Publications

Cytoplasmic dynein, a microtubule-based motor protein, transports many intracellular cargos by means of its light intermediate chain (LIC). In this study, we have determined the crystal structure of the conserved LIC domain, which binds the motor heavy chain, from a thermophilic fungus. We show that the LIC has a Ras-like fold with insertions that distinguish it from Ras and other previously described G proteins. Despite having a G protein fold, the fungal LIC has lost its ability to bind nucleotide, while the human LIC1 binds GDP preferentially over GTP. We show that the LIC G domain binds the dynein heavy chain using a conserved patch of aromatic residues, whereas the less conserved C-terminal domain binds several Rab effectors involved in membrane transport. These studies provide the first structural information and insight into the evolutionary origin of the LIC as well as revealing how this critical subunit connects the dynein motor to cargo.

BACKGROUND

Identifying factors associated with tuberculosis (TB) deaths will inform efforts to prevent deaths.

METHODS

We examined deaths among patients with culture-confirmed TB reported to the California TB Registry during 1994-2008. We calculated the age-adjusted percentage of deaths before and during TB treatment and estimated trends. We constructed multivariable logistic regression models to identify factors associated with death during treatment.

RESULTS

Of 40 125 patients with culture-confirmed TB, 4565 (11%) died: 1146 (25%) died before treatment started, and 3419 (75%) died during treatment. The age-adjusted percentage of patients who died before and during treatment declined from 1994 to 2008 (3.5% to 2%, and 10.4% to 7.2%, respectively, both P < .0001). We identified several risk factors for death that may be addressed with public health efforts: acquired multidrug resistance (adjusted odds ratio [aOR] = 4.67; 95% confidence interval [CI], 2.09-10.45); care in the private sector (aOR = 3.08; 95% CI, 2.75-3.44); and an initial treatment regimen of <3 drugs (aOR = 2.07; 95% CI, 1.63-2.64). We identified other risk factors for death that could be used as markers for intensified diagnostic and treatment processes in hospital: human immunodeficiency virus coinfection; meningeal, peritoneal, and disseminated TB; substance use; and abnormal chest radiograph without cavities.

CONCLUSIONS

In California, 1 in 9 TB patients died with a potentially curable disease. Public health departments might prevent deaths in patients with TB by strengthening partnerships with private providers, intensifying diagnostic and treatment processes for patients at risk of death in hospital, optimizing treatment regimens for patients with comorbidities, and preventing the acquisition of drug resistance.