This project focuses on Totten and Denman glaciers, East Antarctica, which are influenced by ice-shelf melting. In situ observations constraining the ocean heat content causing the melt, however, are limited. To fill this gap, the project will use Air-Launched Autonomous Micro Observer (ALAMO profilers) to telemeter back repeated hydrographic profiles near the ice-shelf fronts to complement other planned ship-based efforts in these areas. Remote sensing data will be used to provide updated and improved estimates of the melt rate for each shelf. The combined melt and oceanographic data will be used to constrain parameterized transfer functions for cavity melting in response to ocean temperature, improving on current parametrizations based on limited data. These melt functions will be used with ocean temperatures from climate models to force a basin-scale, open-source ice-flow model to determine the century-scale response for a variety of scenarios, helping to reduce uncertainty in sea level contributions from this part of Antarctica. Processes other than melt that might further alter the response will also be examined. For example, as flow speed increases, damage to ice-shelf shear margins increases, potentially introducing a positive feedback. Another potential factor is reductions in ice-shelf extent that decrease buttressing and increase ice loss. To investigate these processes, numerical experiments using varying degrees of damage and ice-shelf loss will help determine the extent to which these factors might further increase sea level. Through the air-deployment of float profilers from a sonobuoy launch tube in polar settings, a long-term impact of the project will be to raise the technology readiness of operational in-situ monitoring of the rapidly changing polar shelf seas, paving the way for a transformative expansion of observations of ocean hydrographic properties from remote areas that currently are understood poorly.

Over 40% of the human body is made up of skeletal muscle, which are essential for breathing, and for movement. Skeletal muscles are composed of numerous cells called muscle fibres. Within the muscle fibres, two main proteins called myosin and actin are organised into thick and thin filaments respectively, and these filaments have highly precise, lengths. These filaments are organised into muscle sarcomeres, which are in turn organised in long linear arrays from one end of the muscle fibre to the other. The interaction of myosin with actin in each muscle sarcomere drives a small shortening of each sarcomere (known as a contraction), which is summed along the muscle fibre, to drive muscle shortening, which in turn drives movement. Genetic alterations to the genes that encode part of the myosin molecule mean that a faulty (or mutant) protein is made, and this leads to severe muscle weakness in patients, in a type of disease known as myosinopathies. We do not understand how these faulty (or mutant) myosin proteins cause skeletal muscle weakness. Our research will help us to obtain a new understanding of how faulty myosin proteins cause myosinopathies. We will be able to test how mutations affect the molecular structure of the myosin, how this affects its ability to form precisely built filaments, and how this then results in changes to muscle structure, leading to muscle weakness. Our approaches will range from investigating individual fragments of myosin to investigating the organisation and properties of myosin in intact human patient samples to enable us to obtain a deep understanding. This new knowledge will not only greatly advance our understanding of myosinopathies, but, most importantly, suggest pharmacological targets that may be exploited for effective therapeutic interventions.

United States

Since the discovery of Sedna in 2007, the past decade has seen the discovery of a population of distant Solar System objects (often referred to as Inner Oort cloud objects [IOCs]) on a highly eccentric orbits beyond the Kuiper belt. The very existence of these distant small bodies challenges our understanding of the Solar System. These orbits are well beyond the reach of the known giant planets and could not be scattered into their highly eccentric orbits from interactions with Neptune alone. IOCs orbit too far from the edge of the Solar System to feel the perturbing effects of passing stars or galactic tides in the present-day solar neighborhood. Some other mechanism in the Solar System current or past architecture is required to emplace these extreme Solar System minor planets on their orbits. The orbits of these distant planetoids are the fossilized record of their formation. Each of the proposed scenarios offered to explain the formation of the IOCs leaves a distinctive imprint on the members of this distant population and has profound consequences for our understanding of the Solar System's origin and evolution. The majority of the known IOCs appear to come to perihelion at similar locations on the sky, which is currently proposed to be due to the active gravitational shepherding from an unseen 9th planet at ~200 au or beyond. Although there is compelling evidence to suggest the possibility of an ice giant planet beyond Neptune, there are results from other modern-day out Solar System surveys that seem to conflict with this hypothesis. To help unravel this mystery, this New Applicant Scheme proposal seeks to study the origin and properties of this distant collection of planetesimals and what they reveal about the dynamical history and environment of the outer Solar System.

Injectable scaffolds can offer the possibility of homogeneously distributing cells and molecular signals throughout the scaffold, and can be injected directly into cavities with irregular shape and size. Most studies have been on the development of injectable scaffolds for bone and cartilage tissue repair, some others for corneal wound healing. The most challenging issue is to find suitable materials which can solidify in situ to form 3-D scaffolds. Crosslinking via photopolymerisation provides many benefits, including rapid polymerisation times under physiological conditions. At present, most synthetic polymers used in tissue engineering are linear structure, however, they suffer from poor solution properties, non-homogenous crosslinking properties and limited control of polymer modification. Dendritic polymers have unique properties, such as good solubility, low viscosity and high functionality, due to their 3-D architecture. Grinstaff synthesised a photocrosslinkable dendrimer for corneal wound healing sealant and cartilage repair. However, dendrimers have to be prepared by solvent-intensive and multi-step synthetic routes, most importantly, it is difficult to tailor the composition and structure of dendrimers for a wide range of special applications. By contrast, hyperbranched polymers, less controlled dendritic polymer architectures, can be synthesised more easily by a single-step reaction via a range of synthetic strategies. Could the use of such hyperbranched polymers overcome the synthetic barrier of dendrimers? The limitation of current synthetic strategies for hyperbranched polymers are either the need of special monomers (ABn or AB* inimer), and/or, only poor controlled structure and low degree of branching polymers can be obtained. Therefore, up till now, such materials are difficult to be considered in medical applications. I have recognised that a breakthrough in synthesis of hyperbranched materials with controlled chain structure and high degree of branching using more accessible monomers could facilitate a completely new approach to their biological and biomedical applications.Recently, the Nottingham team has developed a deactivation enhanced ATRP method, which opens up the field significantly and allows simple use of readily available and inexpensive multifunctional vinyl monomers to synthesise hyperbranched polymers with high degree of branching, controlled molecular weight and chain structure. Such hyperbranched polymer materials could be extremely important for biological and biomedical applications. Furthermore, the products carry a multitude of reactive functionalities (e.g. double bonds and halogen functional groups) that can be post-functionalised and modified for specific applications by end capping with short chains, organic molecules and terminal grafting. By these modifications, the material properties, such as functionality, polarity, solubility and flexibility of the hyperbranched polymers, can be conveniently tailored to meet the application requirements. The polyvinyl functional groups can be used as corsslinking sites by photo stimuli to form 3-D structure. My aim is to design and synthesise a broad spectrum of tailored, novel hyperbranched polymers for biological and biomedical applications using the recently developed facile synthetic strategy, deactivation enhanced ATRP. This proposal targets the development of novel photocrosslinkable hyperbranched polymers as injectable scaffold materials for cartilage tissue repair. The hydrogels from the targeted hyperbranched polymers will achieve better biological response with tailored mechanical properties, integrin-mediated cell adhesion and control of growth factor release. The research will include three tasks with some subtasks as detailed in the Case of Support.