preserved in their native state in aqueous solution, imaged by cryo- transmission electron microscopy and structural models were obtained using the single particle reconstruction method. New and physiologically relevant insights into RNAPs subunit architecture, the general transcription mechanism and its regulation were gained. The structure of an archaeal RNA polymerase identified similarities to its eukaryotic counterpart, RNA polymerase II. The conservation of the overall enzyme architecture as well as the close resemblance of structural elements and functional surfaces needed for basic transcription mechanisms underlines the evolutionary relationship between archaeal and eukaryotic RNAPs. The comprehensive study of RNA polymerase III and its regulation by Maf1 gave profound insights into the molecular basis of how eukaryotic transcription is shutdown under stress conditions to ensure cell survival. Maf1 binds RNAP III at its clamp domain and rearranges a specific subcomplex needed for interaction with the initiation factor Brf1. This specifically impairs binding of RNAP III to its promoters and inhibits transcription initiation. Furthermore, it was demonstrated that Maf1 binds to RNAP III that is already engaged in transcription elongation, thus leaving activity intact but preventing re-initiation. Taken altogether, these results converge on the essential mechanism of RNAP III-specific transcription repression by Maf1

Molecular basis of RNA polymerase III transcription repression by Maf1

RNA polymerase III (Pol III) transcribes short RNAs required for cell growth. Under stress conditions, the conserved protein Maf1 rapidly represses Pol III transcription. We report the crystal structure of Maf1 and cryo-electron microscopic structures of Pol III, an active Pol III-DNA-RNA complex, and a repressive Pol III-Maf1 complex. Binding of DNA and RNA causes ordering of the Pol III-specific subcomplex C82/34/31 that is required for transcription initiation. Maf1 binds the Pol III clamp and rearranges C82/34/31 at the rim of the active center cleft. This impairs recruitment of Pol III to a complex of promoter DNA with the initiation factors Brf1 and TBP and thus prevents closed complex formation. Maf1 does however not impair binding of a DNA-RNA scaffold and RNA synthesis. These results explain how Maf1 specifically represses transcription initiation from Pol III promoters and indicate that Maf1 also prevents reinitiation by binding Pol III during transcription elongation

Age-related Defects in CD4 T Cell Cognate Helper Function Lead to Reductions in Humoral Responses

With increasing age, the ability to produce protective antibodies in response to immunization declines, leading to a reduced efficacy of vaccination in the elderly. To examine the effect of age on the cognate function of CD4 T cells, we have used a novel adoptive transfer model that allows us to compare identical numbers of antigen-specific naive T cells from young and aged TCR transgenic (Tg) donors. Upon transfer of aged donor CD4 T cells to young hosts, there was significantly reduced expansion and germinal center (GC) differentiation of the antigen-specific B cell population after immunization. This reduced cognate helper function was seen at all time points and over a wide range of donor cell numbers. In hosts receiving aged CD4 cells, there were also dramatically lower levels of antigen-specific IgG. These age-related defects were not due to defects in migration of the aged CD4 T cells, but may be attributable to reduced CD154 (CD40L) expression. Furthermore, we found that there was no difference in B cell expansion and differentiation or in IgG production when young CD4 T cells were transferred to young or aged hosts. Our results show that, in this model, age-related reductions in the cognate helper function of CD4 T cells contribute significantly to defects in humoral responses observed in aged individuals

Use of long-term microdialysis subcutaneous glucose monitoring in the management of neonatal diabetes - A first case report

In neonatal diabetes mellitus (NDM), a rare genetic disorder, insulin therapy is required but the management is difficult. Frequent blood glucose determinations are necessary in most cases. Microdialysis subcutaneous glucose monitoring (MSGM) is feasible in neonates and has been proposed to reduce painful blood sampling and blood loss. We have applied long-term MSGM to a small-fordate female newborn with transient NDM. We found a good correlation of subcutaneous and blood glucose concentration over a wide range of values. MSGM enabled a reduction in blood glucose determinations during optimization of intravenous insulin treatment and initiation of continuous subcutaneous insulin infusion. We conclude that long-term MSGM is feasible and may reduce painful blood sampling and blood loss in NDM. Furthermore, long-term MSGM may hold a potential for avoiding hypoglycemic episodes and earlier discharge. Copyright (C) 2006 S. Karger AG, Basel

Colonic Patch and colonic SILT development are independent and differentially-regulated events

Intestinal lymphoid tissues have to simultaneously ensure protection against pathogens and tolerance towards commensals. Despite such vital functions, their development in the colon is poorly understood. Here, we show that the two distinct lymphoid tissues of the colon–colonic patches and colonic SILTs–can easily be distinguished based on anatomical location, developmental timeframe and cellular organization. Furthermore, whereas colonic patch development depended on CXCL13-mediated LTi cell clustering followed by LTα-mediated consolidation, early LTi clustering at SILT anlagen did not require CXCL13, CCR6 or CXCR3. Subsequent dendritic cell recruitment to and gp38+VCAM-1+ lymphoid stromal cell differentiation within SILTs required LTα; B cell recruitment and follicular dendritic cell differentiation depended on MyD88-mediated signalling, but not the microflora. In conclusion, our data demonstrate that different mechanisms, mediated mainly by programmed stimuli, induce the formation of distinct colonic lymphoid tissues, therefore suggesting that these tissues may have different functions

The archaeal RNA polymerase subunit P and the eukaryotic polymerase subunit Rpb12 are interchangeable in vivo and in vitro

The general subunit of all three eukaryotic RNA polymerases, Rpb12, and subunit P of the archaeal enzyme show sequence similarities in their N-terminal zinc ribbon and some highly conserved residues in the C-terminus. We report here that archaeal subunit P under the control of a strong yeast promoter could complement the lethal phenotype of a RPB12 deletion mutant and that subunit Rpb12 from yeast can functionally replace subunit P during reconstitution of the archaeal RNA polymerase. The ΔP enzyme is unable to form stable open complexes, but can efficiently extend a dinucleotide on a premelted template or RNA on an elongation scaffold. This suggests that subunit P is directly or indirectly involved in promoter opening. The activity of the ΔP enzyme can be rescued by the addition of Rpb12 or subunit P to transcription reactions. Mutation of cysteine residues in the zinc ribbon impair the activity of the enzyme in several assays and this mutated form of P is rapidly replaced by wild-type P in transcription reactions. The conserved zinc ribbon in the N-terminus seems to be important for proper interaction of the complete subunit with other RNA polymerase subunits and a 17-amino-acid C-terminal peptide is sufficient to support all basic RNA polymerase functions in vitro