Joint geodetic and seismic analysis of surface crevassing near a seasonal glacier-dammed lake at Gornergletscher, Switzerland

Seasonal lake Gornersee forms at the confluence of Gornergletscher and Grenzgletscher, Switzerland, and experiences outburst floods annually in midsummer. To study the interplay between lake drainage, glacier movement and crevasse activity, high-frequency seismometers and GPS receivers were deployed in networks near Gornersee during the summer ablation seasons of 2004, 2006 and 2007. We use a Rayleigh wave coherence method to locate 3289, 7939 and 4087 icequakes, respectively, primarily along well-defined surface crevasses. We calculate two-dimensional strains from triads of GPS stations and find mean differential strain rates of similar to 300 x 10(-6) d(-1) with diurnal variations up to 800 x 10(-6) d(-1). Crevasse icequake activity and glacial velocity are highest during early season, then decrease as meltwater channels erode and subglacial water pressure decreases. Glacial response to Gornersee drainage varied year-to-year, with icequake activity promoted at some crevasses and inhibited at others, suggesting syn-drainage icequakes may be indicative of local drainage patterns and small-scale features of the stress field. Diurnal pulses in icequake activity exhibit peak activity at different times of day in different locations, coincident with a southeast-to-northwest trending concentrated shear zone near the Gornergletscher-Grenzgletscher confluence, likely due to differences in the timing of peak strain rate in these regions

Computational Modeling for the Activation Cycle of G-proteins by G-protein-coupled Receptors

In this paper, we survey five different computational modeling methods. For comparison, we use the activation cycle of G-proteins that regulate cellular signaling events downstream of G-protein-coupled receptors (GPCRs) as a driving example. Starting from an existing Ordinary Differential Equations (ODEs) model, we implement the G-protein cycle in the stochastic Pi-calculus using SPiM, as Petri-nets using Cell Illustrator, in the Kappa Language using Cellucidate, and in Bio-PEPA using the Bio-PEPA eclipse plug in. We also provide a high-level notation to abstract away from communication primitives that may be unfamiliar to the average biologist, and we show how to translate high-level programs into stochastic Pi-calculus processes and chemical reactions.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

β-Arrestin Based Receptor Signaling Paradigms: Potential Therapeutic Targets for Complex Age-Related Disorders

G protein coupled receptors (GPCRs) were first characterized as signal transducers that elicit downstream effects through modulation of guanine (G) nucleotide-binding proteins. The pharmacotherapeutic exploitation of this signaling paradigm has created a drug-based field covering nearly 50% of the current pharmacopeia. Since the groundbreaking discoveries of the late 1990s to the present day, it is now clear however that GPCRs can also generate productive signaling cascades through the modulation of β-arrestin functionality. β-Arrestins were first thought to only regulate receptor desensitization and internalization – exemplified by the action of visual arrestin with respect to rhodopsin desensitization. Nearly 20 years ago, it was found that rather than controlling GPCR signal termination, productive β-arrestin dependent GPCR signaling paradigms were highly dependent on multi-protein complex formation and generated long-lasting cellular effects, in contrast to G protein signaling which is transient and functions through soluble second messenger systems. β-Arrestin signaling was then first shown to activate mitogen activated protein kinase signaling in a G protein-independent manner and eventually initiate protein transcription – thus controlling expression patterns of downstream proteins. While the possibility of developing β-arrestin biased or functionally selective ligands is now being investigated, no additional research has been performed on its possible contextual specificity in treating age-related disorders. The ability of β-arrestin-dependent signaling to control complex and multidimensional protein expression patterns makes this therapeutic strategy feasible, as treating complex age-related disorders will likely require therapeutics that can exert network-level efficacy profiles. It is our understanding that therapeutically targeting G protein-independent effectors such as β-arrestin will aid in the development of precision medicines with tailored efficacy profiles for disease/age-specific contextualities

Fulfilling the promise of "biased" G protein-coupled receptor agonism

The fact that over 30% of current pharmaceuticals target heptahelical G protein–coupled receptors (GPCRs) attests to their tractability as drug targets. Although GPCR drug development has traditionally focused on conventional agonists and antagonists, the growing appreciation that GPCRs mediate physiologically relevant effects via both G protein and non–G protein effectors has prompted the search for ligands that can "bias" downstream signaling in favor of one or the other process. Biased ligands are novel entities with distinct signaling profiles dictated by ligand structure, and the potential prospect of biased ligands as better drugs has been pleonastically proclaimed. Indeed, preclinical proof-of-concept studies have demonstrated that both G protein and arrestin pathway-selective ligands can promote beneficial effects in vivo while simultaneously antagonizing deleterious ones. But along with opportunity comes added complexity and new challenges for drug discovery. If ligands can be biased, then ligand classification becomes assay dependent, and more nuanced screening approaches are needed to capture ligand efficacy across several dimensions of signaling. Moreover, because the signaling repertoire of biased ligands differs from that of the native agonist, unpredicted responses may arise in vivo as these unbalanced signals propagate. For any given GPCR target, establishing a framework relating in vitro efficacy to in vivo biologic response is crucial to biased drug discovery. This review discusses approaches to describing ligand efficacy in vitro, translating ligand bias into biologic response, and developing a systems-level understanding of biased agonism in vivo, with the overall goal of overcoming current barriers to developing biased GPCR therapeutics