Then ability of sperm to swim is vital for human fertilization. Not only must sperm be motile, they must also be able to perform different swimming 'styles' with different functions and employ them as needed. As the sperm migrates form the vagina to the oviduct, where it will fertilise an egg, it must progress through very different types of fluid and gel, must navigate through complex, 3-dimensional environments and must then penetrate two 'coats' that surround the egg, first a thick layer of small cells embedded in jelly (the cumulus cells) and inside this a tough, protein shell (the zona pellucida). To succeed at all these different stages of its journey the sperm must, at each stage, select correctly from its various swimming styles or even use them in combination, alternating between two. This sophisticated process is orchestrated by cues provided by the female tract but also depends on events inside the sperm. The cues cause a change in the concentration of calcium ions (Ca2+) inside the sperm cell, which in turn acts a as a signal to select the type of swimming to use. Our initial experiments have shown us that there are at least two different methods by which the sperm can control the concentration of Ca2+ inside the cell and that when we stimulate the cells with drugs selectively to activate one or other of these two Ca2+ 'pathways', we can cause the sperm to swim in very different styles according to which method we turn on. In this study we will measure sperm Ca2+ concentration and sperm swimming style when they are provided with cues that they would meet as they travel through the female tract and meet the egg. We will investigate the types of Ca2+ 'signal' that are turned on (which Ca2+ pathway is used), the characteristics of the signal produced and how the different cues provided by the female tract can select different types of Ca2+ signal and thus how they are able to control what kind of swimming the sperm does. The understanding that we gain from these experiments will be used to study sperm from subfertile men. We will investigate how these processes go wrong in men whose sperm cannot regulate their motility and swimming style - an important cause of male infertility. Finally, we will use this information on how sperm swimming is controlled to test drugs that will potentially be used to 'activate' sperm that normally fail to swim properly and therefore cannot reach the egg and/or cannot fertilise it when they get there. For men where this problem significantly affects their fertility, correcting or bypassing the problem in this way will provide a route for simple, low cost treatment without needing to use the highly invasive, potentially traumatic and very expensive techniques of in vitro assisted reproduction.

The global oceans act as a sponge, soaking up significant amounts of the excess heat and carbon that have been added to the atmosphere due to human activity. Our oceans therefore play a key role in buffering the magnitude of climate change. However, the future storage capacity of the ocean sponge is uncertain, alongside the distribution of nutrients and oxygen, key ingredients for a healthy marine ecosystem. To address these uncertainties, we need to better understand how the oceans flow deep below the surface layers - in particular current flows that span scales of tens of metres to hundreds of kilometers, otherwise known as submesoscales. Submesoscale currents matter because they provide a pathway to harness energy from the winds and tides and use it to stir and mix different water masses around the globe, along with the heat, carbon and nutrients that they carry. Despite their importance, little is known about ocean submesoscales because of their intermediate size and intermittent nature. This means they are both difficult to capture in nature or model with computers. In this project, my team will conduct a pioneering experiment that will capture for the first time the full range of current flows that exist beneath the surface ocean layers, alongside the mixing and stirring that they generate. A targeted sea-going programme using active acoustics will sample the ocean at unprecedented resolutions (two orders of magnitude better than other techniques) and fully capture submesoscale currents. Similar to how bats echo-locate, a ship at the surface releases sound pulses into the water and records reflections from water layers. Acoustic measurements will be combined for the first time with cutting-edge robotics, vessel-mounted and moored instrumentation. In parallel, state-of-the-art model simulations will be both validated and improved using our new ocean observation data. The result will be the most realistic representation of the sub-surface ocean to date. The simulations will be used to quantify submesoscale initiation, ubiquity and interactions, and assess their role in driving energy and property exchanges in the global ocean. The experiment will take place at a global hotspot of ocean activity: the Brazil-Malvinas Confluence off the coast of Argentina. Here sub-tropical waters from the Atlantic collide with polar waters from the Southern Ocean. Water mass exchanges at this confluence, which are likely driven by submesoscale currents, play a key role in the distribution of heat, salt, carbon and life sustaining nutrients and oxygen throughout the global oceans. By revealing interior ocean dynamics in unparalleled detail at the Brazil-Malvinas Confluence, COSSMoSS will shed light on a significant missing piece of the scientific ocean puzzle helping us to better understand our future biosphere and climate.

The entry of Calcium Ions in excitable cells is the most ubiquitous electro-chemical trigger for vital processes in human physiology. Calcium entry is the common upstream message for the propagation of signals between brain cells (neurons), the contraction of the heart cells (cardiac myocytes), and the arterial blood pressure smooth muscle cells (SMCs). The excitation - evoked Calcium entry in all these cell types is controlled by a specialized class of protein complexes, called Voltage - Gated Calcium channels (VGCCs). VGCCs form a specialised pore in the otherwise impermeable cell membrane to regulate selectively the flux of Calcium among other charged ions into the excitable cells. Even minimal alterations from the normal VGCCs functions in the heart and blood vessels can lead to severe human diseases. As a consequence, VGCCs regulation is targeted by clinically important small - molecule drugs prescribed to reduce arterial blood pressure and treat cardiac dysfunctions. However, their wide distribution often results in off-target effects and there is a pressing need to find novel therapeutic approaches. To form a fully functional complex VGCCs requires co-assembly of several proteins (subunits) a central protein forming the calcium selective pore (called a1 subunit), and at least two auxiliary proteins (beta and a2d subunits) modulating VGCCs properties. Despite their pathological relevance, the structural and functional mechanisms underlying the regulation of VGCCs channels by a2d subunits remains poorly understood. Understanding of the molecular basis this regulation is of basic biological importance, and of medical importance, as a2d subunits are recognised as a potential route for developing novel VGCCs - directed therapeutic approaches. I will pursue multidisciplinary approach by combining electrophysiological, biochemical, imaging and optical techniques to investigate the molecular mechanisms underlying the regulation of VGCCs by a2d1 subunits. I will focus on a novel physiological pathway for control VGCCs functionality determined by the enzymatic cleavage of a2d proteins. I will investigate both structural and functional aspects of this mechanism to determine how VGCCs ability to sense and respond to electrical signals is controlled by a2d by the novel enzymatic mechanism. In addition, I will assess the efficacy of novel VGCCs - directed inhibitors that act by supressing the enzymatic cleavage of a2d. I will examine the implications of targeting this pathway for the regulation of a2d1 in arterial SMCs. I will benefit from building on my existing collaborations with several leading laboratories of complementary expertise in studies of electrical sensitivity of VGCCs using optical techniques (Professor Riccardo Olcese, UCLA) and structural biology (Dr. Mathew Gold, UCL). In addition, I will share expertise with specialists in studies of arterial SMCs in the host institution (Professors Iain Greenwood / Anthony Albert, SGUL) and a2d -knock out mice with Professor Annette Dolphin (UCL). Our studies can break new ground in the understanding of the molecular basis of VGGCs regulation by a2d subunits that remains unresolved. By investigating the implications of this regulatory pathway for the physiological functions of a2d in arterial SMCs, we can provide rationale for development of future therapeutic approaches targeting pathological VGCCs dysfunctions in (such as hypertension). In addition to this, our experiments can provide conceptual advances applicable to other biological systems with different composition of VGCCs channel subtypes that are also regulated by a2d subunits (such as brain, and sensory neurons) relevant to different therapeutic areas (for example chronic pain).

The turbulent oceanic flows consist of complex motions - jets, vortices and waves that co-exist on very different spatio-temporal scales but also without clear scale separation. Along with computational challenges to simulate multiscale oceanic circulation in high numerical resolution, as well as resulting difficulties in dynamically and kinematical understanding of multiscale flows, naturally goes practical need to develop emulators, i.e. prognostic models of reduced complexity that would reproduce dynamically the whole complexity of turbulent oceanic motions across scales. This initiative aims to develop such emulators by mathematical, i.e. equations-based as well as data-driven reduction methods, describing evolution of relatively few (from tens to hundreds) spatio-temporal modes and capturing essential statistical properties of the underlying multiscale oceanic flow and stratification. It will combine development and applications of state-of-the-art data-adaptive methods and rigorous mathematical theory for dynamical and empirical reduction in the hierarchy of oceanic models from the quasi-geostrophic to primitive equations. The goals of this proposal are (i) to extend recent theoretical results and to emulate the full spectrum of dynamically important scales including mesoscale eddies; (ii) to demonstrate that the stochastic and nonlinear flow emulators can provide fundamental novel insights into dynamical and kinematical properties of the multiscale transient flow patterns and their interactions, and to search for dynamical interpretations of nonlinear mode interactions; (iii) to extend empirical and dynamical reduction methods to spatially inhomogeneous and turbulent flows; (iv) to consider several types of dynamically simulated eddying flows of the ocean circulation in the hierarchy of oceanic models across full spectrum of complexity and geography, from anisotropic beta-plane turbulence on zonal currents, and wind-driven gyres with western boundary currents, to comprehensive solutions by Regional Oceanic Modeling System, and, thus, to develop efficient emulators for the eddying multiscale flows, (v) to embed the stochastic and nonlinear flow emulators into non-eddy-resolving dynamical oceanic models as effective parameterizations of the eddy effects. The intellectual merit of this project is in developing versatile and novel methods to construct stochastic oceanic emulators of reduced complexity, based either on high-end model simulations or underlying dynamical equations, or both, and capturing oceanic dynamics across scales, i.e., from large-scale decadal variability to mesoscale eddies, and resulting dynamical and kinematical understanding of multiscale flows. The project's broader impacts lie in developing methods that are very general and can be easily adopted to other sciences. The statistical models that emulate the turbulent flows in a coarse-grained sense can be adopted as efficient and low-cost emulators for oceanic components of general circulation models. The project represents perfect fit to NSF-NERC program goals of fostering USA-UK research and perfect opportunity for the postdocs to get engaged into the leading-edge international research. Eddy-resolving solutions data and software will be made public.

How do stars like the Sun drive fast supersonic winds into their local environments? Why is the solar atmosphere hundreds of times hotter than the Sun itself? Can the damaging effects of space weather be reliably predicted? What might we discover in parts of space we have yet to explore? The coming decade presents an unprecedented opportunity answer these, and other, major outstanding questions in plasma astrophysics. NASA's Parker Solar Probe (PSP) will soon become the first spacecraft to fly through the solar corona, while the Voyager spacecraft are now beginning to explore the local interstellar medium (LISM) beyond the heliosphere for the first time. There are many mysteries to be investigated in these regions of space, but they also hold the key to understanding the universal physical processes at the heart of the above unanswered questions. In addition, space weather - the changing plasma conditions in the near-Earth space - is being realised as increasingly urgent to understand and predict due to its potentially severe consequences for us on Earth. Space weather is high on the UK's National Risk Register, alongside infectious diseases, with the potential for substantial harm to the economy and public health, putting lives at risk, due to the vulnerabilities of our modern society's increasing reliance on its technological infrastructure. I consider the essential key to answering these questions and challenges to be the importance of plasma turbulence - the fundamental complex chaotic behaviour of the ionised gasses that make up most of the known matter in the universe. Plasma turbulence is ubiquitous in nature, governing the flow of energy and dynamics of these environments, but basic questions remain about how it works, to what degree it is universal, and how it impacts the astrophysical systems that it pervades. Until recently, the effect of turbulence in astrophysics had been under-appreciated, but with recent progress in understanding it is now seen to play a key role in many important scenarios, e.g., solar and stellar wind generation, heating of the solar corona, accretion disk transport, galaxy cluster heating, magnetic field generation, and space weather impacts. My research vision is to connect these related themes in a new and unique interdisciplinary project on the fundamentals and impacts of plasma turbulence, which will answer these important and timely questions. The proposed research, which builds on my proven expertise in space plasma turbulence, involves using PSP to make the first measurements in the solar corona to determine how turbulence generates the solar wind and heats the corona, using Voyager to understand interstellar turbulence and its effect on the global heliosphere, novel lab experiments on the Large Plasma Device to probe the fundamental interactions at the heart of plasma turbulence, and new techniques to understand the effect of turbulence on space weather and make urgent improvements to forecast accuracy. An interdisciplinary approach will be taken to this ambitious and unique project to achieve maximum impact, allowing me to establish myself as a new leader in the field. Academic impact will be achieved by answering important long-standing questions of fundamental plasma physics and space plasma physics. Socioeconomic impact will be achieved from improved space weather predictions to help protect us from its damaging effects and preventing billions of pounds worth of damage to the economy. In summary, this proposal describes a highly timely programme of interdisciplinary research that covers important fundamental topics in plasma physics, long-standing open questions in astrophysics, space exploration with the potential for significant discoveries, and direct application to space weather forecasting with a clear path to major societal impact.