High-throughput genomic/proteomic studies : finding structure and meaning by similarity

The post-genomic challenge was to develop high-throughput technologies for measuring genome scale mRNA expression levels. Analyses of these data rely on computers in an unprecedented way to make the results accessible to researchers. My research in this area enabled the first compendium of microarray experiments for a multi-cellular eukaryote, Caenorhabditis elegans. Prior to this research approximately 6% of the C. elegans genome had been studied, and little was known about global expression patterns in this organism. Here I cluster data from 553 different microarray experiments and show that the results are stable, statistically significant and highly enriched for specific biological functions. These enrichments allow identification of gene function for the majority of C. elegans genes. Tissue specific expression patterns are discovered suggesting the role of particular proteins in digestion, tumor suppression, protection from bacteria and from heavy metals. I report evidence that genome instability in males involves transposons, and find co-expression patterns between sperm proteins, protein kinases and phosphatases suggesting that sperm, that are transcriptionally inactive cells, commonly use phosphorylation to regulate protein activities. My subsequent research addresses protein concentrations and interactions, beginning with a simultaneous comparison of multiple data sets to analyze Saccharomyces cerevisiae gene-expression (cell cycle and exit from stationary phase/G0) and protein-interaction studies. Here, I find that G1-regulated genes are not co-regulated during exit from stationary phase, indicating that the cells are not synchronized. The tight clustering of other genes during exit from stationary-phase does indicate that the physiological responses during G0 exit are separable from cell-cycle events. Subsequently, I report in vivo proteomic research investigating population phenotypes in stationary phase cultures using the yeast Green Fluorescent Protein-fusion library (4156 strains) together with flow cytometry. Stationary phase cultures consist of dense quiescent (Q) and less dense non-quiescent (NQ) fractions. The Q-cell fraction is generally composed of daughter cells with high concentrations of proteins involved in the citric acid cycle and the electron transport chain, for example Cit1p. The NQ fraction has subpopulations of cells that can be separated by the low and high concentrations of these mitochondrial proteins, i.e., NQ cells often have double intensity peaks: a bright fraction and a much dimmer fraction, which is the case for Cit1p. The Q fraction uses oxygen 6 times as rapidly as the NQ fraction, and 1.6 times as rapidly as exponentially growing cells. NQ cells are less reproductively capable than Q cells, and show evidence of reactive oxygen species stress. These phenotypes develop as early as 20-24 hours after the diauxic shift, which is as early as we can make a differentiating measurement using fluorescence intensities. Finally, I propose a new way to analyze multidimensional flow cytometry data, which may lead to better understanding of Q/NQ cell differentiation

1990 Accounting Hall of Fame induction: Charles T. Horngren

Introduction by Sidney Davidson (Arthur Young Distinguished Service Professor Emeritus of Accounting and former Dean, University of Chicago Graduate School of Business) Induction citation by Thomas J. Burns (Professor and Chairman Committee on Accounting Hall of Fame Faculty of Accounting & Management Information Systems The Ohio State University College of Business); Response by Charles T. Horngren (Edmund W. Littlefield Professor of Accounting Stanford University Graduate School of Business

Identifying Patients at High Risk of a Cardiovascular Event in the Near Future Current Status and Future Directions: Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute convened a working group to provide basic and clinical research recommendations to the National Heart, Lung, and Blood Institute on the development of an integrated approach for identifying those individuals who are at high risk for a cardiovascular event such as acute coronary syndromes (ACS) or sudden cardiac death in the “near term.” The working group members defined near-term as occurring within 1 year of the time of assessment. The participants reviewed current clinical cardiology practices for risk assessment and state-of-the-science techniques in several areas, including biomarkers, proteomics, genetics, psychosocial factors, imaging, coagulation, and vascular and myocardial susceptibility. This report presents highlights of these reviews and a summary of suggested research directions

Political opportunity structures, democracy, and civil war

Theories of mobilization suggest that groups are more likely to resort to violence in the presence of political opportunity structures that afford greater prospects for extracting concessions from the government or better opportunities to topple ruling governments. However, existing efforts to consider the possible influences of political opportunity structures on incentives for violence and civil war empirically have almost invariably relied upon measures of democracy to proxy for the hypothesized mechanisms, most notably the argument that the opposing effects of political accommodation and repression will give rise to an inverted U-shaped relationship between democracy and the risk of civil war. The authors detail a number of problems with measures of democracy as proxies for political opportunity structures and develop alternative measures based on the likely risks that political leaders will lose power in irregular challenges and their implications for the incentives for resort to violence. The authors evaluate empirically how the security with which leaders hold office influences the prospects of violent civil conflict. The findings indicate that recent irregular leader entry and transitions indeed increase the risk of conflict onset, while democratic institutions are found to decrease the risk of civil war, after controlling for the new measures of state weakness. </jats:p

Anhedonia and reward-circuit connectivity distinguish nonresponders from responders to dorsomedial prefrontal rTMS in major depression

Background Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain’s emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. Methods Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. Results Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. Conclusions The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection

Resting state cortico-thalamic-striatal connectivity predicts pesponse to dorsomedial prefrontal rTMS in major depressive disorder

Despite its high toll on society, there has been little recent improvement in treatment efficacy for Major Depressive Disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting state functional connectivity predicted response to treatment with rapid transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased sgACC-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work

Afterword: three letters

The essays consider issues of affect and emotion in terms of three early English letters - by Chaucer, the Paston family, and Henry VIII - in order to consider issues of the personal and the literary. It also comments on the volume of essays as a whole, and consider the field of the history of emotions and affect studies

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe