Biomedical subjects

Mark Carr

Publications and source records attributed to Mark Carr.

3 recordsLinked to original sources

PubMed2006

Structural diversity in p160/CREB-binding protein coactivator complexes.

Ligand-induced transcription by nuclear receptors involves the recruitment of p160 coactivators such as steroid receptor coactivator 1 (SRC1), in complex with histone acetyltransferases such as CREB-binding protein (CBP) and p300. Here we describe the solution structure of a complex formed by the SRC1 interaction domain (SID) of CBP and the activation domain (AD1) of SRC1, both of which contain four helical regions (Calpha1, Calpha2, Calpha3, and Calpha3' in CBP and Salpha1, Salpha2', Salpha2, and Salpha3 in SRC1). A tight four-helix bundle is formed between Salpha1, Calpha1, Calpha2, and Calpha3 that is capped by Salpha3. In contrast to the structure of the AD1 domain of the related p160 protein ACTR in complex with CBP SID, the sequences forming Salpha2' and Salpha2 in SRC1 AD1 are not involved in the interface between the two domains but rather serve to position Salpha3. Thus, although the CBP SID domain adopts a similar fold in complex with different p160 proteins, the topologies of the AD1 domains are strikingly different, a feature that is likely to contribute to functional specificity of these coactivator complexes.

Amino Acid Sequence↗

PubMed2005

Superior T cell activation by ESAT-6 as compared with the ESAT-6-CFP-10 complex.

Using intracellular cytokine staining we show herein that T cells will respond to short-term (6 h) activation with phorbol ester plus ionomycin by production of tumor necrosis factor (TNF), IFN-gamma or both. Here CD4 T cells preferentially produce TNF and CD8 cells IFN-gamma. The same pattern is seen when T cells are activated with the Mycobacterium tuberculosis protein early secretory antigenic target-6 (ESAT-6). Responses with >0.02% IFN-gamma+ CD3 cells were seen in 8 of 10 patients diagnosed with tuberculosis and in 12 of 14 healthy individuals selected for likely exposure to M. tuberculosis. T cell responses to the 1:1 complex of ESAT-6 and culture filtrate protein-10 (CFP-10) were inferior to ESAT-6 alone, and only reached the level of T cell response achieved with CFP-10 alone. Extending the time of incubation to 18 h leads to an increased response to the complex, but it still reached only the level of CFP-10 alone. In vitro digestion with lysosomal enzymes cathepsin L and S at 2000:1 protein to enzyme ratio demonstrates rapid digestion of the individual proteins while the ESAT-6-CFP-10 complex is resistant. The data suggest that the natural complex of ESAT-6-CFP-10 is less amenable to antigen processing leading to a lower T cell response as compared with the individual proteins.

Antigen Presentation↗

PubMed2005

Two outbreaks of occupationally acquired histoplasmosis: more than workers at risk.

OBJECTIVE: The objective of this study was to determine the etiology and risk factors for acute histoplasmosis in two outbreaks in Illinois among laborers at a landfill in 2001 and at a bridge reconstruction site in 2003. DESIGN: We performed environmental investigations during both outbreaks and also performed an analytic cohort study among bridge workers. PARTICIPANTS: Workers at the landfill during May 2001 and those at the bridge site during August 2003 participated in the study. At the landfill, workers moved topsoil from an area that previously housed a barn; at the bridge, workers observed bat guano on bridge beams. EVALUATIONS/MEASUREMENTS: We defined a case by positive immunodiffusion serology, a > or = 4-fold titer rise in complement fixation between acute and convalescent sera, or positive urinary Histoplasma capsulatum (HC) antigen. Relative risks (RR) for disease among bridge workers were calculated using bivariate analysis. RESULTS: Eight of 11 landfill workers (73%) and 6 of 12 bridge workers (50%) were laboratory-confirmed histoplasmosis cases. Three bridge workers had positive urinary HC antigen. At the bridge, seeing or having contact with bats [RR = 7.0; 95% confidence interval (CI), 1.1-43.0], jack-hammering (RR = 4.0; 95% CI, 1.2-13.3), and waste disposal (RR = 4.0; 95% CI, 1.2-13.3) were the most significant job-related risk factors for acquiring histoplasmosis. CONCLUSIONS: Workers performing activities that aerosolized topsoil and dust were at increased risk for acquiring histoplasmosis. Relevance to professional and clinical practice: Employees should wear personal protective equipment and use dust-suppression techniques when working in areas potentially contaminated with bird or bat droppings. Urinary HC antigen testing was important in rapidly identifying disease in the 2003 outbreak.

Adult↗