Search algorithms as a framework for the optimization of drug combinations

Combination therapies are often needed for effective clinical outcomes in the management of complex diseases, but presently they are generally based on empirical clinical experience. Here we suggest a novel application of search algorithms, originally developed for digital communication, modified to optimize combinations of therapeutic interventions. In biological experiments measuring the restoration of the decline with age in heart function and exercise capacity in Drosophila melanogaster, we found that search algorithms correctly identified optimal combinations of four drugs with only one third of the tests performed in a fully factorial search. In experiments identifying combinations of three doses of up to six drugs for selective killing of human cancer cells, search algorithms resulted in a highly significant enrichment of selective combinations compared with random searches. In simulations using a network model of cell death, we found that the search algorithms identified the optimal combinations of 6-9 interventions in 80-90% of tests, compared with 15-30% for an equivalent random search. These findings suggest that modified search algorithms from information theory have the potential to enhance the discovery of novel therapeutic drug combinations. This report also helps to frame a biomedical problem that will benefit from an interdisciplinary effort and suggests a general strategy for its solution.Comment: 36 pages, 10 figures, revised versio

Disordered Structural Ensembles of Vasopressin and Oxytocin and Their Mutants

Vasopressin and oxytocin are intrinsically disordered cyclic nonapeptides belonging to a family of neurohypophysial hormones. Although unique in their functions, these peptides differ only by two residues and both feature a tocin ring formed by the disulfide bridge between first and sixth cysteine residues. This sequence and structural similarity are experimentally linked to oxytocin agonism at vasopressin receptors and vasopressin antagonism at oxytocin receptors. Yet single- or double-residue mutations in both peptides have been shown to have drastic impacts on their activities at either receptor, and possibly the ability to bind to their neurophysin carrier protein. In this study we perform molecular dynamics simulations of the unbound native and mutant sequences of the oxytocin and vasopressin hormones to characterize their structural ensembles. We classify the subpopulations of these structural ensembles on the basis of the distributions of radius of gyration and secondary structure and hydrogen-bonding features of the canonical tocin ring and disordered tail region. We then relate the structural changes observed in the unbound form of the different hormone sequences to experimental information about peptide receptor binding, and more indirectly, carrier protein binding affinity, receptor activity, and protease degradation. This study supports the hypothesis that the structural characteristics of the unbound form of an IDP can be used to predict structural or functional preferences of its functional bound form

Drawing to Remember: External Support of Older Adults’ Eyewitness Performance

Although healthy aging is accompanied by a general decline in memory functioning, environmental support at retrieval can improve older adults’ (+65 years) episodic remembering. Despite those over the age of 65years representing a growing proportion of the population, few environmental retrieval support methods have been empirically evaluated for use with older witnesses and victims of crime. Here, the efficacy of a novel retrieval technique, the Sketch Mental Reinstatement of Context, is compared with a standard Mental Reinstatement of Context and a no support control (Control). Fifty-one participants witnessed an unexpected live event, and 48 hours later were interviewed using one of three aforementioned techniques. In line with predictions emanating from cognitive theories of aging and the environmental support hypothesis, participants in the Sketch Mental Reinstatement of Context condition recalled significantly more correct information and fewer inaccurate items. The Sketch Mental Reinstatement of Context technique appears to scaffold memory retrieval in an age-appropriate manner during a post-event interview, possibly by encouraging more effortful retrieval and reducing dual-task load. As such, this procedure offers an effective alternative to current approaches, adding to the toolbox of techniques available to forensic and other interviewers

Актуальність впровадження систем газового обліку в сучасних умовах

Free energy calculation has long been an important goal for molecular dynamics simulation and force field development, but historically it has been challenged by limited performance, accuracy, and creation of topologies for arbitrary small molecules. This has made it difficult to systematically compare different sets of parameters to improve existing force fields, but in the past few years several authors have developed increasingly automated procedures to generate parameters for force fields such as Amber, CHARMM, and OPLS. Here, we present a new framework that enables fully automated generation of GROMACS topologies for any of these force fields and an automated setup for parallel adaptive optimization of high-throughput free energy calculation by adjusting lambda point placement on the fly. As a small example of this automated pipeline, we have calculated solvation free energies of 50 different small molecules using the GAFF, OPLS-AA, and CGenFF force fields and four different water models, and by including the often neglected polarization costs, we show that the common charge models are somewhat underpolarized.QC 20150505</p

Periodic venting of MABR lumen allows high removal rates and high gas-transfer efficiencies

The membrane-aerated biofilm reactor (MABR) is a novel treatment technology that employs gas-supplying membranes to deliver oxygen directly to a biofilm growing on the membrane surface. When operated with closed-end membranes, the MABR provides 100-percent oxygen transfer efficiencies (OTE), resulting in significant energy savings. However, closed-end MABRs are more sensitive to back-diffusion of inert gases, such as nitrogen. Back-diffusion reduces the average oxygen transfer rates (OTR), consequently decreasing the average contaminant removal fluxes (J). We hypothesized that venting the membrane lumen periodically would increase the OTR and J. Using an experimental flow cell and mathematical modeling, we showed that back-diffusion gas profiles developed over relatively long timescales. Thus, very short ventings could re-establish uniform gas profiles for relatively long time periods. Using modeling, we systematically explored the effect of the venting interval (time between ventings). At moderate venting intervals, opening the membrane for 20 s every 30 min, the venting significantly increased the average OTR and J without substantially impacting the OTEs. When the interval was short enough, in this case shorter than 20 min, the OTR was actually higher than for continuous open-end operation. Our results show that periodic venting is a promising strategy to combine the advantages of open-end and closed end operation, maximizing both the OTR and OTE.Primary funding for this work was from Water Environment Research Foundation (WERF) project U2R14. Additional funding was provided by the Basque Government, partially financing Patricia Pérez, and the Spanish Ministry of Economics and Competitiveness and the European Regional Development Fund (FEDER), project “Innovative Integrated Biological Processes for Nutrients Removal (PBi2)” (CTM2012-36227)

The effect of biofilms on turbulent flow over permeable beds

Despite an increasingly large body of work advancing our understanding of flow interactions occurring at the interface of a turbulent flow overlying a permeable bed, little is known concerning how such flow may be affected by the presence of biofilms, which exist in nearly all aquatic environments. This study quantifies the effects on flow exerted by biofilms grown over experimental laboratory permeable beds until biofilm detachment, and then compares this to the residual effects after its detachment. The investigation is conducted in a flow channel by immersing two-dimensional permeable beds with idealized geometry and different porosities in order to explore different bed permeabilities. Sequences of increasingly higher flow velocity conditions, followed by lower flow, were considered to explore the effect of detachment. Measurements were performed using particle image velocimetry. The total wall shear stress and friction velocity were found to increase in the presence of pregrown biofilm, and decrease after biofilm detachment, when compared at the same pump frequency. The dimensionless Reynolds stresses, at constant pump frequency, collapsed for different bed configurations in the outer layer, while for the inner layer, the presence of biofilm led to a decrease in dimensionless Reynolds stress. Quadrant analysis shows that this decrease was primarily due to a reduction in strong Q2 contributions. These results suggest that models for flow and transport over permeable media in aquatic environments cannot neglect the role of biofilms in modifying turbulence

Energy transport in diffusive waveguides

The guiding and transport of energy, for example of electromagnetic waves underpins many technologies that have shaped modern society, ranging from long distance optical fibre telecommunications to on-chip optical processors. Traditionally, a mechanism is required that exponentially localises the waves or particles in the confinement region, e.g. total internal reflection at a boundary. We introduce a waveguiding mechanism that relies on a different origin for the exponential confinement and that arises due to the physics of diffusion. We demonstrate this concept using light and show that photon density waves can propagate as a guided mode along a core-structure embedded in a scattering, opaque material, enhancing light transmission by orders of magnitude and along non-trivial, e.g. curved trajectories. This waveguiding mechanism can also occur naturally, for example in the cerebral spinal fluid surrounding the brain, along tendons in the human body and is to be expected in other systems that follow the same physics e.g. neutron diffusion