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

A probability-conserving cross-section biasing mechanism for variance reduction in Monte Carlo particle transport calculations

In Monte Carlo particle transport codes, it is often important to adjust reaction cross sections to reduce the variance of calculations of relatively rare events, in a technique known as non-analogous Monte Carlo. We present the theory and sample code for a Geant4 process which allows the cross section of a G4VDiscreteProcess to be scaled, while adjusting track weights so as to mitigate the effects of altered primary beam depletion induced by the cross section change. This makes it possible to increase the cross section of nuclear reactions by factors exceeding 10^4 (in appropriate cases), without distorting the results of energy deposition calculations or coincidence rates. The procedure is also valid for bias factors less than unity, which is useful, for example, in problems that involve computation of particle penetration deep into a target, such as occurs in atmospheric showers or in shielding

Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

Poorly differentiated thyroid carcinomas (PDTC) represent a heterogeneous, aggressive entity, presenting features that suggest a progression from well-differentiated carcinomas. To elucidate the mechanisms underlying such progression and identify novel therapeutic targets, we assessed the genome-wide expression in normal and tumour thyroid tissues.info:eu-repo/semantics/publishe

Activated Leukocyte Cell Adhesion Molecule Expression and Shedding in Thyroid Tumors

Activated leukocyte cell adhesion molecule (ALCAM, CD166) is expressed in various tissues, cancers, and cancer-initiating cells. Alterations in expression of ALCAM have been reported in several human tumors, and cell adhesion functions have been proposed to explain its association with cancer. Here we documented high levels of ALCAM expression in human thyroid tumors and cell lines. Through proteomic characterization of ALCAM expression in the human papillary thyroid carcinoma cell line TPC-1, we identified the presence of a full-length membrane-associated isoform in cell lysate and of soluble ALCAM isoforms in conditioned medium. This finding is consistent with proteolytically shed ALCAM ectodomains. Nonspecific agents, such as phorbol myristate acetate (PMA) or ionomycin, provoked increased ectodomain shedding. Epidermal growth factor receptor stimulation also enhanced ALCAM secretion through an ADAM17/TACE-dependent pathway. ADAM17/TACE was expressed in the TPC-1 cell line, and ADAM17/TACE silencing by specific small interfering RNAs reduced ALCAM shedding. In addition, the CGS27023A inhibitor of ADAM17/TACE function reduced ALCAM release in a dose-dependent manner and inhibited cell migration in a wound-healing assay. We also provide evidence for the existence of novel O-glycosylated forms and of a novel 60-kDa soluble form of ALCAM, which is particularly abundant following cell stimulation by PMA. ALCAM expression in papillary and medullary thyroid cancer specimens and in the surrounding non-tumoral component was studied by western blot and immunohistochemistry, with results demonstrating that tumor cells overexpress ALCAM. These findings strongly suggest the possibility that ALCAM may have an important role in thyroid tumor biology

Continental sources of halocarbons and nitrous oxide

Estimates of continental sources of CFC-11, CFC-12, CCl4, CH3CCl3 and N2O are derived from the atmospheric lifetime experiment in Adrigole, Ireland, and anthropogenic emissions of CCl4 and N2O from Europe have been identified. Relative source strengths are consistent with global budgets for the halocarbons and N2O. Different industrial release patterns for halocarbons are observed for Europe, the western United States and Australia. © 1985 Nature Publishing Group

Liquids with permanent porosity

International audiencePorous solids such as zeolites1 and metal–organic frameworks2, 3 are useful in molecular separation and in catalysis, but their solid nature can impose limitations. For example, liquid solvents, rather than porous solids, are the most mature technology for post-combustion capture of carbon dioxide because liquid circulation systems are more easily retrofitted to existing plants. Solid porous adsorbents offer major benefits, such as lower energy penalties in adsorption–desorption cycles4, but they are difficult to implement in conventional flow processes. Materials that combine the properties of fluidity and permanent porosity could therefore offer technological advantages, but permanent porosity is not associated with conventional liquids5. Here we report free-flowing liquids whose bulk properties are determined by their permanent porosity. To achieve this, we designed cage molecules6, 7 that provide a well-defined pore space and that are highly soluble in solvents whose molecules are too large to enter the pores. The concentration of unoccupied cages can thus be around 500 times greater than in other molecular solutions that contain cavities8, 9, 10, resulting in a marked change in bulk properties, such as an eightfold increase in the solubility of methane gas. Our results provide the basis for development of a new class of functional porous materials for chemical processes, and we present a one-step, multigram scale-up route for highly soluble ‘scrambled’ porous cages prepared from a mixture of commercially available reagents. The unifying design principle for these materials is the avoidance of functional groups that can penetrate into the molecular cage cavities

Estimated whole-brain and lobe-specific radiofrequency electromagnetic fields doses and brain volumes in preadolescents

Objective: To assess the association between estimated whole-brain and lobe-specific radiofrequency electromagnetic fields (RF-EMF) doses, using an improved integrated RF-EMF exposure model, and brain volumes in preadolescents at 9-12 years old. Methods: Cross-sectional analysis in preadolescents aged 9-12 years from the Generation R Study, a population-based birth cohort set up in Rotterdam, The Netherlands (n = 2592). An integrated exposure model was used to estimate whole-brain and lobe-specific RF-EMF doses (mJ/kg/day) from different RF-EMF sources including mobile and Digital Enhanced Cordless Telecommunications (DECT) phone calls, other mobile phone uses than calling, tablet use, laptop use, and far-field sources. Whole-brain and lobe-specific RF-EMF doses were estimated for all RF-EMF sources together (i.e. overall) and for three groups of RF-EMF sources that lead to a different pattern of RF-EMF exposure. Information on brain volumes was extracted from magnetic resonance imaging scans. Results: Estimated overall whole-brain RF-EMF dose was 84.3 mJ/kg/day. The highest overall lobe-specific dose was estimated in the temporal lobe (307.1 mJ/kg/day). Whole-brain and lobe-specific RF-EMF doses from all RF-EMF sources together, from mobile and DECT phone calls, and from far-field sources were not associated with global, cortical, or subcortical brain volumes. However, a higher whole-brain RF-EMF dose from mobile phone use for internet browsing, e-mailing, and text messaging, tablet use, and laptop use while wirelessly connected to the internet was associated with a smaller caudate volume. Conclusions: Our results suggest that estimated whole-brain and lobe-specific RF-EMF doses were not related to brain volumes in preadolescents at 9-12 years old. Screen activities with mobile communication devices while wirelessly connected to the internet lead to low RF-EMF dose to the brain and our observed association may thus rather reflect effects of social or individual factors related to these specific uses of mobile communication devices. However, we cannot discard residual confounding, chance finding, or reverse causality. Further studies on mobile communication devices and their potential negative associations with brain development are warranted, regardless whether associations are due to RF-EMF exposure or to other factors related to their use