Pistons modeled by potentials

In this article we consider a piston modelled by a potential in the presence of extra dimensions. We analyze the functional determinant and the Casimir effect for this configuration. In order to compute the determinant and Casimir force we employ the zeta function scheme. Essentially, the computation reduces to the analysis of the zeta function associated with a scalar field living on an interval $[0,L]$ in a background potential. Although, as a model for a piston, it seems reasonable to assume a potential having compact support within $[0,L]$, we provide a formalism that can be applied to any sufficiently smooth potential.Comment: 10 pages, LaTeX. A typo in eq. (3.5) has been corrected. In "Cosmology, Quantum Vacuum and Zeta Functions: In Honour of Emilio Elizalde", Eds. S.D. Odintsov, D. Saez-Gomez, and S. Xambo-Descamps. (Springer 2011) pp 31

Cancer mortality in IBM Endicott plant workers, 1969–2001: an update on a NY production plant

<p>Abstract</p> <p>Background</p> <p>In response to concerns expressed by workers at a public meeting, we analyzed the mortality experience of workers who were employed at the IBM plant in Endicott, New York and died between 1969–2001. An epidemiologic feasibility assessment indicated potential worker exposure to several known and suspected carcinogens at this plant.</p> <p>Methods</p> <p>We used the mortality and work history files produced under a court order and used in a previous mortality analysis. Using publicly available data for the state of New York as a standard of comparison, we conducted proportional cancer mortality (PCMR) analysis.</p> <p>Results</p> <p>The results showed significantly increased mortality due to melanoma (PCMR = 367; 95% CI: 119, 856) and lymphoma (PCMR = 220; 95% CI: 101, 419) in males and modestly increased mortality due to kidney cancer (PCMR = 165; 95% CI: 45, 421) and brain cancer (PCMR = 190; 95% CI: 52, 485) in males and breast cancer (PCMR = 126; 95% CI: 34, 321) in females.</p> <p>Conclusion</p> <p>These results are similar to results from a previous IBM mortality study and support the need for a full cohort mortality analysis such as the one being planned by the National Institute for Occupational Safety and Health.</p

Polypharmacological in Silico Bioactivity Profiling and Experimental Validation Uncovers Sedative-Hypnotic Effects of Approved and Experimental Drugs in Rat

In this work, we describe the computational ("in silico") mode-of-action analysis of CNS-active drugs, which is taking both multiple simultaneous hypotheses as well as sets of protein targets for each mode-of-action into account, and which was followed by successful prospective in vitro and in vivo validation. Using sleep-related phenotypic readouts describing both efficacy and side effects for 491 compounds tested in rat, we defined an "optimal" (desirable) sleeping pattern. Compounds were subjected to in silico target prediction (which was experimentally confirmed for 21 out of 28 cases), followed by the utilization of decision trees for deriving polypharmacological bioactivity profiles. We demonstrated that predicted bioactivities improved classification performance compared to using only structural information. Moreover, DrugBank molecules were processed via the same pipeline, and compounds in many cases not annotated as sedative-hypnotic (alcaftadine, benzatropine, palonosetron, ecopipam, cyproheptadine, sertindole, and clopenthixol) were prospectively validated in vivo. Alcaftadine, ecopipam cyproheptadine, and clopenthixol were found to promote sleep as predicted, benzatropine showed only a small increase in NREM sleep, whereas sertindole promoted wakefulness. To our knowledge, the sedative-hypnotic effects of alcaftadine and ecopipam have not been previously discussed in the literature. The method described extends previous single-target, single-mode-of-action models and is applicable across disease areas.This research was supported by Unilever (A.B.), the EPSRC (G.D.), and Eli Lilly (G.D.). A.B. thanks the ERC for an ERC Starting Grant

Inhalant use, inhalant-use disorders, and antisocial behavior: findings from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

OBJECTIVE: Few studies have explored the topography of antisocial behavior in a nationally representative sample of inhalant users. We examined (a) the lifetime prevalence of 20 childhood and adult antisocial behaviors in inhalant users with inhalant-use disorders (IUD+) and without IUDs (IUD-); (b) the nature and strength of associations between inhalant use, IUDs, and specific antisocial behaviors in multivariate analyses; and (c) the relationships between inhalant use, IUDs, and antisocial behaviors in a national sample of adults with antisocial personality disorder. METHOD: The National Epidemiologic Survey on Alcohol and Related Conditions was a multistage national survey of 43,093 U.S. residents. Respondents completed a structured psychiatric interview. RESULTS: IUD+ and IUD- respondents were significantly younger and more likely to be unemployed, to be male, to have never married, and to report family and personal histories of alcohol and drug problems than inhalant nonusers. Family histories of alcohol problems and personal histories of drug problems were significantly more prevalent among IUD+ respondents, compared with IUD- respondents. In bivariate analyses, IUD+ and IUD- respondents evidenced significantly higher lifetime levels of all childhood and adult antisocial behaviors than inhalant nonusers. IUD+ respondents were significantly more likely than their IUD- counterparts to report bullying behavior, starting physical fights, using dangerous weapons, physical cruelty to people, staying out all night without permission, running away, and frequent truancy in childhood, as well as greater deceitfulness, impulsivity, irritability/aggressiveness, recklessness, and irresponsibility in adulthood. Multivariate analyses indicated that IUD+ respondents had a significantly elevated risk for childhood and adult antisocial behaviors, compared with inhalant nonusers, with the strongest effects for using dangerous weapons, physical cruelty to animals, and physical cruelty to people. Similarly, IUD+ respondents differed significantly from their IUD- counterparts primarily across measures of interpersonal violence. Among persons with antisocial personality disorder, inhalant use and IUDs were associated with greater antisocial behavior, albeit with fewer and weaker effects. CONCLUSIONS: Respondents with IUDs had pervasively elevated levels of antisocial conduct, including diverse forms of early-onset and interpersonally violent behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78177/1/4743.pd

Information-Derived Mechanistic Hypotheses for Structural Cardiotoxicity

Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs’ biological targets. In this study, we have used data mining techniques and mutual information statistical approaches to find associations between reported adverse events collected from the FDA Adverse Event Reporting System and assay outcomes from ToxCast, with the aim to generate mechanistic hypotheses related to structural cardiotoxicity (morphological damage to cardiomyocytes and/or loss of viability). Our workflow identified 22 adverse event-assay outcome associations. From these associations, 10 implicated targets could be substantiated with evidence from previous studies reported in the literature. For two of the identified targets, we also describe a more detailed mechanism, forming putative adverse outcome pathways associated with structural cardiotoxicity. Our study also highlights the difficulties deriving these type of associations from the very limited amount of data available

Influence of dental metallic artifact from multislice CT in the assessment of simulated mandibular lesions

OBJECTIVE: This study evaluated the influence of metallic dental artifacts on the accuracy of simulated mandibular lesion detection by using multislice technology. MATERIAL AND METHODS: Fifteen macerated mandibles were used. Perforations were done simulating bone lesions and the mandibles were subjected to axial 16 rows multislice CT images using 0.5 mm of slice thickness with 0.3 mm interval of reconstruction. Metallic dental restorations were done and the mandibles were subjected again to CT in the same protocol. The images were analyzed to detect simulated lesions in the mandibles, verifying the loci number and if there was any cortical perforation exposing medullar bone. The analysis was performed by two independent examiners using e-film software. RESULTS: The samples without artifacts presented better results compared to the gold standard (dried mandible with perforations). In the samples without artifacts, all cortical perforation were identified and 46 loci were detected (of 51) in loci number analysis. Among the samples with artifacts, 12 lesions out of 14 were recognized regarding medullar invasion, and 40 out of 51 concerning loci number. The sensitivity in samples without artifacts was 90% and 100% regarding loci number and medullar invasion, respectively. In samples with artifacts, these values dropped to 78% and 86%, respectively. The presence of metallic restorations affected the sensitivity values of the method, but the difference was not significant (p>0.05). CONCLUSIONS: Although there were differences in the results of samples with and without artifacts, the presence of metallic restoration did not lead to misinterpretation of the final diagnosis. However, the validity of multislice CT imaging in this study was established for detection of simulated mandibular bone lesions.CNPqFAPESPCoordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES

Statistical power considerations in genotype-based recall randomized controlled trials

Randomized controlled trials (RCT) are often underpowered for validating gene-treatment interactions. Using published data from the Diabetes Prevention Program (DPP), we examined power in conventional and genotype-based recall (GBR) trials. We calculated sample size and statistical power for genemetformin interactions (vs. placebo) using incidence rates, gene-drug interaction effect estimates and allele frequencies reported in the DPP for the rs8065082 SLC47A1 variant, a metformin transported encoding locus. We then calculated statistical power for interactions between genetic risk scores (GRS), metformin treatment and intensive lifestyle intervention (ILI) given a range of sampling frames, clinical trial sample sizes, interaction effect estimates, and allele frequencies; outcomes were type 2 diabetes incidence (time-to-event) and change in small LDL particles (continuous outcome). Thereafter, we compared two recruitment frameworks: GBR (participants recruited from the extremes of a GRS distribution) and conventional sampling (participants recruited without explicit emphasis on genetic characteristics). We further examined the influence of outcome measurement error on statistical power. Under most simulated scenarios, GBR trials have substantially higher power to observe gene-drug and gene-lifestyle interactions than same-sized conventional RCTs. GBR trials are becoming popular for validation of gene-treatment interactions; our analyses illustrate the strengths and weaknesses of this design

Multisite Phosphorylation of the Guanine Nucleotide Exchange Factor Cdc24 during Yeast Cell Polarization

BACKGROUND:Cell polarization is essential for processes such as cell migration and asymmetric cell division. A common regulator of cell polarization in most eukaryotic cells is the conserved Rho GTPase, Cdc42. In budding yeast, Cdc42 is activated by a single guanine nucleotide exchange factor, Cdc24. The mechanistic details of Cdc24 activation at the onset of yeast cell polarization are unclear. Previous studies have suggested an important role for phosphorylation of Cdc24, which may regulate activity or function of the protein, representing a key step in the symmetry breaking process. METHODOLOGY/PRINCIPAL FINDINGS:Here, we directly ask whether multisite phosphorylation of Cdc24 plays a role in its regulation. We identify through mass spectrometry analysis over thirty putative in vivo phosphorylation sites. We first focus on sites matching consensus sequences for cyclin-dependent and p21-activated kinases, two kinase families that have been previously shown to phosphorylate Cdc24. Through site-directed mutagenesis, yeast genetics, and light and fluorescence microscopy, we show that nonphosphorylatable mutations of these consensus sites do not lead to any detectable consequences on growth rate, morphology, kinetics of polarization, or localization of the mutant protein. We do, however, observe a change in the mobility shift of mutant Cdc24 proteins on SDS-PAGE, suggesting that we have indeed perturbed its phosphorylation. Finally, we show that mutation of all identified phosphorylation sites does not cause observable defects in growth rate or morphology. CONCLUSIONS/SIGNIFICANCE:We conclude that lack of phosphorylation on Cdc24 has no overt functional consequences in budding yeast. Yeast cell polarization may be more tightly regulated by inactivation of Cdc42 by GTPase activating proteins or by alternative methods of Cdc24 regulation, such as conformational changes or oligomerization

Physics, Astrophysics and Cosmology with Gravitational Waves

Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.Comment: 137 pages, 16 figures, Published version <http://www.livingreviews.org/lrr-2009-2