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 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.

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).

Wynn (1992) made the controversial claim that young infants understand addition and subtraction, finding that they looked longer at events with numerically incorrect outcomes. Although alternative interpretations of Wynn's influential results have been offered, investigations have stopped short of the systematic manipulation of relevant factors needed to identify an appropriate interpretation. This proposal is motivated by the pressing need to provide a firmly based account of how young infants process single and multiple object occlusion events. Alternative explanations include the object file account, which although based on representational processes does not assume a symbolic understanding of number. It does, however, make predictions regarding the outcome of certain manipulations of Wynn's task, but these predictions conflict with each other. Secondly, a lower level object tracking account makes specific predictions regarding infants' responses to violations of existence, featural identity, and position of objects in Wynn's task, and is parsimonious through not assuming mental representation. It is apparent that manipulation of Wynn's task has potential to answer key questions regarding infants' object tracking that go well beyond Wynn's initial question. This proposal involves a core set of 23 experiments with 5-month-olds, as a systematic investigation of infants' ability to keep track of objects. Our main measure will be infants' looking time as an indicator of violation of expectation. (The assumption of this well tried measure is that infants look longer at events that violate their expectations.) This will be supplemented by eye-tracking and pupillometry data to investigate whether infants look more at an object that violates expectation regarding its existence, featural identity, or position. In cases where young infants do not respond to a particular violation, the experiments will also be run with a group of older infants to seek evidence for developmental increase in sensitivity. Experimental series 1 and 2 will involve a single object, and will involve the numerical operations 0 + 1 = 1 and 1 - 1 = 0, respectively (see Annexe 2 for a figural description). The 0 + 1 experiments will begin with an empty stage whereupon a screen will rotate to vertical, and an object will be introduced and placed behind the screen. On violation trials the screen will rotate down to reveal, (i) no object, (ii) the object in the wrong place, (iii) a different object in the right place, or (iv) a different object in the wrong place. The 1 - 1 Experiments will commence with an object present, the screen will rotate to hide it whereupon a hand will appear and remove the object. On violation trials, the screen will rotate down to reveal one of the same sorts of violation as in the 0 + 1 case. Series 3 and 4 relate directly to Wynn's work, involving two objects and concerning the numerical operations 1 + 1 = 2 (initial state one object present, screen rotates whereupon a second object is added) and 2 - 1 = 1 (initial state two objects present, screen is rotated whereupon one object is removed). In the case of series 3 and 4, we shall assess the degree to which infants detect different forms of violation applied to the first versus the second placed objects. In the 1 + 1 case we shall also assess performance on a variant in which both objects are added once the screen is rotated, to test the object file account prediction that an object perceived in position before occlusion leads to a stronger object file representation than one seen disappearing behind a screen. We anticipate that these studies will provide an important body of evidence arising from systematic variations of a single procedure. This should clarify apparent contradictions in the literature and will provide a superior account of the processes through which young infants keep track of multiple objects.

In the past two decades numerous viruses have emerged from animals to cause outbreaks in the human population. These include Swine Flu, Ebola viruses, Zika virus, and three coronaviruses, including SARS-CoV-2, the cause of the ongoing COVID-19 pandemic. The frequency of virus emergence is accelerating likely due to our increased travel as well as global environmental and climate changes that bring humans and animals in ever closer contact. To identify which viruses pose the most risk for future pandemics, it's important to understand what it is about pandemic viruses that enables them to spread so efficiently between humans. One of our most important front-line defences against infection is our innate immune system. This system is present in all cells, and is made up of a network of sensors that can detect invading viruses, activate antiviral defences and initiate a warning system that places neighbouring cells in a state of readiness to stop infection. To infect us and transmit, all viruses must overcome this front-line defence, by escaping detection or by disabling the response or usually a complex combination of both. Viruses that jump between species, such as coronaviruses, must overcome this defence system in each new host. I previously found that, despite having only recently emerged in humans, isolates of SARS-CoV-2 collected at the start of the pandemic could effectively suppress activation of the human innate immune system to allow viral spread. This suggests the virus was pre-armed with countermeasures to overcome human defences. The emergence of more transmissible variants throughout the pandemic, called variants of concern (VOCs), suggests that SARS-CoV-2 is adapting to spread better in its new human host. I discovered that the VOCs were able to suppress activation of the innate immune system even more potently than the early isolates, which may increase their chance of establishing infection to transmit. Virus manipulation can change the course of the innate immune response and drive disease, resulting from inappropriate immune activation that damages tissues, as occurs in severe COVID-19. All together our new understanding helps explain how the innate immune system is a key determinant in pandemic virus emergence, transmission, and disease. The goal of my research programme is to understand how emerging viruses overcome the innate immune system to become pandemic. Studying SARS-CoV-2, and its adaptation to humans in real time, provides an unparalleled opportunity to understand the molecular mechanisms underlying human infection. I will firstly identify the countermeasures the original SARS-CoV-2 virus used to overcome human innate immune defences. This will lead me to discover key innate immune barriers to emerging viruses and understand how they work. Secondly, I will investigate how SARS-CoV-2 variants have adapted to get better at overcoming the human innate immune system to transmit more effectively. This will reveal what aspects of the innate immune system are unique to humans. Thirdly, I will discover how SARS-CoV-2 manipulation of the innate immune system drives inappropriate responses that cause disease. The virus is a master manipulator of the cell environment to make it conducive for viral replication. Because of this, we can use it as an excellent tool to learn how the innate immune response works, which is relevant to understanding other diseases where the innate immune system is defective. Through this fellowship, I will maximise what we can learn from SARS-CoV-2 to lay the groundwork for understanding future emerging viruses, which all encounter the same defences, and discover exciting new biology about how the innate immune system works in health and disease.