Receptor activity-modifying protein-dependent effects of mutations in the calcitonin receptor-like receptor:implications for adrenomedullin and calcitonin gene-related peptide pharmacology

Background and Purpose Receptor activity-modifying proteins (RAMPs) define the pharmacology of the calcitonin receptor-like receptor (CLR). The interactions of the different RAMPs with this class B GPCR yield high-affinity calcitonin gene-related peptide (CGRP) or adrenomedullin (AM) receptors. However, the mechanism for this is unclear. Experimental Approach Guided by receptor models, we mutated residues in the N-terminal helix of CLR, RAMP2 and RAMP3 hypothesized to be involved in peptide interactions. These were assayed for cAMP production with AM, AM2 and CGRP together with their cell surface expression. Binding studies were also conducted for selected mutants. Key Results An important domain for peptide interactions on CLR from I32 to I52 was defined. Although I41 was universally important for binding and receptor function, the role of other residues depended on both ligand and RAMP. Peptide binding to CLR/RAMP3 involved a more restricted range of residues than that to CLR/RAMP1 or CLR/RAMP2. E101 of RAMP2 had a major role in AM interactions, and F111/W84 of RAMP2/3 was important with each peptide. Conclusions and Implications RAMP-dependent effects of CLR mutations suggest that the different RAMPs control accessibility of peptides to binding residues situated on the CLR N-terminus. RAMP3 appears to alter the role of specific residues at the CLR-RAMP interface compared with RAMP1 and RAMP2

Multiscale Bone Remodelling with Spatial P Systems

Many biological phenomena are inherently multiscale, i.e. they are characterized by interactions involving different spatial and temporal scales simultaneously. Though several approaches have been proposed to provide "multilayer" models, only Complex Automata, derived from Cellular Automata, naturally embed spatial information and realize multiscaling with well-established inter-scale integration schemas. Spatial P systems, a variant of P systems in which a more geometric concept of space has been added, have several characteristics in common with Cellular Automata. We propose such a formalism as a basis to rephrase the Complex Automata multiscaling approach and, in this perspective, provide a 2-scale Spatial P system describing bone remodelling. The proposed model not only results to be highly faithful and expressive in a multiscale scenario, but also highlights the need of a deep and formal expressiveness study involving Complex Automata, Spatial P systems and other promising multiscale approaches, such as our shape-based one already resulted to be highly faithful.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

Magnetic-interference patterns in Josephson junctions with d+is symmetry

The magnetic interference pattern and the spontaneous flux in unconventional Josephson junctions of superconductors with d+is symmetry are calculated for different reduced junction lengths and the relative factor of the d and s wave components. This is a time reversal broken symmetry state. We study the stability of the fractional vortex and antivortex which are spontaneously formed and examine their evolution as we change the length and the relative factor of d and s wave components. The asymmetry in the field modulated diffraction pattern exists for lengths as long as L=10\lambda_J.Comment: 8 pages, 6 eps files, submitted to PR

Can forest management based on natural disturbances maintain ecological resilience?

Given the increasingly global stresses on forests, many ecologists argue that managers must maintain ecological resilience: the capacity of ecosystems to absorb disturbances without undergoing fundamental change. In this review we ask: Can the emerging paradigm of natural-disturbance-based management (NDBM) maintain ecological resilience in managed forests? Applying resilience theory requires careful articulation of the ecosystem state under consideration, the disturbances and stresses that affect the persistence of possible alternative states, and the spatial and temporal scales of management relevance. Implementing NDBM while maintaining resilience means recognizing that (i) biodiversity is important for long-term ecosystem persistence, (ii) natural disturbances play a critical role as a generator of structural and compositional heterogeneity at multiple scales, and (iii) traditional management tends to produce forests more homogeneous than those disturbed naturally and increases the likelihood of unexpected catastrophic change by constraining variation of key environmental processes. NDBM may maintain resilience if silvicultural strategies retain the structures and processes that perpetuate desired states while reducing those that enhance resilience of undesirable states. Such strategies require an understanding of harvesting impacts on slow ecosystem processes, such as seed-bank or nutrient dynamics, which in the long term can lead to ecological surprises by altering the forest's capacity to reorganize after disturbance

Shared Care, Elder and Family Member Skills Used to Manage Burden

Aim. The aim of this paper is to further develop the construct of Shared Care by comparing and contrasting it to related research, and to show how the construct can be used to guide research and practice. Background. While researchers have identified negative outcomes for family caregivers caused by providing care, less is known about positive aspects of family care for both members of a family dyad. Understanding family care relationships is important to nurses because family participation in the care of chronically ill elders is necessary to achieve optimal outcomes from nursing interventions. A previous naturalistic inquiry identified a new construct, Shared Care, which was used to describe a family care interaction that contributed to positive care outcomes. Methods. A literature review was carried out using the databases Medline, CINAHL, and Psych-info and the keywords home care, care receiver, disability, family, communication, decision-making and reciprocity. The results of the review were integrated to suggest how Shared Care could be used to study care difficulties and guide interventions. Results. The literature confirmed the importance of dyad relationships in family care. Shared Care extended previous conceptualizations of family care by capturing three critical components: communication, decision-making, and reciprocity. Shared Care provides a structure to expand the conceptualization of family care to include both members of a care dyad and account for positive and negative aspects of care. Conclusions. The extended view provided by the construct of Shared Care offers practitioners and scholars tools to use in the context of our ageing population to improve the effectiveness of family care relationships

Entanglement preparation using symmetric multiports

We investigate the entanglement produced by a multi-path interferometer that is composed of two symmetric multiports, with phase shifts applied to the output of the first multiport. Particular attention is paid to the case when we have a single photon entering the interferometer. For this situation we derive a simple condition that characterize the types of entanglement that one can generate. We then show how one can use the results from the single photon case to determine what kinds of multi-photon entangled states one can prepare using the interferometer.Comment: 6 pages, 2 figures, accepted for publication in European Journal of Physics

Entanglement preparation using symmetric multiports

We investigate the entanglement produced by a multi-path interferometer that is composed of two symmetric multiports, with phase shifts applied to the output of the first multiport. Particular attention is paid to the case when we have a single photon entering the interferometer. For this situation we derive a simple condition that characterize the types of entanglement that one can generate. We then show how one can use the results from the single photon case to determine what kinds of multi-photon entangled states one can prepare using the interferometer.Comment: 6 pages, 2 figures, accepted for publication in European Journal of Physics

Confined granular packings: structure, stress, and forces

The structure and stresses of static granular packs in cylindrical containers are studied using large-scale discrete element molecular dynamics simulations in three dimensions. We generate packings by both pouring and sedimentation and examine how the final state depends on the method of construction. The vertical stress becomes depth-independent for deep piles and we compare these stress depth-profiles to the classical Janssen theory. The majority of the tangential forces for particle-wall contacts are found to be close to the Coulomb failure criterion, in agreement with the theory of Janssen, while particle-particle contacts in the bulk are far from the Coulomb criterion. In addition, we show that a linear hydrostatic-like region at the top of the packings unexplained by the Janssen theory arises because most of the particle-wall tangential forces in this region are far from the Coulomb yield criterion. The distributions of particle-particle and particle-wall contact forces $P(f)$ exhibit exponential-like decay at large forces in agreement with previous studies.Comment: 11 pages, 11 figures, submitted to PRE (v2) added new references, fixed typo

Cost and cost‐effectiveness of a simplified treatment model with direct‐acting antivirals for chronic hepatitis C in Cambodia

Background & Aims In 2016, Médecins Sans Frontières established the first general population Hepatitis C virus (HCV) screening and treatment site in Cambodia, offering free direct‐acting antiviral (DAA) treatment. This study analysed the cost‐effectiveness of this intervention. Methods Costs, quality adjusted life years (QALYs) and cost‐effectiveness of the intervention were projected with a Markov model over a lifetime horizon, discounted at 3%/year. Patient‐level resource‐use and outcome data, treatment costs, costs of HCV‐related healthcare and EQ‐5D‐5L health states were collected from an observational cohort study evaluating the effectiveness of DAA treatment under full and simplified models of care compared to no treatment; other model parameters were derived from literature. Incremental cost‐effectiveness ratios (cost/QALY gained) were compared to an opportunity cost‐based willingness‐to‐pay threshold for Cambodia ($248/QALY). Results The total cost of testing and treatment per patient for the full model of care was$925(IQR $668‐1631), reducing to$376(IQR $344‐422) for the simplified model of care. EQ‐5D‐5L values varied by fibrosis stage: decompensated cirrhosis had the lowest value, values increased during and following treatment. The simplified model of care was cost saving compared to no treatment, while the full model of care, although cost‐effective compared to no treatment ($187/QALY), cost an additional $14 485/QALY compared to the simplified model, above the willingness‐to‐pay threshold for Cambodia. This result is robust to variation in parameters. Conclusions The simplified model of care was cost saving compared to no treatment, emphasizing the importance of simplifying pathways of care for improving access to HCV treatment in low‐resource settings

Peripheral NF-κB dysregulation in people with schizophrenia drives inflammation: putative anti-inflammatory functions of NF-κB kinases

Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined 'high inflammation' individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying 'high inflammation' compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.Caitlin E. Murphy, Adam K. Walker, Maryanne O, Donnell, Cherrie Galletly, Andrew R. Lloyd, Dennis Liu, Cynthia Shannon Weickert, and Thomas W. Weicker