Many drugs have been withdrawn from the market worldwide, at a cost of billions of dollars, because of patient fatalities due to them unexpectedly disturbing heart rhythm. Even drugs for ailments as mild as hay fever have been withdrawn due to an unacceptable increase in risk of these heart rhythm disturbances. Consequently, the whole pharmaceutical industry expends a huge effort in checking all new drugs for any unwanted side effects on the heart. The predominant root cause has been identified as drug molecules blocking ionic current flows in the heart. Block of individual types of ionic currents can now be measured experimentally at an early stage of drug development, and this is the standard screening approach for a number of ion currents in many large pharmaceutical companies. However, clinical risk is a complex function of the degree of block of many different types of cardiac ion currents, and this is difficult to understand by looking at results of these screens independently. By using ordinary differential equation models for the electrical activity of heart cells (electrophysiology models) we can integrate information from different types of currents, to predict the effect on whole heart cells and subsequent risk of side effects. The resulting simulations can provide a more accurate summary of the risk of a drug earlier in development and hence more cheaply than the pre-existing approaches.
Stochastic fluctuations of molecular abundances are a ubiquitous feature of cellular processes and lead to significant cell-to-cell variability. Recent theoretical work established lower bounds for stochastic fluctuations in cells for broad classes of cellular processes by analyzing the dynamics of reaction motifs that are embedded within a larger network with arbitrary interactions and dynamics. For example, a class of generalized assembly processes in which two co-regulated subunits irreversibly form a complex was shown to exhibit an unavoidable trade-off between assembly efficiency and subunit fluctuations: Regardless of rate constants and details of feedback control, subunit fluctuations were shown to diverge as the assembly efficiency approaches 100%. In contrast, other work has reported how efficient assembly processes work as stochastic noise filters or can achieve robust adaptation through integral control. While all of these results are technically correct their seemingly contradictory conclusions raise the question of how broadly applicable the previously reported efficiency-fluctuation trade-off is. Here, we show that a much broader class of assembly processes than previously considered is subject to an efficiency-fluctuation trade-off which diverges in the high efficiency regime. We find the proposed noise filtering property of efficient assembly processes corresponds to a singular limit of this class of systems. Additionally, we show that combining feedback control with distinct subunit synthesis rates is a necessary condition to overcome the generalized efficiency-fluctuation trade-off. Through numerical examples, we show that biomolecular integral controllers are one of several realizations of such control. How small a change to joint subunit control is sufficient to avoid diverging fluctuations in the high-efficiency limit remains an open question.
We continue to study 5d N = 1 supersymmetric field theories and their compactifications on a circle through brane configurations. We develop a model, which we call (p,q) Webs, which enables simple geometrical computations to reproduce the known results, and facilitates further study. The physical concepts of field theory are transparent in this picture, offering an interpretation for global symmetries, local symmetries, the effective (running) coupling, the Coulomb and Higgs branches, the monopole tensions, and the mass of BPS particles. A rule for the dimension of the Coulomb branch is found by introducing Grid Diagrams. Some known classifications of field theories are reproduced. In addition to the study of the vacuum manifold we develop methods to determine the BPS spectrum. Some states, such as quarks, correspond to instantons inside the 5-brane which we call strips. In general, these may not be identified with (p,q) strings. We describe how a strip can bend out of a 5-brane, becoming a string. A general BPS state corresponds to a Web of strings and strips. For special values of the string coupling a few strips can combine and leave the 5-brane as a string.
Lukas Spantzel, Iván Pérez, Thomas Heitkamp
et al.
The human neurotensin receptor 1 (NTSR1) is a G protein-coupled receptor. The receptor is activated by a small peptide ligand neurotensin. NTSR1 can be expressed in HEK cells by stable transfection. Previously we used the fluorescent protein markers mRuby3 or mNeonGreen fused to NTSR1 for EMCCD-based structured illumination microscopy (SIM) in living HEK cells. Ligand binding induced conformational changes in NTSR1 which triggered the intracellular signaling processes. Recent single-molecule studies revealed a dynamic monomer/dimer equilibrium of this receptor in artificial lipid bilayers. Here we report on the oligomerization state of human NTSR1 from living cells by trapping them into lipid nanodiscs. Briefly, SMALPs (styrene-maleic acid copolymer lipid nanoparticles) were produced directly from the plasma membranes of living HEK293T FlpIn cells. SMALPs with a diameter of 15 nm were soluble and stable. NTSR1 in SMALPs were analyzed by single-molecule intensity measurements one membrane patch at a time using a custom-built confocal anti-Brownian electrokinetic trap (ABEL trap) microscope. We found oligomerization changes before and after stimulation of the receptor with its ligand neurotensin.
We describe the polarization topology of the vector beams emerging from a patterned birefringent liquid crystal plate with a topological charge q at its center (q-plate). The polarization topological structures for different q-plates and different input polarization states have been studied experimentally by measuring the Stokes parameters point-by-point in the beam transverse plane. Furthermore, we used a tuned q=1/2-plate to generate cylindrical vector beams with radial or azimuthal polarizations, with the possibility of switching dynamically between these two cases by simply changing the linear polarization of the input beam.
Diseased conditions are a consequence of some abnormality that are associated with clinical conditions in numerous cells and tissues affecting various organs. The common role of EBV (Epstein-Barr virus) in causing infectious mononucleosis (IM) affecting B-cells and epithelial cells and the development of EBV-associated cancers has been an area of active research. Investigating such significant interactions may help discover new therapeutic targets for certain EBV-associated lymphoproliferative (Burkitt's Lymphoma and Hodgkin's Lymphoma) and non-lymphoproliferative diseases (Gastric cancer and Nasopharyngeal cancer). Based on the DisGeNET (v7.0) data set, we constructed a disease-gene network bipartite graph to identify genes that are involved in various carcinomas namely, gastric cancer (GC), nasopharyngeal cancer (NPC), Hodgkin's lymphoma (HL) and Burkitt's lymphoma (BL). Using the community detection algorithm (Louvain method), we identified communities followed by functional enrichment using over-representation analysis methodology. In this study, we identified the modular communities to explore the relation of this common causative pathogen (EBV) with different carcinomas such as GC, NPC, HL and BL. We could identify the top 10 genes as CASP10, BRAF, NFKBIA, IFNA2, GSTP1, CSF3, GATA3, UBR5, AXIN2 and POLE based on their degree of distribution. Further over-representation analysis showed that the ABL1 gene was significantly over-represented in 3 out of 9 critical biological processes. As a result, we can infer that the EBV pathogen is selective in targeting critical pathways to bring about cellular growth arrest/apoptosis and interfering with vital biological processes, including the TP53 network of genes that leads to further proliferation of damage to vital cellular activities.
A general model is presented for coupling of high-Q whispering-gallery modes in optical microsphere resonators with coupler devices that possess a discrete and continuous spectrum of propagating modes. By contrast to conventional high-Q optical cavities, in microspheres the independence of high intrinsic quality-factor and controllable parameters of coupling via an evanescent field offer a variety of regimes similar to those that are already available in rf devices. The theory is applied to data reported earlier on different types of couplers to microsphere resonators and is complemented by the experimental demonstration of enhanced coupling efficiency (∼80%) and variable loading regimes with Q>108 fused-silica microspheres.
Maintenance of epidermal thickness is critical to the barrier function of the skin. Decreased tissue thickness, specifically in the stratum corneum (the outermost layer of the tissue), causes discomfort and inflammation, and is related to several severe diseases of the tissue. In order to maintain both stratum corneum thickness and overall tissue thickness it is necessary for the system to balance cell proliferation and cell loss. Cell proliferation in the epidermis occurs in the basal layer and causes constant upwards movement in the tissue. Cell loss occurs when dead cells at the top of the tissue are lost to the environment through a process called desquamation. Desquamation is thought to occur through a gradual reduction in adhesion between cells, due to the cleaving of adhesion proteins by enzymes, in the stratum corneum. In this paper we will investigate combining a (mass action) subcellular model of desquamation with a three dimensional (cell centre based) multicellular model of the interfollicular epidermis to better understand maintenance of epidermal thickness. These investigations show that hypothesised biological models for the degradation of cell-cell adhesion from the literature are able to provide a consistent rate of cell loss in the multicellular model. This loss balances proliferation, and hence maintains a homeostatic tissue thickness. Moreover, we find that multiple proliferative cell populations in the basal layer can be represented by a single proliferative cell population, simplifying investigations with this model. The model is used to investigate a disorder (Netherton Syndrome) which disrupts desquamation. The model shows how biochemical changes can cause disruptions to the tissue, resulting in a reduced tissue thickness and consequently diminishing the protective role of the tissue. A hypothetical treatment result is also investigated. [ABR]