Quantum mechanics/molecular mechanics minimum free-energy path for accurate reaction energetics in solution and enzymes: Sequential sampling and optimization on the potential of mean force surface

To accurately determine the reaction path and its energetics for enzymatic and solution-phase reactions, we present a sequential sampling and optimization approach that greatly enhances the efficiency of the ab initio quantum mechanics/molecular mechanics minimum free-energy path (QM/MM-MFEP) method. In the QM/MM-MFEP method, the thermodynamics of a complex reaction system is described by the potential of mean force (PMF) surface of the quantum mechanical (QM) subsystem with a small number of degrees of freedom, somewhat like describing a reaction process in the gas phase. The main computational cost of the QM/MM-MFEP method comes from the statistical sampling of conformations of the molecular mechanical (MM) subsystem required for the calculation of the QM PMF and its gradient. In our new sequential sampling and optimization approach, we aim to reduce the amount of MM sampling while still retaining the accuracy of the results by first carrying out MM phase-space sampling and then optimizing the QM subsystem in the fixed-size ensemble of MM conformations. The resulting QM optimized structures are then used to obtain more accurate sampling of the MM subsystem. This process of sequential MM sampling and QM optimization is iterated until convergence. The use of a fixed-size, finite MM conformational ensemble enables the precise evaluation of the QM potential of mean force and its gradient within the ensemble, thus circumventing the challenges associated with statistical averaging and significantly speeding up the convergence of the optimization process. To further improve the accuracy of the QM/MM-MFEP method, the reaction path potential method developed by Lu and Yang [Z. Lu and W. Yang, J. Chem. Phys. 121, 89 (2004)] is employed to describe the QM/MM electrostatic interactions in an approximate yet accurate way with a computational cost that is comparable to classical MM simulations. The new method was successfully applied to two example reaction processes, the classical SN 2 reaction of Cl- + CH3 Cl in solution and the second proton transfer step of the reaction catalyzed by the enzyme 4-oxalocrotonate tautomerase. The activation free energies calculated with this new sequential sampling and optimization approach to the QM/MM-MFEP method agree well with results from other simulation approaches such as the umbrella sampling technique with direct QM/MM dynamics sampling, demonstrating the accuracy of the iterative QM/MM-MFEP method. © 2008 American Institute of Physics.published_or_final_versio

Iteratively regularized Newton-type methods for general data misfit functionals and applications to Poisson data

We study Newton type methods for inverse problems described by nonlinear operator equations $F(u)=g$ in Banach spaces where the Newton equations $F'(u_n;u_{n+1}-u_n) = g-F(u_n)$ are regularized variationally using a general data misfit functional and a convex regularization term. This generalizes the well-known iteratively regularized Gauss-Newton method (IRGNM). We prove convergence and convergence rates as the noise level tends to 0 both for an a priori stopping rule and for a Lepski{\u\i}-type a posteriori stopping rule. Our analysis includes previous order optimal convergence rate results for the IRGNM as special cases. The main focus of this paper is on inverse problems with Poisson data where the natural data misfit functional is given by the Kullback-Leibler divergence. Two examples of such problems are discussed in detail: an inverse obstacle scattering problem with amplitude data of the far-field pattern and a phase retrieval problem. The performence of the proposed method for these problems is illustrated in numerical examples

Appetite suppressants and valvular heart disease - a systematic review

Background Although appetite suppressants have been implicated in the development of valvular heart disease, the exact level of risk is still uncertain. Initial studies suggested that as many as 1 in 3 exposed patients were affected, but subsequent research has yielded substantially different figures. Our objective was to systematically assess the risk of valvular heart disease with appetite suppressants. Methods We accepted studies involving obese patients treated with any of the following appetite suppressants: fenfluramine, dexfenfluramine, and phentermine. Three types of studies were reviewed: controlled and uncontrolled observational studies, and randomized controlled trials. Outcomes of interest were echocardiographically detectable aortic regurgitation of mild or greater severity, or mitral regurgitation of moderate or greater severity. Results Of the 1279 patients evaluated in seven uncontrolled cohort studies, 236 (18%) and 60 (5%) were found to have aortic and mitral regurgitation, respectively. Pooled data from six controlled cohort studies yielded, for aortic regurgitation, a relative risk ratio of 2.32 (95% confidence intervals 1.79 to 3.01, p < 0.00001) and an attributable rate of 4.9%, and for mitral regurgitation, a relative risk ratio of 1.55 (95% confidence intervals 1.06 to 2.25, p = 0.02) with an attributable rate of 1.0%. Only one case of valvular heart disease was detected in 57 randomized controlled trials, but this was judged unrelated to drug therapy. Conclusions The risk of valvular heart disease is significantly increased by the appetite suppressants reviewed here. Nevertheless, when considering all the evidence, valvulopathy is much less common than suggested by the initial, less methodologically rigorous studies

Low recurrence rate of a two-layered closure repair for primary and recurrent midline incisional hernia without mesh

Background: Incisional hernia is a serious complication after abdominal surgery and occurs in 11-23% of laparotomies. Repair can be done, for instance, with a direct suture technique, but recurrence rates are high. Recent literature advises the use of mesh repair. In contrast to this development, we studied the use of a direct suture repair in a separate layer technique. The objective of this retrospective observational study is to assess the outcomes (recurrences and complications) of a two-layered open closure repair for primary and recurrent midline incisional hernia without the use of mesh. Methods: In an observational retrospective cohort study, we analysed the hospital and outpatient records of 77 consecutive patients who underwent surgery for a primary or recurrent incisional hernia between 1st May 2002 and 8th November 2006. The repair consisted of separate continuous suturing of the anterior and posterior fascia, including the rectus muscle, after extensive intra-abdominal adhesiolysis. Results: Forty-one men (53.2%) and 36 women (46.8%) underwent surgery. Sixty-three operations (81.8%) were primary repairs and 14 (18.2%) were repairs for a recurrent incisional hernia. Of the 66 patients, on physical examination, three had a recurrence (4.5%) after an average follow-up of 2.6 years. The 30-day postoperative mortality was 1.1%. Wound infection was seen in five patients (6.5%). Conclusions: A two-layered suture repair for primary and recurrent incisional hernia repair without mesh with extensive adhesiolysis was associated with a recurrence rate comparable to mesh repair and had an acceptable complication rate

Formation and Propagation of Matter Wave Soliton Trains

Attraction between atoms in a Bose-Einstein-Condensate renders the condensate unstable to collapse. Confinement in an atom trap, however, can stabilize the condensate for a limited number of atoms, as was observed with 7Li, but beyond this number, the condensate collapses. Attractive condensates constrained to one-dimensional motion are predicted to form stable solitons for which the attractive interactions exactly compensate for the wave packet dispersion. Here we report the formation or bright solitons of 7Li atoms created in a quasi-1D optical trap. The solitons are created from a stable Bose-Einstein condensate by magnetically tuning the interactions from repulsive to attractive. We observe a soliton train, containing many solitons. The solitons are set in motion by offsetting the optical potential and are observed to propagate in the potential for many oscillatory cycles without spreading. Repulsive interactions between neighboring solitons are inferred from their motion

Using self-organizing maps to investigate environmental factors regulating colony size and breeding success of the White Stork (Ciconia ciconia)

We studied variations in the size of breeding colonies and in breeding performance of White Storks Ciconia ciconia in 2006–2008 in north-east Algeria. Each colony site was characterized using 12 environmental variables describing the physical environment, land-cover categories, and human activities, and by three demographic parameters: the number of breeding pairs, the number of pairs with chicks, and the number of fledged chicks per pair. Generalized linear mixed models and the self-organizing map algorithm (SOM, neural network) were used to investigate effects of biotic, abiotic, and anthropogenic factors on demographic parameters and on their relationships. Numbers of breeding pairs and of pairs with chicks were affected by the same environmental factors, mainly anthropogenic, which differed from those affecting the number of fledged chicks per pair. Numbers of fledged chicks per pair was not affected by colony size or by the number of nests with chicks. The categorization of the environmental variables into natural and anthropogenic, in connection with demographic parameters, was relevant to detect factors explaining variation in colony size and breeding parameters. The SOM proved a relevant tool to help determine actual dynamics in White Stork colonies, and thus to support effective conservation decisions at a regional scale

Feasibility of school students Skyping care home residents to reduce loneliness

Background Intergenerational friendship has proved useful for older people in increasing socialisation. We explored the feasibility of school students Skyping older people in care homes with the long-term aim of reducing loneliness. Methods Six school students from one secondary school and twenty older people, including seven with mild to moderate dementia, from three care homes, engaged in Skype video-calls over six weeks. A conversational aid aimed to help school students maintain conversations was employed. Students and care staff completed feedback forms after each session on video-call usage, usefulness of the conversational aid, and barriers and benefits of video-calls. Six care staff provided further feedback on residents’ experiences through unstructured interviews. Interviews and field notes were thematically analysed. Results Residents enjoyed Skype-calls with school students. Over six weeks, video-calls became longer, and more residents participated. Analysis revealed four themes. First, the intervention led to increased mobility for three older people and improved self-care in regard to personal appearance for five residents. Second, school students and older people formed friendships which inspired the need to meet in person. Third, the use of video-calls enabled participants to view each other’s environments in real time. Last, directly experiencing the intervention was important for the continued participation of the care staff in the study. Skype-calls between schools and care homes are feasible and may help reduce loneliness. Conclusions Institutional collaboration between educational settings and care homes through cost effective video-calls can be useful to increase socialisation for older people, and promote later on-going use with other external organisations to help reduce loneliness and social isolation

A Semi-Lagrangian scheme for a modified version of the Hughes model for pedestrian flow

In this paper we present a Semi-Lagrangian scheme for a regularized version of the Hughes model for pedestrian flow. Hughes originally proposed a coupled nonlinear PDE system describing the evolution of a large pedestrian group trying to exit a domain as fast as possible. The original model corresponds to a system of a conservation law for the pedestrian density and an Eikonal equation to determine the weighted distance to the exit. We consider this model in presence of small diffusion and discuss the numerical analysis of the proposed Semi-Lagrangian scheme. Furthermore we illustrate the effect of small diffusion on the exit time with various numerical experiments