A statistical framework for protein quantitation in bottom-up MS-based proteomics.

MOTIVATION: Quantitative mass spectrometry-based proteomics requires protein-level estimates and associated confidence measures. Challenges include the presence of low quality or incorrectly identified peptides and informative missingness. Furthermore, models are required for rolling peptide-level information up to the protein level. RESULTS: We present a statistical model that carefully accounts for informative missingness in peak intensities and allows unbiased, model-based, protein-level estimation and inference. The model is applicable to both label-based and label-free quantitation experiments. We also provide automated, model-based, algorithms for filtering of proteins and peptides as well as imputation of missing values. Two LC/MS datasets are used to illustrate the methods. In simulation studies, our methods are shown to achieve substantially more discoveries than standard alternatives. AVAILABILITY: The software has been made available in the open-source proteomics platform DAnTE (http://omics.pnl.gov/software/).

Cortical inhibition and excitation in abstinent cocaine-dependent patients: a transcranial magnetic stimulation study.

Prior transcranial magnetic stimulation studies showed that resting motor threshold is elevated in abstinent cocaine-dependent patients, suggesting a decrease in axonal excitability. In contrast, the increased incidence of seizures and psychosis in this group suggests increased excitability or decreased inhibition. Here, we studied long-interval intracortical facilitation and long-interval intracortical inhibition, paired-pulse transcranial magnetic stimulation measures that are more directly linked to glutamatergic cortical facilitation and GABAergic inhibition, respectively. Ten cocaine-dependent and 10 healthy controls were examined. Resting motor threshold, long-interval intracortical facilitation and long-interval intracortical inhibition were tested from the left motor cortex. The cocaine group showed an elevated resting motor threshold and an increased long-interval intracortical facilitation, whereas long-interval intracortical inhibition was normal. Although the increase in long-interval intracortical facilitation suggests exaggerated cortical glutamatergic excitability, the increase in resting motor threshold may signify a protective mechanism against seizures and psychosis.

Premorbid characterization in schizophrenia: the Pittsburgh High Risk Study.

Prospective studies of young relatives at risk for schizophrenia can shed light on the possible premorbid precursors of the disease. Ongoing studies in Pittsburgh suggest that young non-psychotic high risk relatives have neurobehavioral, brain structural, physiological, and neurochemical deficits that may date back to childhood or earlier. We summarize these data, review the relevant literature in this emerging field, and provide some new data suggesting alterations in sleep architecture in young relatives at risk for schizophrenia. Collectively, such data are likely to help us to predict the eventual emergence of schizophrenia, schizophrenia spectrum or non-spectrum psychopathology.

1H MRS brain measures and acute lorazepam administration in healthy human subjects.

The effects of acute lorazepam administration on 1H magnetic resonance spectroscopy (MRS) in vivo brain spectra were examined in the left dorsolateral prefrontal cortex (L-DLPFC) of healthy human subjects. We wanted to examine whether lorazepam administration would result in significant changes in the levels of 1H-MRS metabolites in this brain region. Ten healthy controls underwent a short echo-time 1H-MRS session immediately before, and a second one 1 h after lorazepam administration (2mg/orally). The measured 1H-metabolites included N-acetyl-aspartate, phosphocreatine+creatine, trimethylamines, myo-inositol, glutamate, and glutamine, which were expressed as absolute values and ratios. No significant differences were found after lorazepam administration for any of the measured metabolite levels or ratios (paired t-tests, p >.05). This study demonstrated that lorazepam can potentially be utilized to acutely sedate psychiatric subjects during in vivo 1H-MRS sessions, as it does not appear to produce significant changes in the 1H-MRS spectra in this specific brain region.