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Weighted ensemble (WE) is an enhanced sampling method based on periodically replicating and pruning trajectories generated in parallel. WE has grown increasingly popular for computational biochemistry problems due, in part, to improved hardware and accessible software implementations. Algorithmic and analytical improvements have played an important role, and progress has accelerated in recent years. Here, we discuss and elaborate on the WE method from a mathematical perspective, highlighting recent results that enhance the computational efficiency. The mathematical theory reveals a new strategy for optimizing trajectory management that approaches the best possible variance while generalizing to systems of arbitrary dimension.

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The E. coli glucose-galactose chemosensory receptor is a 309 residue, 32 kDa protein consisting of two distinct structural domains. We used two computational methods to examine the protein's thermal fluctuations, including both the large-scale interdomain movements that contribute to the receptor's mechanism of action, as well as smaller-scale motions. We primarily employ extremely fast, "semi-atomistic" Library-Based Monte Carlo (LBMC) simulations, which include all backbone atoms but "implicit" side chains. Our results were compared with previous experiments and all-atom molecular dynamics (MD) simulation. Both LBMC and MD simulations were performed using both the apo and glucose-bound form of the protein, with LBMC exhibiting significantly larger fluctuations. The LBMC simulations are in general agreement with the disulfide trapping experiments of Careaga & Falke (J. Mol. Biol., 1992, Vol. 226, 1219-35), which indicate that distant residues in the crystal structure (i.e. beta carbons separated by 10 to 20 angstroms) form spontaneous transient contacts in solution. Our simulations illustrate several possible "mechanisms" (configurational pathways) for these fluctuations. We also observe several discrepancies between our calculations and experimental rate constants. Nevertheless, we believe that our semi-atomistic approach could be used to study fluctuations in other proteins, perhaps for ensemble docking or other analyses of protein flexibility in virtual screening studies.

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Debye-Hückel (DH) theory is extended to treat two-component size- and charge-asymmetric primitive models, focusing primarily on the 1:1 additive hard-sphere electrolyte with, say, negative ion diameters a(--) larger than the positive ion diameters a(++). The treatment highlights the crucial importance of the charge-unbalanced "border zones" around each ion into which other ions of only one species may penetrate. Extensions of the DH approach that describe the border zones in a physically reasonable way are exact at high T and low density rho and, furthermore, are also in substantial agreement with recent simulation predictions for trends in the critical parameters, T(c) and rho(c), with increasing size asymmetry. Conversely, the simplest linear asymmetric DH description, which fails to account for physically expected behavior in the border zones at low T, can violate a new lower bound on the energy (which applies generally to models asymmetric in both charge and size). Other theories, including those based on the mean spherical approximation, predict trends in the critical parameters quite opposite to those established by the simulations.

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Exploiting stochastic path-integral theory, we obtain by simulation substantial gains in efficiency for the computation of reaction rates in one-dimensional, bistable, overdamped stochastic systems. Using a well-defined measure of efficiency, we compare implementations of "dynamic importance sampling" (DIMS) methods to unbiased simulation. The best DIMS algorithms are shown to increase efficiency by factors of approximately 20 for a 5k(B)T barrier height and 300 for 9k(B)T, compared to unbiased simulation. The gains result from close emulation of natural (unbiased), instantonlike crossing events with artificially decreased waiting times between events that are corrected for in rate calculations. The artificial crossing events are generated using the closed-form solution to the most probable crossing event described by the Onsager-Machlup action. While the best biasing methods require the second derivative of the potential (resulting from the "Jacobian" term in the action, which is discussed at length), algorithms employing solely the first derivative do nearly as well. We discuss the importance of one-dimensional models to larger systems, and suggest extensions to higher-dimensional systems.

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Many of the more than 182,000 women who will be newly diagnosed with breast cancer this year will not have access to all the information they need to make the surgical and treatment choices that are most appropriate for them. Research clearly shows that lumpectomy and other breast-conserving surgeries are just as safe as mastectomy for most women with early stage disease, and yet approximately half will undergo the more disfiguring procedures. Choices about breast implants and autologous tissue reconstruction are based, at best, on a few published studies that provide limited information about the long-term safety of these procedures. Many healthy women who have strong family histories of breast cancer consider prophylactic mastectomies, and their decisions are also based on very limited information, because there are few studies showing the effectiveness of that procedure. This paper delineates how limited information and biased recommendations can undermine breast cancer patients' ability to make informed choices.

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Public concern with the national level of violence is discussed, and the complexity of the issue delineated. Research findings in two key areas of the topic, media violence and availability of firearms, are examined, as is their applicability to public policy efforts and recommendations for the prevention of violence. An approach that combines efforts to counteract media violence with those aimed at effective gun control is outlined in terms of bringing about changes in attitudes toward violence and firearm possession.

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Similar theories of etiology have been postulated for child abuse and nonorganic failure to thrive (FTT). This study compared individual, familial, and environmental conditions in cases of child abuse to cases of FTT. Assessment of the mother's childhood home, supports, current living situation, attitudes toward her child, and child characteristics (such as temperament, social maturity, and complicating medical conditons) showed the groups to be remarkably alike. The major significant difference was that although both groups were poor, the abuse group was even more impoverished and lived in more crowded conditions than the families with a child with FTT. These data suggest a common etiologic context for different pediatric social illnesses and the need for a broad collaborative approach by pediatricians and colleagues in related disciplines.

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A survey was conducted to determine the prevalence of bulimia and bulimic symptoms in a nonclinical sample of 907 college freshmen and seniors. Using criteria based on the Diagnostic and Statistical Manual of Mental Disorders, 4 per cent of the women and 0.4 per cent of the men were classified as bulimic. Symptoms of bulimia, such as binge eating, purging behaviors, and extreme fear of gaining weight, were much more prevalent.

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Television has a major impact on children's knowledge, attitudes, and behavior. Research has demonstrated the association between television viewing and four areas: (1) children's aggressive behavior; (2) racial and sex-role stereotypes; (3) decreased interest in reading and school activities; and (4) poorer health habits and attitudes. Methodological limitations make it difficult to draw firm conclusions about a causal relationship between television viewing and children's behavior. Representative studies in these four areas are reviewed, important methodological concerns are pointed out, and conclusions from the research findings are drawn. The implications of the data for pediatricians and other health professionals are discussed.

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Mortality data during a two-year follow-up were obtained on some 400 elderly poor residents of New Haven, Hartford, and West Haven, Connecticut, in 1972-1974. These subjects were cases and controls in a study of the health effects of residential relocation. Initial data collection included a detailed health history, sociodemographic and background variables, and a variety of behavioral and psychological data. The variables selected for analysis in this report were: religious beliefs, social contacts, feelings of well-being, and affective states. Stepwise logistic regressions were used to determine the role of these psychosocial variables in predicting mortality, while controlling for case/control status, demographic variables, and health status (measured by an index maximally predictive of mortality in this sample). Three psychosocial variables were significant predictors: religiousness, happiness (as rated by the interviewers), and presence of living offspring. The first two reduced the risk of mortality primarily among the elderly who were in poor health, while the third one did not interact with health status.

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An inexpensive portable fluorometer has been designed which can be used to determine the concentration of zinc protoporphyrin (ZPP) in a drop of unprocessed blood deposited on a disposable glass slide. No volume measurement of the blood sample need be made. The instrument displays the ZPP level in micrograms per deciliter of blood accurately and reproducibly, automatically calibrating each determination by comparing the blood fluorescence with that of a stable dye. The instrument, which we call a hematofluorometer, is ideally suited for use in primary screening for childhood and occupational lead intoxication. It can be used by public health personnel after a few minutes of instruction. Comparisons of ZPP levels obtained with the use of the hematofluorometer with erythrocyte protoporphyrin levels obtained using accepted extraction methods are presented.

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A portable filter fluorometer, the hematofluorometer--which utilizes "front face" optics, internal standards, and digital computation capabilities--has been specifically designed for the rapid (approximately 5 s) assay of erythrocyte zinc protoporphyrin in unprocessed blood. A small (unmeasured) drop of blood, such as is obtained from a finger puncture, is placed on disposable cover slip and inserted in the sample holder of the instrument. The operator pushes the holder of the instrument. The operator pushes the holder, which also holds the permanent blank and standard, into the instrument. Zinc protoporphyrin concentration is automatically and instantaneously computed and the value is displayed on a digital readout as micrograms of zinc protoporphyrin per deciliter of blood for some standard hematocrit. No calibration adjustment need be performed by the operator. The hematofluorometer is designed for "field" use as well as for laboratory assays.

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