Range and strength of mechanical interactions of force dipoles in elastic fiber networks.

Mechanical forces generated by myosin II molecular motors drive diverse cellular processes, most notably shape change, division and locomotion. These forces may be transmitted over long range through the cytoskeletal medium - a disordered, viscoelastic network of biopolymers. The resulting cell size scale force chains can in principle mediate mechanical interactions between distant actomyosin units, leading to self-organized structural order in the cell cytoskeleton.

Optimal foraging strategies for mutually avoiding competitors.

Many animals are known to exhibit foraging patterns where the distances they travel in a given direction are drawn from a heavy-tailed Lévy distribution. Previous studies have shown that, under sparse and random resource conditions, solitary non-destructive (with regenerating resources) foragers perform a maximally efficient search with Lévy exponent μ equal to 2, while for destructive foragers, efficiency decreases with μ monotonically and there is no optimal μ. However, in nature, there also exist situations where multiple foragers, displaying avoidance behavior, interact with each other competitively.

Vertical Fracture of the Odontoid Process.

Fractures of the odontoid process of the axis usually occur transversely at the neck or base of the odontoid, are often displaced, and frequently require surgical fixation. Sagittal or coronal fractures are uncommon and can best be visualized on coronal or sagittal reconstruction of CT scans. Routine radiographs may not allow precise diagnosis.

Intranasal GSK2245035, a Toll-like receptor 7 agonist, does not attenuate the allergen-induced asthmatic response in a randomized, double-blind, placebo-controlled experimental medicine study.

Background: Allergic asthma is a heterogenous disorder predominantly driven by a type 2 inflammatory response to aeroallergens. Therapeutic modulation to rebalance these type 2 responses may offer clinical benefit for allergic respiratory inflammatory diseases, with the potential for disease modification. GSK2245035, a selective toll-like receptor-7 agonist, preferentially stimulates the induction of type 1 interferon alpha, reducing type 2 responses.

Chiral twisting in a bacterial cytoskeletal polymer affects filament size and orientation.

In many rod-shaped bacteria, the actin homolog MreB directs cell-wall insertion and maintains cell shape, but it remains unclear how structural changes to MreB affect its organization in vivo. Here, we perform molecular dynamics simulations for Caulobacter crescentus MreB to extract mechanical parameters for inputs into a coarse-grained biophysical polymer model that successfully predicts MreB filament properties in vivo. Our analyses indicate that MreB double protofilaments can exhibit left-handed twisting that is dependent on the bound nucleotide and membrane binding; the degree of twisting correlates with the length and orientation of MreB filaments observed in vitro and in vivo.

Membrane mediated motor kinetics in microtubule gliding assays.

Motor-based transport mechanisms are critical for a wide range of eukaryotic cell functions, including the transport of vesicle cargos over long distances. Our understanding of the factors that control and regulate motors when bound to a lipid substrate is however incomplete. We used microtubule gliding assays on a lipid bilayer substrate to investigate the role of membrane diffusion in kinesin-1 on/off binding kinetics and thereby transport velocity.

Cargo diffusion shortens single-kinesin runs at low viscous drag.

Molecular motors such as kinesin-1 drive active, long-range transport of cargos along microtubules in cells. Thermal diffusion of the cargo can impose a randomly directed, fluctuating mechanical load on the motor carrying the cargo. Recent experiments highlighted a strong asymmetry in the sensitivity of single-kinesin run length to load direction, raising the intriguing possibility that cargo diffusion may non-trivially influence motor run length.

The inflammasome adapter ASC assembles into filaments with integral participation of its two Death Domains, PYD and CARD.

The inflammasome is a multiprotein complex necessary for the onset of inflammation. The adapter protein ASC assembles inflammasome components by acting as a molecular glue between danger-signal sensors and procaspase-1. The assembly is mediated by ASC self-association and protein interactions via its two Death Domains, PYD and CARD.

Microvascular Brainstem Ischemia After Vestibular Schwannoma Surgery: A Clinical and Microanatomic Study.

Objective: To identify a potential microvascular etiology in patients who underwent vestibular schwannoma surgery (VSS) complicated by postoperative microvascular brainstem ischemia.

Methods: Charts were retrospectively reviewed of all patients who had an MRI within 14 days of VSS in years 2005-2016. Patient characteristics, preoperative and postoperative imaging features, clinical course and potential predictors of brainstem ischemia were recorded.

Plasmon-actuated nano-assembled microshells.

We present three-dimensional microshells formed by self-assembly of densely-packed 5 nm gold nanoparticles (AuNPs). Surface functionalization of the AuNPs with custom-designed mesogenic molecules drives the formation of a stable and rigid shell wall, and these unique structures allow encapsulation of cargo that can be contained, virtually leakage-free, over several months. Further, by leveraging the plasmonic response of AuNPs, we can rupture the microshells using optical excitation with ultralow power (<2 mW), controllably and rapidly releasing the encapsulated contents in less than 5 s.

Safety and pharmacodynamics of intranasal GSK2245035, a TLR7 agonist for allergic rhinitis: A randomized trial.

Background: Toll-like receptor 7 (TLR7) stimulation in the airways may reduce responses to aeroallergens by induction of type 1 interferons (IFNs). GSK2245035 is a novel selective TLR7 agonist in pharmaceutical development.

Objective: Assessment of safety, pharmacodynamics and nasal allergic reactivity following repeated weekly intranasal (i.

Shape Selection of Surface-Bound Helical Filaments: Biopolymers on Curved Membranes.

Motivated to understand the behavior of biological filaments interacting with membranes of various types, we employ a theoretical model for the shape and thermodynamics of intrinsically helical filaments bound to curved membranes. We show that filament-surface interactions lead to a host of nonuniform shape equilibria, in which filaments progressively unwind from their native twist with increasing surface interaction and surface curvature, ultimately adopting uniform-contact curved shapes. The latter effect is due to nonlinear coupling between elastic twist and bending of filaments on anisotropically curved surfaces such as the cylindrical surfaces considered here.

Self-organized sorting limits behavioral variability in swarms.

Swarming is a phenomenon where collective motion arises from simple local interactions between typically identical individuals. Here, we investigate the effects of variability in behavior among the agents in finite swarms with both alignment and cohesive interactions. We show that swarming is abolished above a critical fraction of non-aligners who do not participate in alignment.

Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma.

Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate.

Rigid Cluster Decomposition Reveals Criticality in Frictional Jamming.

We study the nature of the frictional jamming transition within the framework of rigidity percolation theory. Slowly sheared frictional packings are decomposed into rigid clusters and floppy regions with a generalization of the pebble game including frictional contacts. Our method suggests a second-order transition controlled by the emergence of a system-spanning rigid cluster accompanied by a critical cluster size distribution.

Cerebrospinal fluid velocity amplitudes within the cerebral aqueduct in healthy children and patients with Chiari I malformation.

Purpose: To assess the effects of cerebrospinal fluid (CSF) bidirectional motion in Chiari malformation type I (CMI), we monitored CSF velocity amplitudes on phase contrast MRI (PC-MRI) in patients before and after surgery; and in healthy volunteers.

Materials And Methods: 10 pediatric volunteers and 10 CMI patients participated in this study. CMI patients underwent PC-MRI scans before and approximately 14 months following surgery.

Interobserver Variation in Cerebellar Tonsillar Tip Localization: Comparison of 3 Different Osseous Landmarks on Magnetic Resonance Imaging.

Purpose: The aim was to evaluate the interobserver agreement in the assessment of cerebellar tonsil position on sagittal magnetic resonance imaging using 3 different osseous landmarks.

Materials And Methods: This retrospective study consisted of brain magnetic resonance imagings performed at our institution in patients with and without Chiari I malformation between January 2010 and 2012. Sagittal T1-weighted images were reviewed by 2 senior board-certified neuroradiologists (blinded to underlying clinical diagnosis) with measurement of both cerebellar tonsillar positions based on lines drawn perpendicular from the tonsillar tip to the foramen magnum [FM] line, C1 line, and C2 line.

Topologically induced swarming phase transition on a 2D percolated lattice.

The emergence of collective motion, or swarming, in groups of moving individuals who orient themselves using only information from their neighbors is a very general phenomenon that occurs at multiple spatio-temporal scales. Swarms that occur in natural environments typically have to contend with spatial disorder such as obstacles that can hinder an individual's motion or can disrupt communication with neighbors. We study swarming agents, possessing both aligning and mutually avoiding repulsive interactions, in a 2D percolated network representing a topologically disordered environment.

Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement.

Modulation of the airways' immune milieu is a key therapeutic goal for remission from respiratory allergies. To explore this hypothesis, GSK2245035, a selective Toll-like receptor 7 (TLR7) agonist with preferential Type-1 interferon (IFN)-stimulating properties, was developed for intranasal application. Doses for clinical assessment were extrapolated from translational biomarker studies in primates.

Characterisation of a K390R ITK kinase dead transgenic mouse--implications for ITK as a therapeutic target.

Interleukin-2 inducible tyrosine kinase (ITK) is expressed in T cells and plays a critical role in signalling through the T cell receptor. Evidence, mainly from knockout mice, has suggested that ITK plays a particularly important function in Th2 cells and this has prompted significant efforts to discover ITK inhibitors for the treatment of allergic disease. However, ITK is known to have functions outside of its kinase domain and in general kinase knockouts are often not good models for the behaviour of small molecule inhibitors.