Metareasoning for Planning Under Uncertainty

The conventional model for online planning under uncertainty assumes that an agent can stop and plan without incurring costs for the time spent planning. However, planning time is not free in most real-world settings. For example, an autonomous drone is subject to nature's forces, like gravity, even while it thinks, and must either pay a price for counteracting these forces to stay in place, or grapple with the state change caused by acquiescing to them. Policy optimization in these settings requires metareasoning---a process that trades off the cost of planning and the potential policy improvement that can be achieved. We formalize and analyze the metareasoning problem for Markov Decision Processes (MDPs). Our work subsumes previously studied special cases of metareasoning and shows that in the general case, metareasoning is at most polynomially harder than solving MDPs with any given algorithm that disregards the cost of thinking. For reasons we discuss, optimal general metareasoning turns out to be impractical, motivating approximations. We present approximate metareasoning procedures which rely on special properties of the BRTDP planning algorithm and explore the effectiveness of our methods on a variety of problems.Comment: Extended version of IJCAI 2015 pape

Characterizing and Predicting Email Deferral Behavior

Email triage involves going through unhandled emails and deciding what to do with them. This familiar process can become increasingly challenging as the number of unhandled email grows. During a triage session, users commonly defer handling emails that they cannot immediately deal with to later. These deferred emails, are often related to tasks that are postponed until the user has more time or the right information to deal with them. In this paper, through qualitative interviews and a large-scale log analysis, we study when and what enterprise email users tend to defer. We found that users are more likely to defer emails when handling them involves replying, reading carefully, or clicking on links and attachments. We also learned that the decision to defer emails depends on many factors such as user's workload and the importance of the sender. Our qualitative results suggested that deferring is very common, and our quantitative log analysis confirms that 12% of triage sessions and 16% of daily active users had at least one deferred email on weekdays. We also discuss several deferral strategies such as marking emails as unread and flagging that are reported by our interviewees, and illustrate how such patterns can be also observed in user logs. Inspired by the characteristics of deferred emails and contextual factors involved in deciding if an email should be deferred, we train a classifier for predicting whether a recently triaged email is actually deferred. Our experimental results suggests that deferral can be classified with modest effectiveness. Overall, our work provides novel insights about how users handle their emails and how deferral can be modeled

Slowly cycling Rho kinase-dependent actomyosin cross-bridge slippage explains intrinsic high compliance of detrusor smooth muscle

Biological soft tissues are viscoelastic because they display timeindependent pseudoelasticity and time-dependent viscosity. However, there is evidence that the bladder may also display plasticity, defined as an increase in strain that is unrecoverable unless work is done by the muscle. In the present study, an electronic lever was used to induce controlled changes in stress and strain to determine whether rabbit detrusor smooth muscle (rDSM) is best described as viscoelastic or viscoelastic plastic. Using sequential ramp loading and unloading cycles, stress-strain and stiffness-stress analyses revealed that rDSM displayed reversible viscoelasticity, and that the viscous component was responsible for establishing a high stiffness at low stresses that increased only modestly with increasing stress compared with the large increase produced when the viscosity was absent and only pseudoelasticity governed tissue behavior. The study also revealed that rDSM underwent softening correlating with plastic deformation and creep that was reversed slowly when tissues were incubated in a Ca2+ -containing solution. Together, the data support a model of DSM as a viscoelastic-plastic material, with the plasticity resulting from motor protein activation. This model explains the mechanism of intrinsic bladder compliance as slipping cross bridges, predicts that wall tension is dependent not only on vesicle pressure and radius but also on actomyosin cross-bridge activity, and identifies a novel molecular target for compliance regulation, both physiologically and therapeutically

Update on antiarrhythmic drug pharmacology.

Cardiac arrhythmias constitute a major public health problem. Pharmacological intervention remains mainstay to their clinical management. This, in turn, depends upon systematic drug classification schemes relating their molecular, cellular, and systems effects to clinical indications and therapeutic actions. This approach was first pioneered in the 1960s Vaughan-Williams classification. Subsequent progress in cardiac electrophysiological understanding led to a lag between the fundamental science and its clinical translation, partly addressed by The working group of the European Society of Cardiology (1991), which, however, did not emerge with formal classifications. We here utilize the recent Revised Oxford Classification Scheme to review antiarrhythmic drug pharmacology. We survey drugs and therapeutic targets offered by the more recently characterized ion channels, transporters, receptors, intracellular Ca2+ handling, and cell signaling molecules. These are organized into their strategic roles in cardiac electrophysiological function. Following analysis of the arrhythmic process itself, we consider (a) pharmacological agents directly targeting membrane function, particularly the Na+ and K+ ion channels underlying depolarizing and repolarizing events in the cardiac action potential. (b) We also consider agents that modify autonomic activity that, in turn, affects both the membrane and (c) the Ca2+ homeostatic and excitation-contraction coupling processes linking membrane excitation to contractile activation. Finally, we consider (d) drugs acting on more upstream energetic and structural remodeling processes currently the subject of clinical trials. Such systematic correlations of drug actions and arrhythmic mechanisms at different molecular to systems levels of cardiac function will facilitate current and future antiarrhythmic therapy

Molecular dissection of the mechanism by which EWS/FLI expression compromises actin cytoskeletal integrity and cell adhesion in Ewing sarcoma.

Ewing sarcoma is the second-most-common bone cancer in children. Driven by an oncogenic chromosomal translocation that results in the expression of an aberrant transcription factor, EWS/FLI, the disease is typically aggressive and micrometastatic upon presentation. Silencing of EWS/FLI in patient-derived tumor cells results in the altered expression of hundreds to thousands of genes and is accompanied by dramatic morphological changes in cytoarchitecture and adhesion. Genes encoding focal adhesion, extracellular matrix, and actin regulatory proteins are dominant targets of EWS/FLI-mediated transcriptional repression. Reexpression of genes encoding just two of these proteins, zyxin and α5 integrin, is sufficient to restore cell adhesion and actin cytoskeletal integrity comparable to what is observed when the EWS/FLI oncogene expression is compromised. Using an orthotopic xenograft model, we show that EWS/FLI-induced repression of α5 integrin and zyxin expression promotes tumor progression by supporting anchorage-independent cell growth. This selective advantage is paired with a tradeoff in which metastatic lung colonization is compromised

Pessimistic explanatory style and response to illness

Previous studies have shown that a pessimistic explanatory style is a risk factor for illness, but the factors linking explanatory style and illness are unknown. One's characteristic response to poor health may mediate this relationship. Perhaps pessimistic individuals act helplessly in the face of their symptoms, thereby exacerbating disease. In the present study, we investigated this possibility by asking 96 young adults to complete measures of explanatory style, habitual response to illness, and ways of coping during their most recent episode of illness. Subjects who explain bad events pessimistically (with internal, stable, and global causes) reported more frequent illnesses during the past year and rated their overall health more poorly than those who habitually favor external, unstable, and specific explanations. When ill, the pessimistic subjects were less likely than their optimistic counterparts to take active steps to combat their illness. Our results suggest that one pathway leading from pessimistic explanatory style to poor health is mundane: passivity in the face of disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28849/1/0000684.pd

Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study

<p>Abstract</p> <p>Background</p> <p>Increased circulating levels of hemostatic factors as well as anemia have been associated with increased risk of cardiovascular disease (CVD). Known associations between hemostatic factors and sequence variants at genes encoding these factors explain only a small proportion of total phenotypic variation. We sought to confirm known putative loci and identify novel loci that may influence either trait in genome-wide association and linkage analyses using the Affymetrix GeneChip 100K single nucleotide polymorphism (SNP) set.</p> <p>Methods</p> <p>Plasma levels of circulating hemostatic factors (fibrinogen, factor VII, plasminogen activator inhibitor-1, von Willebrand factor, tissue plasminogen activator, D-dimer) and hematological phenotypes (platelet aggregation, viscosity, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin concentration) were obtained in approximately 1000 Framingham Heart Study (FHS) participants from 310 families. Population-based association analyses using the generalized estimating equations (GEE), family-based association test (FBAT), and multipoint variance components linkage analyses were performed on the multivariable adjusted residuals of hemostatic and hematological phenotypes.</p> <p>Results</p> <p>In association analysis, the lowest GEE p-value for hemostatic factors was p = 4.5*10^-16for factor VII at SNP rs561241, a variant located near the <it>F7 </it>gene and in complete linkage disequilibrium (LD) (r²= 1) with the Arg353Gln <it>F7 </it>SNP previously shown to account for 9% of total phenotypic variance. The lowest GEE p-value for hematological phenotypes was 7*10^-8at SNP rs2412522 on chromosome 4 for mean corpuscular hemoglobin concentration. We presented top 25 most significant GEE results with p-values in the range of 10^-6to 10^-5for hemostatic or hematological phenotypes. In relating 100K SNPs to known candidate genes, we identified two SNPs (rs1582055, rs4897475) in erythrocyte membrane protein band 4.1-like 2 (<it>EPB41L2</it>) associated with hematological phenotypes (GEE p < 10^-3). In linkage analyses, the highest linkage LOD score for hemostatic factors was 3.3 for factor VII on chromosome 10 around 15 Mb, and for hematological phenotypes, LOD 3.4 for hemoglobin on chromosome 4 around 55 Mb. All GEE and FBAT association and variance components linkage results can be found at <url>http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007</url></p> <p>Conclusion</p> <p>Using genome-wide association methodology, we have successfully identified a SNP in complete LD with a sequence variant previously shown to be strongly associated with factor VII, providing proof of principle for this approach. Further study of additional strongly associated SNPs and linked regions may identify novel variants that influence the inter-individual variability in hemostatic factors and hematological phenotypes.</p

AEGIS: Enhancement of Dust-enshrouded Star Formation in Close Galaxy Pairs and Merging Galaxies up to z ~ 1

Using data from the DEEP2 Galaxy Redshift Survey and HST/ACS imaging in the Extended Groth Strip, we select nearly 100 interacting galaxy systems including kinematic close pairs and morphologically identified merging galaxies. Spitzer MIPS 24 micron fluxes of these systems reflect the current dusty star formation activity, and at a fixed stellar mass (M_{*}) the median infrared luminosity (L_{IR}) among merging galaxies and close pairs of blue galaxies is twice (1.9 +/- 0.4) that of control pairs drawn from isolated blue galaxies. Enhancement declines with galaxy separation, being strongest in close pairs and mergers and weaker in wide pairs compared to the control sample. At z ~ 0.9, 7.1% +/- 4.3% of massive interacting galaxies (M_{*} > 2*10^{10} M_{solar}) are found to be ULIRGs, compared to 2.6% +/- 0.7% in the control sample. The large spread of IR luminosity to stellar mass ratio among interacting galaxies suggests that this enhancement may depend on the merger stage as well as other as yet unidentified factors (e.g., galaxy structure, mass ratio, orbital characteristics, presence of AGN or bar). The contribution of interacting systems to the total IR luminosity density is moderate (<= 36 %).Comment: 12 pages, 2 figures, 1 table, minor changes to match the proof version, accepted for publication in the ApJL AEGIS Special Issu