Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

The human genome contains thousands of genes, activities of which are important for a functioning healthy human body. Our organism is made up of billions of cells, all originating from one single cell. This is possible, since that original cell divided into two cells, which subsequently produced four cells, and so on. It is of crucial importance that the entire genome is duplicated accurately during each division. The genome is constantly subjected to damage from a variety of sources from inside or outside the cell. If cells fail to maintain an intact genome,, mutations can arise, which can cause a number of severe diseases, such as cancer. To counter-act the effects of damage, our cells have evolved sophisticated mechanisms to protect DNA, so called DNA repair pathways. These pathways safeguard the genome to prevent harmful mutations from arising. When one of these pathways fails to function properly, it allows for mutations to arise unhindered. One particularly serious example of this is when the Fanconi Anemia DNA repair pathway is not operational. When that happens, it causes the disease Fanconi Anemia (FA). FA is a genetic disease characterized by various developmental defects and predisposition to cancer in patients. Many patients do not survive beyond their teenage years, underscoring the seriousness of the disease. So far, 18 FA proteins have been identified, which includes the BRCA1 and BRCA2 genes, which are mutated in breast cancer. Together, these proteins compose the FA pathway, which is responsible for repairing DNA crosslinks, a dangerous type of DNA damage. Mutation in any of the corresponding 18 genes can cause FA. At the same time, since these DNA crosslinks are so dangerous, drugs causing such crosslinks are used in the clinic to treat cancer in non-FA cancer patients. However, patients often develop resistance to these otherwise so successful drugs. It is believed that resistance is caused by an increased ability of the cancer cells to repair DNA crosslinks. If we could prevent the cancer cells from repairing the crosslinks, we could treat these deadly cancers and cure the patients. The aim of this proposal is to learn more about how cancer cells repair DNA crosslinks, so that we can use this information to design drugs that can treat patients with currently untreatable cancers. More specifically, we will study a protein complex called the FANCD2/FANCI complex. This complex is central and absolutely critical for cells to repair DNA crosslinks. We have recently discovered a novel domain, or part, of this complex, which is fundamental to its function. We are going to make use of this unique discovery to further our understanding of how the FANCD2/FANCI complex controls DNA crosslink repair. The increased understanding will in turn pave the way for the development of novel cancer drugs.

The function of striated muscles, so called because of their highly regular striation pattern when viewed in a microscope, is crucial for the movement of our body and heart muscles. These stripes are formed from the repetitive arrangements of molecular machines, called sarcomeres that generate force and movement. In the sarcomere, three systems of molecular filaments are working together: actin filaments, which are held together at the Z-disk, myosin filaments, held together at the M-band, and the giant protein filament titin, which links the actin and myosin filaments. Muscle responds rapidly to changes in use, with disuse leading to muscle loss (called atrophy) and exercise leading to muscle growth (called hypertrophy). These processes need to be constantly balanced, and are linked in a coordinated way to those controlling muscle repair by making new proteins for sarcomere repair and replacement of other unwanted or damaged components of the cell. Signals controlling muscle growth, atrophy and repair signals are emerging to originate at the M-band and the Z-disk. These structures contain proteins that can sense mechanical stress, the most important factor controlling muscle growth and atrophy (as seen by the rapid loss of more than half the muscle mass in two weeks when muscles are immobilised in a plaster cast). Many of these proteins, however, remain enigmatic or haven't even been discovered, and often even their most fundamental functions have not been elucidated. Yet, when the integration of the M-band as a machinery combining structural, mechanical and communication functions is disrupted by genetic defects or extreme muscle inactivity (for instance in intensive care unit patients), severe muscle diseases are the result. This study will shed light on the compositions and regulation of the M-band, its role as a sensor for mechanical stress, and why mutations in two of the giant proteins that are involved in its assembly, titin and obscurin, can lead to muscle disease.

Statistical physics, one of the pillars of modern physics, describes how macroscopic experimental observations of a physical system (such as temperature and pressure) are related to microscopic variables, not seen with the naked eye. The beauty of the statistical physics approach lies in its ability to neatly describe phase transitions, such as ice melting, and other fundamental phenomena, including magnetism. However, the situation is more complicated: magnetic materials, which touch all technological aspects of our civilisation, contain impurities (disorder) that lead to unexplored properties and defy the standard framework. In fact, disorder is not only unavoidable in solid state materials and ubiquitous in realistic classical examples, but also quantum many-body systems. Disorder is responsible for a variety of interesting novel phenomena that do not have clean counterparts, such as the Anderson localisation, exotic quantum critical points, and glassy phases of matter, that appear solid on a short time scale, but continuously relax towards the liquid state. These phenomena are present in a wide range of condensed matter systems including polymers, metallic alloys, magnetic spin glasses, and many soft materials such as colloids, foams, emulsions or other complex fluids. Understanding the effects of frustration and quenched disorder in condensed matter physics has immense technological consequences that reach up to the design and construction of quantum annealing devices used for future technologies of quantum computers. A vast amount of research has failed to reveal the physical mechanisms at play due to the rough energy landscape of these systems that disarms analytical and numerical approaches. Fortunately, years of consistent effort have enabled us to develop exceptionally versatile tools, including some extremely powerful numerical and theoretical approaches, that have unblocked the path towards a direct attack on the problem. Using this new toolbox of methods, the proposed project aims at clarifying the effects of random fields, one of the most common yet less understood types of disorder with many experimental analogues in physics, on a variety of spin models and unveiling their critical behaviour and universality principles. In addition, we also intend to clarify other ambiguous theoretical conjectures, like supersymmetry and dimensional reduction. We expect our results to pave the way for novel experiments and technological breakthroughs made possible by the development of an unambiguous interpretation of the underlying phenomena. As the concepts used for deciphering complexity in disordered systems apply to other fields involving emerging collective behaviour (e.g., financial markets, social networks), the progress achieved will underpin advancements in other scientific areas as well.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.