How Personalized Networks Can Limit Free Riding: A Multi-Group Version of the Public Goods Game

People belong to many different groups, and few belong to the same network of groups. Moreover, people routinely reduce their involvement in dysfunctional groups while increasing involvement in those they find more attractive. The net effect can be an increase in overall cooperation and the partial isolation of free-riders, even if free-riders are never punished, excluded, or recognized. We formalize and test this conjecture with an agent-based social simulation and a multi-good extension of the standard repeated public goods game. Our initial results from three treatments suggest that the multi-group setting indeed raises overall cooperation and dampens the impact of freeriders. We extend our understanding of this setting by imposing greater heterogeneity between groups through interweaving automated bot players amongst human subjects; whereby initial sessions of this amplify the aforementioned effects

Single-Electron Spectroscopy

Contains research goals and objectives, reports on four research projects and a list of publications.David and Lucille Packard FoundationJoint Services Electronics Program Grant DAAH04-95-1-0038U.S. Navy - Office of Naval Research Grant N00014-93-1-0633National Science Foundation Young Investigator Awar

Balloon dilation of mitral stenosis in adult patients: Postmortem and percutaneous mitral valvuloplasty studies

Preliminary reports have documented the utility of percutaneous balloon valvuloplasty of the mitral valve in adult patients with mitral stenosis, but the mechanism of successful valve dilation and the effect of mitral valvuloplasty on cardiac performance have not been studied in detail. Accordingly, mitral valvuloplasty was performed in five postmortem specimens and in 18 adult patients with rheumatic mitral stenosis, using either one (25 mm) or two (18 and 20 mm) dilation balloons. Postmortem balloon dilation resulted in increased valve orifice area in all five postmortem specimens, secondary to separation of fused commissures and fracture of nodular calcium within the mitral leaflets. In no case did balloon dilation result in tearing of valve leaflets, disruption of the mitral ring or liberation of potentially embolic debris.Percutaneous mitral valvuloplasty in 18 patients with severe mitral stenosis (including 9 with a heavily calcified valve) resulted in an increase in cardiac output (4.3 ± 1.1 to 5.1 ± 1.5 liters/min, p < 0.01) and mitral valve area (0.9 ± 0.2 to 1.6 ± 0.4 cm2, p < 0.0001), and a decrease in mean mitral pressure gradient (15 ± 5 to 9 ± 4 mm Hg, p < 0.0001), pulmonary capillary wedge pressure (23 ± 7 to 18 ± 7 mm Hg, p < 0.0001) and mean pulmonary artery pressure (36 ± 12 to 33 ± 12 mm Hg, p < 0.01). Left ventriculography before and after valvuloplasty in 14 of the 18 patients showed a mild (≤1 +) increase in mitral regurgitation in five patients and no change in the remainder. Embolic phenomena were not observed in any patient.Serial radionuclide ventriculography showed an increase in left ventricular peak filling rate (2.20 ± 1.20 to 2.50 ± 1.20 end-diastolic volumes per second [EDV/s], p < 0.05). Serial echocardiography/phonocardiography showed improvement in mitral valve excursion (11 ± 6 to 14 ± 6 mm, p < 0.001), mitral EF slope (7 ± 4 to 13 ± 5, p < 0.001), left atrial diameter (5.7 ± 0.9 to 5.3 ± 0.8 cm, p < 0.001), S2-opening snap interval (0.07 ± 0.03 to 0.08 ± 0.02 second, p < 0.02) and mitral valve area (0.9 ± 0.2 to 1.5 ± 0.4 cm2, p < 0.0001). All patients were discharged from the hospital with de- creased symptoms after valvuloplasty.It is concluded that percutaneous mitral valvuloplasty can be performed in adult patients with mitral stenosis, including patients with calcific disease, and can result in significant improvement in valvular function. The mechanisms of successful dilation include commissural separation and fracture of nodular calcium

Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints

Aaron Kesselheim and colleagues analyzed unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing, and develop a taxonomy of the various off-label practices

An Introduction to Temporal Graphs: An Algorithmic Perspective

A \emph{temporal graph} is, informally speaking, a graph that changes with time. When time is discrete and only the relationships between the participating entities may change and not the entities themselves, a temporal graph may be viewed as a sequence $G_1,G_2\ldots,G_l$ of static graphs over the same (static) set of nodes $V$. Though static graphs have been extensively studied, for their temporal generalization we are still far from having a concrete set of structural and algorithmic principles. Recent research shows that many graph properties and problems become radically different and usually substantially more difficult when an extra time dimension in added to them. Moreover, there is already a rich and rapidly growing set of modern systems and applications that can be naturally modeled and studied via temporal graphs. This, further motivates the need for the development of a temporal extension of graph theory. We survey here recent results on temporal graphs and temporal graph problems that have appeared in the Computer Science community

Dopamine neurons modulate neural encoding and expression of depression-related behaviour

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia1. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry

ResBoost: characterizing and predicting catalytic residues in enzymes

Abstract Background Identifying the catalytic residues in enzymes can aid in understanding the molecular basis of an enzyme's function and has significant implications for designing new drugs, identifying genetic disorders, and engineering proteins with novel functions. Since experimentally determining catalytic sites is expensive, better computational methods for identifying catalytic residues are needed. Results We propose ResBoost, a new computational method to learn characteristics of catalytic residues. The method effectively selects and combines rules of thumb into a simple, easily interpretable logical expression that can be used for prediction. We formally define the rules of thumb that are often used to narrow the list of candidate residues, including residue evolutionary conservation, 3D clustering, solvent accessibility, and hydrophilicity. ResBoost builds on two methods from machine learning, the AdaBoost algorithm and Alternating Decision Trees, and provides precise control over the inherent trade-off between sensitivity and specificity. We evaluated ResBoost using cross-validation on a dataset of 100 enzymes from the hand-curated Catalytic Site Atlas (CSA). Conclusion ResBoost achieved 85% sensitivity for a 9.8% false positive rate and 73% sensitivity for a 5.7% false positive rate. ResBoost reduces the number of false positives by up to 56% compared to the use of evolutionary conservation scoring alone. We also illustrate the ability of ResBoost to identify recently validated catalytic residues not listed in the CSA

A Human-Curated Annotation of the Candida albicans Genome

Recent sequencing and assembly of the genome for the fungal pathogen Candida albicans used simple automated procedures for the identification of putative genes. We have reviewed the entire assembly, both by hand and with additional bioinformatic resources, to accurately map and describe 6,354 genes and to identify 246 genes whose original database entries contained sequencing errors (or possibly mutations) that affect their reading frame. Comparison with other fungal genomes permitted the identification of numerous fungus-specific genes that might be targeted for antifungal therapy. We also observed that, compared to other fungi, the protein-coding sequences in the C. albicans genome are especially rich in short sequence repeats. Finally, our improved annotation permitted a detailed analysis of several multigene families, and comparative genomic studies showed that C. albicans has a far greater catabolic range, encoding respiratory Complex 1, several novel oxidoreductases and ketone body degrading enzymes, malonyl-CoA and enoyl-CoA carriers, several novel amino acid degrading enzymes, a variety of secreted catabolic lipases and proteases, and numerous transporters to assimilate the resulting nutrients. The results of these efforts will ensure that the Candida research community has uniform and comprehensive genomic information for medical research as well as for future diagnostic and therapeutic applications

Dopamine signaling enriched striatal gene set predicts striatal dopamine synthesis and physiological activity in vivo

The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia