Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Validation of a digital photographic method for assessment of dietary quality of school lunch sandwiches brought from home.

Background: It is a challenge to assess children's dietary intake. The digital photographic method (DPM) may be an objective method that can overcome some of these challenges. Objective: The aim of this study was to evaluate the validity and reliability of a DPM to assess the quality of dietary intake from school lunch sandwiches brought from home among children aged 7–13 years. Design: School lunch sandwiches (n=191) were prepared to represent randomly selected school lunch sandwiches from a large database. All components were weighed to provide an objective measure of the composition. The lunches were photographed using a standardised DPM. From the digital images, the dietary components were estimated by a trained image analyst using weights or household measures and the dietary quality was assessed using a validated Meal Index of Dietary Quality (Meal IQ). The dietary components and the Meal IQ obtained from the digital images were validated against the objective weighed foods of the school lunch sandwiches. To determine interrater reliability, the digital images were evaluated by a second image analyst. Results: Correlation coefficients between the DPM and the weighed foods ranged from 0.89 to 0.97. The proportion of meals classified in the same or an adjacent quartile ranged from 98% (starch) to 100% (fruits, vegetables, fish, whole grain, and Meal IQ). There was no statistical difference between fish, fat, starch, whole grains, and Meal IQ using the two methods. Differences were found for fruits and vegetables; Bland–Altman analyses showed a tendency to underestimate high amounts of these variables using the DPM. For interrater reliability, kappa statistics ranged from 0.59 to 0.82 across the dietary components and Meal IQ. Conclusions: The standardised DPM is a valid and reliable method for assessing the dietary quality of school lunch sandwiches brought from home

No association of alcohol use and the risk of ulcerative colitis or Crohn’s disease: data from a European Prospective cohort study (EPIC)

Background The role of long -term alcohol consumption for the risk of developing ulcerative colitis (UC) and Crohn’s disease (CD) is unclear. Aim s For the first time, t o prospectively assess the role of pre -disease alcohol consumption o n the risk of developing UC or CD. Methods Nested within the European Prospective Investigation into Cancer and Nutrition (EPIC - IBD ), incident UC and CD cases and ma tched controls where included. At recruitment, participants completed validated food frequency and lifestyle questionnaires. Alcohol consumption was classified as either: non -use, former, light ( ≤ 0.5 and 1 drink/week), below the recommended limits (BRL) ( ≤ 1 and 2 drinks/day), moderate ( ≤ 2.5 and 5 drinks/day) , or heavy use (>2.5 and >5 drinks/ day) for women and men, respectively ; and was expressed as consumption at enrolment and during lifetime. Conditional logistic regression was applied adjusting for smoking and education , taking light users as the 3 Abstract Background The role of long -term alcohol consumption for the risk of developing ulcerative colitis (UC) and Crohn’s disease (CD) is unclear. Aim s For the first time, t o prospectively assess the role of pre -disease alcohol consumption o n the risk of developing UC or CD. Methods Nested within the European Prospective Investigation into Cancer and Nutrition (EPIC - IBD ), incident UC and CD cases and ma tched controls where included. At recruitment, participants completed validated food frequency and lifestyle questionnaires. Alcohol consumption was classified as either: non -use, former, light ( ≤ 0.5 and 1 drink/week), below the recommended limits (BRL) ( ≤ 1 and 2 drinks/day), moderate ( ≤ 2.5 and 5 drinks/day) , or heavy use (>2.5 and >5 drinks/ day) for women and men, respectively ; and was expressed as consumption at enrolment and during lifetime. Conditional logistic regression was applied adjusting for smoking and education , taking light users as the reference. Results Out of 262,451 participants in 6 countries, 198 UC incident cases/792 controls and 84 CD cases/336 controls were included. At enrolment, 8%/27%/3 2%/2 3%/1 1% UC cases and 7%/2 9%/4 0%/19%/ 5% C D cases were: non -users, light, BRL, moderate and heavy users, respectively. The corresponding figures for lifetime non -use, former, light, BRL, moderate and heavy use were : 3%/5%/2 3%/44%/19%/6% and 5%/2%/25%/44%/23 %/1% for UC and CD cases , respectively. There were no associations between any categories of alcohol consumption and risk of UC or CD in the una djusted and adjusted odds ratios . Conclusion There was no evidence of association s between alcohol use and the odds of developing either UC or CD

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Rectal Transmission of Transmitted/Founder HIV-1 Is Efficiently Prevented by Topical 1% Tenofovir in BLT Humanized Mice

Rectal microbicides are being developed to prevent new HIV infections in both men and women. We focused our in vivo preclinical efficacy study on rectally-applied tenofovir. BLT humanized mice (n = 43) were rectally inoculated with either the primary isolate HIV-1(JRCSF) or the MSM-derived transmitted/founder (T/F) virus HIV-1(THRO) within 30 minutes following treatment with topical 1% tenofovir or vehicle. Under our experimental conditions, in the absence of drug treatment we observed 50% and 60% rectal transmission by HIV-1(JRCSF) and HIV-1(THRO), respectively. Topical tenofovir reduced rectal transmission to 8% (1/12; log rank p = 0.03) for HIV-1(JRCSF) and 0% (0/6; log rank p = 0.02) for HIV-1(THRO). This is the first demonstration that any human T/F HIV-1 rectally infects humanized mice and that transmission of the T/F virus can be efficiently blocked by rectally applied 1% tenofovir. These results obtained in BLT mice, along with recent ex vivo, Phase 1 trial and non-human primate reports, provide a critically important step forward in the development of tenofovir-based rectal microbicides

Does a child’s language ability affect the correspondence between parent and teacher ratings of ADHD symptoms?

Background: Rating scales are often used to identify children with potential Attention-Deficit/Hyperactivity Disorder (ADHD), yet there are frequently discrepancies between informants which may be moderated by child characteristics. The current study asked whether correspondence between parent and teacher ratings on the Strengths and Weakness of ADHD symptoms and Normal behaviour scale (SWAN) varied systematically with child language ability. Method: Parent and teacher SWAN questionnaires were returned for 200 children (aged 61–81 months); 106 had low language ability (LL) and 94 had typically developing language (TL). After exploring informant correspondence (using Pearson correlation) and the discrepancy between raters, we report inter-class correlation coefficients, to assess inter-rater reliability, and Cohen’s kappa, to assess agreement regarding possible ADHD caseness. Results: Correlations between informant ratings on the SWAN were moderate. Children with LL were rated as having increased inattention and hyperactivity relative to children with TL; teachers, however, rated children with LL as having more inattention than parents. Inter-rater reliability of the SWAN was good and there were no systematic differences between the LL and TL groups. Case agreement between parent and teachers was fair; this varied by language group with poorer case agreement for children with LL. Conclusion: Children’s language abilities affect the discrepancy between informant ratings of ADHD symptomatology and the agreement between parents and teachers regarding potential ADHD caseness. The assessment of children’s core language ability would be a beneficial addition to the ADHD diagnostic process.</p

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

Systemic hematogenous maintenance of memory inflation by MCMV infection.

Several low-grade persistent viral infections induce and sustain very large numbers of virus-specific effector T cells. This was first described as a response to cytomegalovirus (CMV), a herpesvirus that establishes a life-long persistent/latent infection, and sustains the largest known effector T cell populations in healthy people. These T cells remain functional and traffic systemically, which has led to the recent exploration of CMV as a persistent vaccine vector. However, the maintenance of this remarkable response is not understood. Current models propose that reservoirs of viral antigen and/or latently infected cells in lymph nodes stimulate T cell proliferation and effector differentiation, followed by migration of progeny to non-lymphoid tissues where they control CMV reactivation. We tested this model using murine CMV (MCMV), a natural mouse pathogen and homologue of human CMV (HCMV). While T cells within draining lymph nodes divided at a higher rate than cells elsewhere, antigen-dependent proliferation of MCMV-specific effector T cells was observed systemically. Strikingly, inhibition of T cell egress from lymph nodes failed to eliminate systemic T cell division, and did not prevent the maintenance of the inflationary populations. In fact, we found that the vast majority of inflationary cells, including most cells undergoing antigen-driven division, had not migrated into the parenchyma of non-lymphoid tissues but were instead exposed to the blood supply. Indeed, the immunodominance and effector phenotype of inflationary cells, both of which are primary hallmarks of memory inflation, were largely confined to blood-localized T cells. Together these results support a new model of MCMV-driven memory inflation in which most immune surveillance occurs in circulation, and in which most inflationary effector T cells are produced in response to viral antigen presented by cells that are accessible to the blood supply

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO

A Search for Dark Higgs Bosons

Recent astrophysical and terrestrial experiments have motivated the proposal of a dark sector with GeV-scale gauge boson force carriers and new Higgs bosons. We present a search for a dark Higgs boson using 516 fb-1 of data collected with the BABAR detector. We do not observe a significant signal and we set 90% confidence level upper limits on the product of the Standard Model-dark sector mixing angle and the dark sector coupling constant.Comment: 7 pages, 5 postscript figures, published version with improved plots for b/w printin