Are you familiar with piping icing onto cakes? Would you be surprised to know that our understanding of many of the flow processes taking place whilst you lay down beads are not actually fully understood? Wherever a fluid is "strained" - slid, squashed, or changed in shape, it responds with a force, or "stress". Studying fluid response to straining is known as "rheology". These forces influence how the rest of the fluid nearby moves, making it vital information to computationally model fluid flow problems: models that inform processing molten plastic into everyday objects, or our understanding of how a spider spins it's silk. Colloquially, rheology describes how "thick" a fluid is, but fluids can have hugely varying behaviours, all dependent on microscopic interactions occurring in the fluid. The flow and straining occurring through a piping nozzle is quite complicated. Near the nozzle walls, icing is mainly undergoing a "shearing" flow, where fluid layers slide over one another - this flow type is well understood and measurable in a lab. Near the centre, the fluid is experiencing "extension", where fluid packets are stretched in the flow direction and squashed in other directions. The nozzle tapering causes this. This extensional flow is less well understood or measureable, but in the last 50 years our understanding has improved, mainly because of the plastics industry. Between the location of the wall and the centre of the flow, simultaneous shear and extension exists - we call this a "kinematically mixed" flow. Not stirred, but mixed as in more than one type of straining present. To date, our only approach to validate models in this region has been to measure fluid velocity (for example) and see if our mathematical model predictions agree - models based on data from pure shear or extensional flows. Until now there hasn't been a way to unambiguously isolate and measure separate stresses within the middle of such flows, something that depends, via microscopic interactions in the fluid, on both shear and extension together. Making the situation even more complex, icing is an example of a "suspension", a class of fluids that display what is called a "yield" stress - it only flows when an applied stress exceeds some threshold. This allows icing to flow when the piping bag is squeezed, but means it resists flow under gravity after being deposited on a cake. The behaviour of suspensions under extension is particularly poorly understood at this time, versus what we know for plastics, let alone their behaviour under kinematically mixed flows. Not just icing cakes is affected. 3D printing cement to build novel houses is conceptually the same process, scaled up, and must handle much more stress without flowing. Depositing solder paste in electronics manufacture has similarities, as does processing graphene fibres into next-gen high performance materials. Plastics processing, a mixed flow, is not perfectly understood, and even lubricant flow in engine bearings is mixed. In fact, few flows are purely shear or extensional, and lacking a method to directly see how fluid stresses are responding under these mixed flows is detrimental to being able to accurately model and predict them. This impacts our ability to design industrial processes around it, and perhaps in the future, to use it to engineer new materials with exacting flow responses for specific applications. This fellowship will develop a new experimental technique that allows us to measure what shearing stress is occurring throughout a kinematically mixed flow by using magnetic resonance imaging - the same technology used in hospitals - and critically, makes whether a fluid is clear or opaque unimportant. With members of the modelling community interested in the project and a "round table" planned, benchmark experiments will be conducted to inform new fluid model development, and thereby facilitate a wide range of next generation materials and manufacturing processes.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Lipids are the fatty molecules that make up the membranes that surround cells; without them life would not exist. However, this is only one of the important roles that lipids play in biology. For example, lipids are also involved in many forms of communication within and between cells, and the lipid composition of the cell membrane affects the activity of proteins embedded in it, such as those that transport molecules in and out of the cell. Damage to lipids by reaction with oxygen, in the same way that cooking oils go rancid, is related to many of their roles in disease. Hence, the analysis of lipids and understanding their roles in biology are very important areas of research. However, the comprehensive analysis of lipids is challenging as they are a very complex set of molecules, with over 100,000 different types in human cells, and many more when bacteria and other microorganisms are included. Many of them have very similar chemical structures, making it hard to tell them apart, but very diverse effects, so it is important to identify them correctly. The equipment we will buy with this grant has an extra dimension for the separation of molecules, based on their shape, which will greatly enhance the number of different lipids that we are able to distinguish and will enable a wide range of research to help understand their complex roles in biology. There are many examples of how lipids are important in life. For example, they play a role in controlling cell growth to cell death, including processes particularly important in conditions such as inflammation. Lipids can also affect the activity of proteins in the cell, and particularly those in the cell membranes, many of which are targets for drugs such as morphine and insulin. Analysis of the lipids associated with membrane proteins, and the effects that changing of these lipids has on the activity of the proteins, is important in understanding these effects and how they may change with age or diet, or in other diverse areas, such as the production of biofuels or processes in bacterial replication that could be new targets for antimicrobials. Lipids contain many sites that can be attacked by reactive chemical species, and these damaged lipids can themselves have biological activity or react with other molecules impairing their function. An example is LDL, or bad cholesterol. Oxidative damage to the lipids in LDL is thought to be responsible for changes that lead to heart attacks and strokes. We need to be able to analyse the different lipids that are generated in these reactions, how they interact with or react with biological systems, and what effects this has on the biological system. This grant proposal is provide instrumentation that will allow us to perform the complex analysis required to confidently identify and measure the amount of lipids that are present in complex biological samples. The main technique to be used is mass spectrometry, which measures the weight of molecules very accurately, as well as being able to break up the molecules to get information on their structure. However, the current methods are not always able to separate all the individual components in complex mixtures to allow their full analysis, especially of low abundance molecules that affect cell behaviour. The new instrument will provide extra capabilities through an additional dimension for separation of the molecules, called ion mobility, which is able to separate molecule based on their shape. The equipment will be the first available of a new design of instrument that allows much finer separation of molecules (it has a cyclic ion mobility cell providing much longer effective separation path lengths). This will allow us to do more accurate measurement of the lipids present and the way in which they are changed, leading to a much better understanding of biology in many important areas.

An exciting innovation in the analysis of a biological system is sampling on a very small nanoscale using a specialised needle (nano capillary sampling). Cells are located under a specialised (confocal) microscope and cells or even small parts of cells can be sampled. This uniquely provides spatial information and can be performed on living cells which will allow scientists to understand important biological phenomenon such as how cells communicate with each other and how cells become cancerous. Our resource which we have called SEISMIC will provide an automated platform based on nano capillary sampling. We will work with users within the UK research community to extract single cells and their sub- cellular compartments under a microscope. The extracted cellular materials can be analysed using a variety of approaches such as mass spectrometry which separates molecules by mass and charge to profile for example drugs, metabolites and lipids or apply other techniques to profile nucleic acids. This will allow an unprecedented view of cells and can be applied to a plethora of biological questions which inform us on for example the rules of life or how pathogens cause disease or how cells age, information which can be harnessed to develop new therapeutic interventions which will ultimately benefit society. The SEISMIC resource will be available free of charge to BBSRC users for the first 36 months, either with or without downstream mass spectrometry analysis. Users will be able to perform their experiments using the facilities at Surrey, and hands on access to SEISMIC will be supported through travel grants. This facility will be the first of its kind in the UK and therefore will play a role in maintaining world leading science in the UK.

Every year in the UK, more than 300,000 hip, knee, shoulder, ankle or elbow devices are implanted into patients for the treatment of orthopaedic pain, disease and trauma. Secure fixation of these implants in bone is essential for the procedure's success, yet is challenging to achieve as bone is a living tissue that adapts and changes postoperatively. Researchers and industry strive to develop new technologies to improve fixation, with many aiming to take advantage of bone's living response by enabling it to grow into the implant. The design intent of these new technologies is always well-meaning, but to protect patients, it is necessary to pre-clinically test them, to confirm they are both safe and achieve their aim. However, there is a lack of appropriate methods for testing this. Traditional laboratory pre-clinical testing methods do not allow for testing with living bone samples and thus cannot measure implant bone ingrowth/adaptation. Live animal testing has ethical issues, is expensive and is complicated by anatomical differences and unknown loading. Computational models require input and validation data and so require a previous laboratory/animal/clinical study. The other alternative is clinical trial, which is effectively experimenting on patients. It also often requires years/decades of waiting to determine the outcome, and thus is only suitable as the final step of new product development. This research project aims to overcome limitations in pre-clinical testing by using a bioreactor system to enable implant fixation technologies to be tested against 'living' bone in the laboratory. The developed methods will be validated with established clinical technologies, before being applied to pre-clinically test a novel implant fixation concept. The long-term ambition for this research is to lower the risk for patients enrolling on clinical trials, reduce the need for ineffective live animal testing, and improve orthopaedic implants through enabling fixation technology to be optimised for in vivo performance.