Efficient minimization of multipole electrostatic potentials in torsion space

The development of models of macromolecular electrostatics capable of delivering improved fidelity to quantum mechanical calculations is an active field of research in computational chemistry. Most molecular force field development takes place in the context of models with full Cartesian coordinate degrees of freedom. Nevertheless, a number of macromolecular modeling programs use a reduced set of conformational variables limited to rotatable bonds. Efficient algorithms for minimizing the energies of macromolecular systems with torsional degrees of freedom have been developed with the assumption that all atom-atom interaction potentials are isotropic. We describe novel modifications to address the anisotropy of higher order multipole terms while retaining the efficiency of these approaches. In addition, we present a treatment for obtaining derivatives of atom-centered tensors with respect to torsional degrees of freedom. We apply these results to enable minimization of the Amoeba multipole electrostatics potential in a system with torsional degrees of freedom, and validate the correctness of the gradients by comparison to finite difference approximations. In the interest of enabling a complete model of electrostatics with implicit treatment of solvent-mediated effects, we also derive expressions for the derivative of solvent accessible surface area with respect to torsional degrees of freedom

Examples of mathematical modeling tales from the crypt

Mathematical modeling is being increasingly recognized within the biomedical sciences as an important tool that can aid the understanding of biological systems. The heavily regulated cell renewal cycle in the colonic crypt provides a good example of how modeling can be used to find out key features of the system kinetics, and help to explain both the breakdown of homeostasis and the initiation of tumorigenesis. We use the cell population model by Johnston et al. (2007) Proc. Natl. Acad. Sci. USA 104, 4008-4013, to illustrate the power of mathematical modeling by considering two key questions about the cell population dynamics in the colonic crypt. We ask: how can a model describe both homeostasis and unregulated growth in tumorigenesis; and to which parameters in the system is the model most sensitive? In order to address these questions, we discuss what type of modeling approach is most appropriate in the crypt. We use the model to argue why tumorigenesis is observed to occur in stages with long lag phases between periods of rapid growth, and we identify the key parameters

On the proportion of cancer stem cells in a tumour

It is now generally accepted that cancers contain a sub-population, the cancer stem cells (CSCs), which initiate and drive a tumour’s growth. At least until recently it has been widely assumed that only a small proportion of the cells in a tumour are CSCs. Here we use a mathematical model, supported by experimental evidence, to show that such an assumption is unwarranted. We show that CSCs may comprise any possible proportion of the tumour, and that the higher the proportion the more aggressive the tumour is likely to be

Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL.

Unlike other tumor necrosis factor family members, the cytotoxic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L contains an unpaired cysteine residue (Cys(230)) in its receptor-binding domain. Here we show that the biological activity of both soluble recombinant TRAIL and cell-associated, full-length TRAIL is critically dependent on the presence of Cys(230). Mutation of Cys(230) to alanine or serine strongly affected its ability to kill target cells. Binding to its receptors was decreased by at least 200-fold, and the stability of its trimeric structure was reduced. In recombinant TRAIL, Cys(230) was found engaged either in interchain disulfide bridge formation, resulting in poorly active TRAIL, or in the chelation of one zinc atom per TRAIL trimer in the active, pro-apoptotic form of TRAIL

Evolutionary history and identification of conservation units in the giant otter, Pteronura brasiliensis.

The giant otter, Pteronura brasiliensis, occupies a range including the major drainage basins of South America, yet the degree of structure that exists within and among populations inhabiting these drainages is unknown. We sequenced portions of the mitochondrial DNA (mtDNA) cytochrome b (612 bp) and control region (383 bp) genes in order to determine patterns of genetic variation within the species. We found high levels of mtDNA haplotype diversity (h = 0.93 overall) and support for subdivision into four distinct groups of populations, representing important centers of genetic diversity and useful units for prioritizing conservation within the giant otter. We tested these results against the predictions of three hypotheses of Amazonian diversification (Pleistocene Refugia, Paleogeography, and Hydrogeology). While the phylogeographic pattern conformed to the predictions of the Refugia Hypothesis, molecular dating using a relaxed clock revealed the phylogroups diverged from one another between 1.69 and 0.84 Ma, ruling out the influence of Late Pleistocene glacial refugia. However, the role of Plio-Pleistocene climate change could not be rejected. While the molecular dating also makes the influence of geological arches according to the Paleogeography Hypothesis extremely unlikely, the recent Pliocene formation of the Fitzcarrald Arch and its effect of subsequently altering drainage pattern could not be rejected. The data presented here support the interactions of both climatic and hydrological changes resulting from geological activity in the Plio-Pleistocene, in shaping the phylogeographic structure of the giant otter

Identification of the growth factor-binding sequence in the extracellular matrix protein MAGP-1

Editorial Análisis de casos Reforma agraria y lucha por la tierra en América Latina La Reforma Agraria en América Latina: una revolución frustrada Plinio Arruda Sampaio A Nova Questão Agrária e a Reinvenção do Campesinato: o caso do MST Carlos Walter Porto-Gonçalves El movimiento campesino en el Paraguay: conflictos, planteamientos y desafíos Tomás Palau Viladesau Movimientos campesinos e indígenas en México: la lucha por la tierra Luciano Concheiro Bórquez y Sergio Grajales Ventura Las luchas campesinas en Colombia en los albores del siglo XXI: de la frustración a la esperanza Isaías Tobasura Acuña Documentos O que precisa ser feito para mudar a vida do povo! Comunicado del Frente Nacional Campesino Ezequiel Zamora de Venezuela Cronología del conflicto La geografía política del conflicto social en América Latina José Seoane y Clara Algranati Región Sur Los sindicatos uruguayos ante el primer gobierno de izquierda Luis Senatore y Jaime Yaffé • Argentina • Brasil • Chile • Paraguay • Uruguay Región Andina Quito en abril: los forajidos derrotan al coronel Mario Unda • Bolivia • Colombia • Ecuador • Perú • Venezuela Región Norte La Guatemala de la resistencia y de la esperanza: las jornadas de lucha contra el CAFTA Simona Violetta Yagenova • Costa Rica • El Salvador • Guatemala • Honduras • México • Nicaragua • Panamá • Puerto Rico • República Dominicana Debates Territorio y movimientos sociales O retorno do território Apresentação por Maria Adélia Aparecida de Souza Milton Santos Outros territórios, outros mapas Ana Clara Torres Ribeiro Movimentos socioterritoriais e movimentos socioespaciais Bernardo Mançano Fernandes Territorios en disputa: iniciativas productivas y acción política en Mosconi, Argentina Norma Giarracca y Juan Wahren Sarjam [Vocablo en lengua aymara que significa ándate] Jorge A. Sainz Cardon

Lambda-proton correlations in relativistic heavy ion collisions

The prospect of using lambda-proton correlations to extract source sizes in relativistic heavy ion collisions is investigated. It is found that the strong interaction induces a large peak in the correlation function that provides more sensitive source size measurements than two-proton correlations under some circumstances. The prospect of using lambda-proton correlations to measure the time lag between lambda and proton emissions is also studied.Comment: 4 pages, 3 figure, revtex style. Two short paragraphs are added at referees' recommendations. Phys. Rev. Lett. in pres

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor.

Wnt signaling is overactivated in triple-negative breast cancer (TNBC) and several other cancers, and its suppression emerges as an effective anticancer treatment. However, no drugs targeting the Wnt pathway exist on the market nor in advanced clinical trials. Here we provide a comprehensive body of preclinical evidence that an anti-leprotic drug clofazimine is effective against TNBC. Clofazimine specifically inhibits canonical Wnt signaling in a panel of TNBC cells in vitro. In several mouse xenograft models of TNBC, clofazimine efficiently suppresses tumor growth, correlating with in vivo inhibition of the Wnt pathway in the tumors. Clofazimine is well compatible with doxorubicin, exerting additive effects on tumor growth suppression, producing no adverse effects. Its excellent and well-characterized pharmacokinetics profile, lack of serious adverse effects at moderate (yet therapeutically effective) doses, its combinability with cytotoxic therapeutics, and the novel mechanistic mode of action make clofazimine a prime candidate for the repositioning clinical trials. Our work may bring forward the anti-Wnt targeted therapy, desperately needed for thousands of patients currently lacking targeted treatments