Type 1 ryanodine receptor interactions

Excitation-contraction coupling is an essential part of skeletal muscle contraction. It encompasses the sensing of depolarisation of the plasma membrane coupled with the release of Ca2+ from intracellular stores. The channel responsible for this release is called the Ryanodine receptor (RyR), and forms a hub of interacting proteins which work in concert to regulate the release of Ca2+ through this channel. The aim of this work was to characterise possible novel interactions with a proline-rich region of the RyR1, to characterise a monoclonal antibody (mAb VF1c) raised against a junctional sarcoplasmic reticulum protein postulated to interact with RyR1, and to characterise the protein recognised by this antibody in models of skeletal muscle disease such as Duchenne Muscular dystrophy (DMD) and sarcopenia. These experiments were performed using cell culture, protein purification via immunoprecipitation, affinity purification, low pressure chromatography and western blotting techniques. It was found that the RyR1 complex isolated from rat skeletal muscle co-purifies with the Growth factor receptor bound protein 2 (GRB2), very possibly via an interaction between the proline rich region of RyR1 and one of the SH3 domains located on the GRB2 protein. It was also found that Pleiotrophin and Phospholipase Cγ1, suggested interactors of the proline rich region of RyR1, did not co-purify with the RyR1 complex. Characterisation of mAb VF1c determined that this monoclonal antibody interacts with junctophilin 1, and binds to this protein between the region of 369-460, as determined by western blotting of JPH1 fragments expressed in yeast. It was also found that JPH1 and JPH2 are differentially regulated in different muscles of rabbit, where the highest amount of both proteins was found in the extensor digitorum longus (EDL) muscle. JPH1 and 2 levels were also examined in three rodent models of disease: the mdx mouse (a model of DMD), chronic intermittent hypoxia (CIH)-treated rat, and aged and adult mice, a model of sarcopenia. In the EDL and soleus muscle of CIH treated rats, no difference in either JPH1 or JPH2 abundance was detected in either muscle. An examination of JPH1 and 2 expression in mdx and wild type controls diaphragm, vastus lateralis, soleus and gastrocnemius muscle found no major differences in JPH1 abundance, while JPH2 was decreased in mdx gastrocnemius compared to wild type. In a mouse model of sarcopenia, JPH1 abundance was found to be increased in aged soleus but not in aged quadriceps, while in exercised quadriceps, JPH2 abundance was decreased compared to unexercised controls. Taken together, these results have implications for the regulation of RyR1 and JPH1 and 2 in skeletal muscle in both physiological and pathological states, and provide a newly characterised antibody to expand the field of JPH1 research.

The emerging ASEAN approach to mutual recognition : a comparison with Europe, trans-Tasman, and North America

Existing studies on mutual recognition agreements (MRAs) are mostly based on the European experience. In this paper, we will examine the ongoing attempts to establish a mutual recognition architecture in the Association of Southeast Asian Nations (ASEAN) and seek to explain the region's unique approach to MRAs, which can be classified as a "hub and spoke" model of mutual recognition. On one hand, ASEAN is attempting to establish a quasi-supranational ASEAN-level mechanism to confer "ASEAN qualification" effective in the entire ASEAN region. On the other hand, ASEAN MRAs respect members' national sovereignty, and it is national authorities, not ASEAN institutions, who have the ultimate power to approve or disapprove the supply of services by ASEAN qualification holders. Such a mixed approach to mutual recognition can be best understood as a centralized mechanism for learning-by-doing, rather than centralized recognition per se.

Molecular mechanism of activation-triggered subunit exchange in Ca(2+)/calmodulin-dependent protein kinase II.

Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.

Molecular mechanism of activation-triggered subunit exchange in Ca(2+)/calmodulin-dependent protein kinase II.

Activation triggers the exchange of subunits in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.

GIS technologies and spatial organization patterns among hunter-gatherers: an archaeological case study from Southern Patagonia (southern South America)

This paper discusses some aspects of hunter-gatherer spatial organization in southern South Patagonia, in later times to 10,000 cal yr BP. Various methods of spatial analysis, elaborated with a Geographic Information System (GIS) were applied to the distributional pattern of archaeological sites with radiocarbon dates. The shift in the distributional pattern of chronological information was assessed in conjunction with other lines of evidence within a biogeographic framework. Accordingly, the varying degrees of occupation and integration of coastal and interior spaces in human spatial organization are explained in association with the adaptive strategies hunter-gatherers have used over time. Both are part of the same human response to changes in risk and uncertainty variability in the region in terms of resource availability and environmental dynamics.

Task sharing within a managed clinical network to improve child health in Malawi

BACKGROUND: Eighty per cent of Malawi's 8 million children live in rural areas, and there is an extensive tiered health system infrastructure from village health clinics to district hospitals which refers patients to one of the four central hospitals. The clinics and district hospitals are staffed by nurses, non-physician clinicians and recently qualified doctors. There are 16 paediatric specialists working in two of the four central hospitals which serve the urban population as well as accepting referrals from district hospitals. In order to provide expert paediatric care as close to home as possible, we describe our plan to task share within a managed clinical network and our hypothesis that this will improve paediatric care and child health.

PRESENTATION OF THE HYPOTHESIS: Managed clinical networks have been found to improve equity of care in rural districts and to ensure that the correct care is provided as close to home as possible. A network for paediatric care in Malawi with mentoring of non-physician clinicians based in a district hospital by paediatricians based at the central hospitals will establish and sustain clinical referral pathways in both directions. Ultimately, the plan envisages four managed paediatric clinical networks, each radiating from one of Malawi's four central hospitals and covering the entire country. This model of task sharing within four hub-and-spoke networks may facilitate wider dissemination of scarce expertise and improve child healthcare in Malawi close to the child's home.

TESTING THE HYPOTHESIS: Funding has been secured to train sufficient personnel to staff all central and district hospitals in Malawi with teams of paediatric specialists in the central hospitals and specialist non-physician clinicians in each government district hospital. The hypothesis will be tested using a natural experiment model. Data routinely collected by the Ministry of Health will be corroborated at the district. This will include case fatality rates for common childhood illness, perinatal mortality and process indicators. Data from different districts will be compared at baseline and annually until 2020 as the specialists of both cadres take up posts.

IMPLICATIONS OF THE HYPOTHESIS: If a managed clinical network improves child healthcare in Malawi, it may be a potential model for the other countries in sub-Saharan Africa with similar cadres in their healthcare system and face similar challenges in terms of scarcity of specialists.

A state-of-the-art review and feasibility analysis of high altitude wind power in Northern Ireland

In many countries wind energy has become an indispensable part of the electricity generation mix. The opportunity for ground based wind turbine systems are becoming more and more constrained due to limitations on turbine hub heights, blade lengths and location restrictions linked to environmental and permitting issues including special areas of conservation and social acceptance due to the visual and noise impacts. In the last decade there have been numerous proposals to harness high altitude winds, such as tethered kites, airfoils and dirigible based rotors. These technologies are designed to operate above the neutral atmospheric boundary layer of 1,300 m, which are subject to more powerful and persistent winds thus generating much higher electricity capacities. This paper presents an in-depth review of the state-of-the-art of high altitude wind power, evaluates the technical and economic viability of deploying high altitude wind power as a resource in Northern Ireland and identifies the optimal locations through considering wind data and geographical constraints. The key findings show that the total viable area over Northern Ireland for high altitude wind harnessing devices is 5109.6 km2, with an average wind power density of 1,998 W/m2 over a 20-year span, at a fixed altitude of 3,000 m. An initial budget for a 2MW pumping kite device indicated a total cost £1,751,402 thus proving to be economically viable with other conventional wind-harnessing devices.

Optimal day-ahead scheduling of integrated urban energy systems

An optimal day-ahead scheduling method (ODSM) for the integrated urban energy system (IUES) is introduced, which considers the reconfigurable capability of an electric distribution network. The hourly topology of a distribution network, a natural gas network, the energy centers including the combined heat and power (CHP) units, different energy conversion devices and demand responsive loads (DRLs), are optimized to minimize the day-ahead operation cost of the IUES. The hourly reconfigurable capability of the electric distribution network utilizing remotely controlled switches (RCSs) is explored and discussed. The operational constraints from the unbalanced three-phase electric distribution network, the natural gas network, and the energy centers are considered. The interactions between the electric distribution network and the natural gas network take place through conversion of energy among different energy vectors in the energy centers. An energy conversion analysis model for the energy center was developed based on the energy hub model. A hybrid optimization method based on genetic algorithm (GA) and a nonlinear interior point method (IPM) is utilized to solve the ODSM model. Numerical studies demonstrate that the proposed ODSM is able to provide the IUES with an effective and economical day-ahead scheduling scheme and reduce the operational cost of the IUES.

Integrated Optimal Power Flow for Distribution Networks in Local and Urban Scales

This paper develops an integrated optimal power flow (OPF) tool for distribution networks in two spatial scales. In the local scale, the distribution network, the natural gas network, and the heat system are coordinated as a microgrid. In the urban scale, the impact of natural gas network is considered as constraints for the distribution network operation. The proposed approach incorporates unbalance three-phase electrical systems, natural gas systems, and combined cooling, heating, and power systems. The interactions among the above three energy systems are described by energy hub model combined with components capacity constraints. In order to efficiently accommodate the nonlinear constraint optimization problem, particle swarm optimization algorithm is employed to set the control variables in the OPF problem. Numerical studies indicate that by using the OPF method, the distribution network can be economically operated. Also, the tie-line power can be effectively managed.

At the dawn of Italo-Chinese modern relations: Ludovico Nocentini's experience

In 1904 Ludovico Nocentini described China as a hub of colonial and commercial development for European powers. Europe in the Far East and the Italian Interests in China was Nocentini’s last and most critical book, in which he compared the performance of the Italian government with that of other countries and showed Rome’s inefficiency overseas. The book expatiated on the “carving up” of China into spheres of influence by the Western powers, while examining how the Italian government’s scant regard for the definition and pursuit of the country’s national interest jeopardized not only the development of its colonial policy, but also its foreign trade and industrial progress.

‘Article 16’ Provision, Commentary on the Law of the International Criminal Court

The Commentary on the Law of the International Criminal Court provides an online provision-by-provision analysis of the Rome Statute and the Rules of Procedure and Evidence of the International Criminal Court.

British economic growth 1270-1870

This is a definitive new account of Britain's economic evolution from a backwater of Europe in 1270 to the hub of the global economy in 1870. For the first time Britain's national accounts are reconstructed right back into the thirteenth century to show what really happened quantitatively during the centuries leading up to the Industrial Revolution. Contrary to traditional views of the earlier period as one of Malthusian stagnation, they reveal how the transition to modern economic growth built on the earlier foundations of a persistent upward trend in GDP per capita which doubled between 1270 and 1700. Featuring comprehensive estimates of population, land use, agricultural production, industrial and service-sector production and GDP per capita, as well as analysis of their implications, this is an essential reference work for those interest in British economic history and the origins of modern economic growth more generally.

Jaquard Laquer

In 2010 Avella worked with the Yves St Laurent (YSL) textiles research team to find elements for a coating that could be applied to weave surfaces in the form of a ‘laquer’ finish. Working with industrial chemists, Avella designed a Jaquard weave pattern to function as substrate for this laquer coating. Successfully used to make womenswear with a high gloss finish, this textile was patented before being displayed in 2010 and much imitated in other collections. Continuing this research for the following collection Avella pursued experiments in laboratory-based industrial chemistry to find a liquid coating that could, like ‘laquer’, be applied as a surface finish to textiles. The resulting metallic iridescent surface was first used in the 20?? Collection (Intellectual Property YSL). Whilst the culture of neophilia in Womenswear fashion at YSL demands permanent innovation for stylistic rather than functional reasons, the innovations in the surface coatings of textiles has potential instrumentality which Avella brings to the resources of the RCA Materials For Living Research Hub and its Inspiring Matter Biennial Conference (2012). Cross disciplinary knowledge transfer between design practices is fundamental to research as process in the School of Material, and textile, as medium, has particularly conformable properties which are especially valuable to this. Anthropologist Susanne Kuechler describes woven textiles as having ’profound meaning as agents of boundary creation’, and Avella’s textiles innovations explore the complexity of the garment as boundary between ‘inside’ and ‘outside’.

Restoring function after neuromuscular trauma: novel paradigms for enhancing volitional control of neural activity in untethered environments and vHAB, a gamified therapy platform

Thesis (Ph.D.)--University of Washington, 2016-08

The Legitimacy Process that Supports the Formation and Development of Cluster Initiatives : The Case of a Tourism Cluster Initiative in Dalarna

Today, large public investments are being made with the aim of creating and developing cooperation between businesses in inter-organizational networks. Such initiatives are commonly denoted cluster initiatives and their underlying purpose are to spur innovation and regional growth. Much research has been conducted in this field, but relatively few studies have examined the process of cluster initiatives. By following the case of a regional cluster project within the tourism industry in the region of Dalarna, Sweden, the objective of this thesis is to deepen the understanding of the formation and development process of cluster initiatives. The investigation has been conducted by examining two main themes; the internal relationships within the cluster initiative and the relationships between the cluster initiative and its external stakeholders, such as funding agencies, regional government and local businesses. The analysis is based on a legitimacy perspective and indicates that the coordinating body of the cluster initiative, the hub, principally deals with a legitimation process. What occurs within the cluster initiative, between the members themselves and between the members and the hub, is legitimation. This also applies to external relationships, between the hub and its external stakeholders. A prerequisite for the realization of its mission is that the hub obtain and sustain legitimacy; legitimacy for itself, for the other members, for the idea, for the different activities and for the industry as such.