Optimal control in heterogeneous domain decomposition methods

Some new domain decomposition methods (DDM) based on optimal control approach are introduced for the coupling of first- and second-order equations on overlapping subdomains. Several cost functionals and control functions are proposed. Uniqueness and existence results are proved for the coupled problem and the convergence of iterative processes is analyze

Library Research for the 99%: Reaching Out to the Occupy Wall Street Movement

This article describes how librarians from three different universities in the greater New York area came together through the myMETRO Researchers Project to reach out to Occupy Wall Street. Using social media and free online tools to partner with Occupy’s environmental subgroup, the authors overcame proprietary roadblocks, copyright challenges, and distrust/skepticism to discover the authentic information needs of activists and compile an annotated bibliography of scholarly research on the real-world impacts of climate change. This successful collaboration is an example of how institutions can be used as contact points through which individuals can affect change on society, and how librarians can partner with local community groups to combat information poverty and digital divides and promote open access and knowledge-sharing

Development of an Optimization-Based Atomistic-to-Continuum Coupling Method

Atomistic-to-Continuum (AtC) coupling methods are a novel means of computing the properties of a discrete crystal structure, such as those containing defects, that combine the accuracy of an atomistic (fully discrete) model with the efficiency of a continuum model. In this note we extend the optimization-based AtC, formulated in arXiv:1304.4976 for linear, one-dimensional problems to multi-dimensional settings and arbitrary interatomic potentials. We conjecture optimal error estimates for the multidimensional AtC, outline an implementation procedure, and provide numerical results to corroborate the conjecture for a 1D Lennard-Jones system with next-nearest neighbor interactions.Comment: 12 pages, 3 figure

Structural basis of the effect of activating mutations on the EGF receptor

Mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are common oncogenic driver events in non-small cell lung cancer. Although the activation of EGFR in normal cells is primarily driven by growth-factor-binding-induced dimerization, mutations on different exons of the kinase domain of the receptor have been found to affect the equilibrium between its active and inactive conformations giving rise to growth-factor-independent kinase activation. Using molecular dynamics simulations combined with enhanced sampling techniques, we compare here the conformational landscape of the monomers and homodimers of the wild-type and mutated forms of EGFR ΔELREA and L858R, as well as of two exon 20 insertions, D770-N771insNPG, and A763-Y764insFQEA. The differences in the conformational energy landscapes are consistent with multiple mechanisms of action including the regulation of the hinge motion, the stabilization of the dimeric interface, and local unfolding transitions. Overall, a combination of different effects is caused by the mutations and leads to the observed aberrant signaling

Design, Synthesis, and Anticancer Activity of a Selenium‐Containing Galectin‐3 and Galectin‐9N Inhibitor

Galectins are soluble β‐D‐galactoside‐binding proteins whose implication in cancer progression and disease outcome makes them prominent targets for therapeutic intervention. In this frame, the development of small inhibitors that block selectively the activity of galectins represents an important strategy for cancer therapy which is, however, still relatively underdeveloped. To this end, we designed here a rationally and efficiently novel diglycosylated compound, characterized by a selenoglycoside bond and the presence of a lipophilic benzyl group at both saccharide residues. The relatively high binding affinity of the new compound to the carbohydrate recognition domain of two galectins, galectin 3 and galectin 9, its good antiproliferative and anti‐migration activity towards melanoma cells, as well as its anti‐angiogenesis properties, pave the way for its further development as an anticancer agent

The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm

The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur

Core regulon of the global anaerobic regulator Anr targets central metabolism functions in Pseudomonas species

A comparative genome analysis of the global anaerobic regulator Anr regulon in five species of Pseudomonas with different life style was performed. Expression of this regulator was detected in all analyzed Pseudomonas. The predicted Anr regulon (pan-regulon) consisted of 253 genes. However, only 11 Anr-boxes located upstream of qor/hemF, hemN, cioA/PA3931, azu, rpsL, gltP, orthologous to PA2867, cspD, tyrZ, slyD and oprG, were common to all species. Whole genome in silico prediction of metabolic pathways identified genes belonging to heme biosynthesis, cytochromes and Entner-Doudoroff pathway as members of Anr regulon in all strains. Extending genome analysis to 28 Pseudomonas spp. spanning all phylogenetic groups showed Anr-boxes conservation in genes related to these functions. When present, genes related to anaerobic metabolism were predicted to hold Anr-boxes. Focused on the genomes of eight P. aeruginosa isolates of diverse origins, we observed a conserved regulon, sharing nearly 80% of the genes, indicating its key role in this opportunistic pathogen. The results suggest that the core Anr regulon comprises genes involved in central metabolism and aerobic electron transport chain, whereas those genes related to anaerobic metabolism and other functions constitute the accessory Anr-regulon, thereby differentially contributing to the ecological fitness of each Pseudomonas species.Fil: Tribelli, Paula Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Lujan, Adela Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Pardo, Agustin Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Ibarra, José Gervasio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Fernández Do Porto, Darío Augusto. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Calculo. - Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Calculo; ArgentinaFil: Smania, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: López, Nancy I.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentin

Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics

Understanding allostery in enzymes and tools to identify it, offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways in two prototypical class A β-lactamases, TEM-1 and KPC-2, which are important determinants of antibiotic resistance. The nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more. Propagation of the signal occurs through cooperative coupling of loop dynamics. Notably, 50% or more of clinically relevant amino acid substitutions map onto the identified signal transduction pathways. This suggests that clinically important variation may affect, or be driven by, differences in allosteric behavior, providing a mechanism by which amino acid substitutions may affect the relationship between spectrum of activity, catalytic turnover and potential allosteric behavior in this clinically important enzyme family. Simulations of the type presented here will help in identifying and analyzing such differences

Standardized Competencies for Parenteral Nutrition Prescribing: The American Society for Parenteral and Enteral Nutrition Model

Parenteral nutrition (PN) provision is complex, as it is a high-alert medication and prone to a variety of potential errors. With changes in clinical practice models and recent federal rulings, the number of PN prescribers may be increasing. Safe prescribing of this therapy requires that competency for prescribers from all disciplines be demonstrated using a standardized process. A standardized model for PN prescribing competency is proposed based on a competency framework, the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.)–published interdisciplinary core competencies, safe practice recommendations, and clinical guidelines. This framework will guide institutions and agencies in developing and maintaining competency for safe PN prescription by their staff