Biomedical subjects

David Thornton

Publications and source records attributed to David Thornton.

6 recordsLinked to original sources

PubMed2003

Juxtaposition of the two distal CX3C motifs via intrachain disulfide bonding is essential for the folding of Tim10.

The TIM10 complex, composed of the homologous proteins Tim10 and Tim9, chaperones hydrophobic proteins inserted at the mitochondrial inner membrane. A salient feature of the TIM10 complex subunits is their conserved "twin CX3C" motif. Systematic mutational analysis of all cysteines of Tim10 showed that their underlying molecular defect is impaired folding (demonstrated by circular dichroism, aberrant homo-oligomer formation, and thiol trapping assays). As a result of defective folding, clear functional consequences were manifested in (i) complex formation with Tim9, (ii) chaperone activity, and (iii) import into tim9ts mitochondria lacking both endogenous Tim9 and Tim10. The organization of the four cysteines in intrachain disulfides was determined by trypsin digestion and mass spectrometry. The two distal CX3C motifs are juxtaposed in the folded structure and disulfide-bonded to each other rather than within each other, with an inner cysteine pair connecting Cys44 with Cys61 and an outer pair between Cys40 and Cys65. These cysteine pairs are not equally important for folding and assembly; mutations of the inner Cys are severely affected and form wrong, non-native disulfides, in contrast to mutations of the outer Cys that can still maintain the native inner disulfide pair and display weaker functional defects. Taken together these data reveal this specific intramolecular disulfide bonding as the crucial mechanism for Tim10 folding and show that the inner cysteine pair has a more prominent role in this process.

Amino Acid Motifs↗

PubMed2003

Distinguishing and combining risks for sexual and violent recidivism.

A two-dimensional risk assessment system for sexual offenders was created that can classify them for risk of sexual recidivism, risk of nonsexual violent recidivism, and the composite risk of reconviction for sexual or nonsexual assaults. Receiver operating characteristic (ROC) analyses of separate follow-up samples were used for cross-validation. The system is easier to score than Static-99, and substantially easier to score than the VRAG or SORAG, while yielding comparable predictive accuracy in cross-validation samples with follow-ups from 2 years to 19 years. ROC AUC coefficients between.74 and.81 were found for the different scales and samples.

Databases as Topic↗

PubMed2002

Hepatitis C virus and human immunodeficiency virus coinfection in an urban population: low eligibility for interferon treatment.

One hundred eighty human immunodeficiency virus (HIV)- and hepatitis C virus (HCV)-coinfected patients were prospectively evaluated for suitability for interferon and ribavirin therapy. Of the 149 patients with chronic HCV infection who completed the evaluation, 44 (30%) were eligible for treatment and 105 (70%) were ineligible, with the main barriers being missed clinic visits, active psychiatric illness, active drug or alcohol use, decompensated liver disease, or medical illness.

Adult↗

PubMed2002

Assembly of Tim9 and Tim10 into a functional chaperone.

The TIM10 complex is localized in the mitochondrial intermembrane space and mediates insertion of hydrophobic proteins at the inner membrane. We have characterized TIM10 assembly and analyzed the structural properties of its subunits, Tim9 and Tim10. Both proteins are alpha-helical with a protease-resistant central domain, and each self-associates to form mainly dimers and trimers in solution. Tim9 and Tim10 bound to one another with submicromolar affinity in equimolar amounts and assembled in a stable, significantly extended complex that was indistinguishable from the native mitochondrial TIM10 complex. Importantly, the reconstituted TIM10 complex is functional because it bound to the physiological substrate ADP/ATP carrier and displayed chaperone activity in refolding the model substrate firefly luciferase. These data demonstrate that the individual subunits can exist as independent, dynamically self-associating proteins. Assembly into the thermodynamically stable hexameric complex is necessary for the TIM10 chaperone function.

Adenosine Diphosphate↗

PubMed2002

Nosocomial pneumonia: emerging concepts in diagnosis, management, and prophylaxis.

Nosocomial pneumonia is a dynamic disease with multiple etiologic agents and a changing natural history. The highest attack rates and mortality occur in patients with ventilator-associated pneumonia. Diagnosis of nosocomial pneumonia is often made by clinical criteria that are sensitive but lack specificity. The use of quantitative endotracheal aspirates or bronchoscopy with bronchoalveolar lavage and protected specimen brush clearly improve diagnostic specificity and outcome in patients who are mechanically ventilated. The rapid spread of multidrug-resistant, spp, and has made initial empiric therapy more difficult. Management principles include the use of techniques for more accurate diagnosis and early antimicrobial therapy with appropriate agents along with careful analysis of culture results, clinical response, and potential complications of pneumonia and therapy. Strategies for prophylaxis are of critical importance for risk reduction, improvement in patient outcome, and reduction of hospital costs.

Aged↗

PubMed2002

Constructing and testing a framework for dynamic risk assessment.

This paper describes the construction and testing of a framework for dynamic risk assessment. A review of previous studies identified 4 domains into which dynamic risk factors for sexual offending seem to fall. These were sexual interests, distorted attitudes, socioaffective functioning, and self-management. Psychometric indicators for 3 of the domains were identified, and 2 studies are reported using these indicators to test the framework. Study 1 divided men serving a prison sentence for a sexual offense against a child into 2 groups--those with a previous conviction of this kind (Repeaters) and those for whom this was the only time they had been sentenced for such an offense (Current Only). The Repeaters were found to show more distorted attitudes, worse socioaffective functioning, and poorer self-management than did the Current Only group. Study 2 used a simple algorithm to combine these psychometric indicators into an overall "Deviance" classification. Reconviction data was obtained for offenders classified as high, moderate, or low on Deviance. Sexual reconviction was found to be monotonically associated with the Deviance classification. Logistic regression analysis showed that both static variables (Static-99) and the Deviance classification made independent contributions to prediction. It is suggested that risk assessment procedures should combine these 2 approaches.

Algorithms↗