New metabolic signature for Chagas disease reveals sex steroid perturbation in humans and mice.

The causative agent of Chagas disease (CD), Trypanosoma cruzi, claims thousands of lives each year. Current diagnostic tools are insufficient to ensure parasitological detection in chronically infected patients has been achieved. A host-derived metabolic signature able to distinguish CD patients from uninfected individuals and assess antiparasitic treatment efficiency is introduced. Serum samples were collected from chronic CD patients, prior to and three years after treatment, and subjected to untargeted metabolomics analysis against demographically matched CD-negative controls. Five metabolites were confirmed by high-resolution tandem mass spectrometry. Several database matches for sex steroids were significantly altered in CD patients. A murine experiment corroborated sex steroid perturbation in T. cruzi-infected mice, particularly in male animals. Proteomics analysis also found increased steroidogenesis in the testes of infected mice. Metabolic alterations identified in this study shed light on the pathogenesis and provide the basis for developing novel assays for the diagnosis and screening of CD patients.

Fasting blood glucose as a predictor of mortality: Lost in translation.

Aging leads to profound changes in glucose homeostasis, weight, and adiposity, which are considered good predictors of health and survival in humans. Direct evidence that these age-associated metabolic alterations are recapitulated in animal models is lacking, impeding progress to develop and test interventions that delay the onset of metabolic dysfunction and promote healthy aging and longevity. We compared longitudinal trajectories, rates of change, and mortality risks of fasting blood glucose, body weight, and fat mass in mice, nonhuman primates, and humans throughout their lifespans and found similar trajectories of body weight and fat in the three species. In contrast, fasting blood glucose decreased late in life in mice but increased over the lifespan of nonhuman primates and humans. Higher glucose was associated with lower mortality in mice but higher mortality in nonhuman primates and humans, providing a cautionary tale for translating age-associated metabolic changes from mice to humans.

Localized Affinity-Based Delivery of Prinomastat for Cancer Treatment.

Glioblastoma multiforme patients suffer a median survival of 14 months, facilitated by the highly invasive nature of this cancer that allows for it to evade conventional therapy. Prinomastat targets the essential matrix metalloproteinase degradation of the extracellular matrix needed for cancer invasion; however, its clinical potential is impeded by adverse musculoskeletal side effects. By localizing delivery of prinomastat via cyclodextrin polymers, systemic side effects can be bypassed. In this letter, we demonstrate that prinomastat delivery from ß-cyclodextrin polymers results in months-long inhibition of MMPs as measured by gelatin zymography, more appropriately addressing the time frame of cancer cell invasion.

Support vector training of protein alignment models.

Sequence to structure alignment is an important step in homology modeling of protein structures. Incorporation of features such as secondary structure, solvent accessibility, or evolutionary information improve sequence to structure alignment accuracy, but conventional generative estimation techniques for alignment models impose independence assumptions that make these features difficult to include in a principled way. In this paper, we overcome this problem using a Support Vector Machine (SVM) method that provides a well-founded way of estimating complex alignment models with hundred of thousands of parameters. Furthermore, we show that the method can be trained using a variety of loss functions. In a rigorous empirical evaluation, the SVM algorithm outperforms the generative alignment method SSALN, a highly accurate generative alignment model that incorporates structural information. The alignment model learned by the SVM aligns 50% of the residues correctly and aligns over 70% of the residues within a shift of four positions.