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SUMMARY BACKGROUND: The number of overweight and obese people is rising all over the world and in the UK. Obesity now affects children, adolescents and adults. Younger people are particularly prone to the lifelong consequences of obesity with type-2 diabetes and high blood pressure. Once obesity is acquired, weight loss is difficult to achieve and in particular to maintain. Therefore, preventing overweight and obesity in the first place, is an attractive ambition to improve public health. The origins of obesity can be traced back to the time we spent in our mother's womb and even before conception. During pregnancy, the developing baby grows in response to the health and weight of its mother. However, the father's weight at the time of conception is also influential, but in the opposite way to the mother's influence. Whereas an overweight or obese mother is predisposed to have a large baby, an overweight or obese man is predisposed to father a small baby. How well a baby grows in the womb is important, as it influences the health of that baby in adult life. Babies that grow poorly in the womb have a low birth weight and are at increased risk of type-2 diabetes, high blood pressure and obesity. Very large babies are also at risk of future type-2 diabetes. AIMS: We wish to discover if humans behave in the same way as animals by passing on acquired characteristics such as obesity, from father to unborn baby. We have designed a multi-staged, integrated study to discover how an obese father might inhibit the growth of his unborn baby and whether paternal weight loss has the potential to improve fetal growth and provide the ultimate primary prevention of life-long disease in the next generation. METHODS: We will discover whether obesity, type-2 diabetes and low birth weight are associated with consistent changes in the chemistry around genes, known as epigenetic change. We have linked with a Norwegian group who have collected DNA from over 11,000 families (mother, father baby). We plan to investigate whether DNA from 1000 obese fathers shows consistent obesity-associated epigenetic changes, compared with 1000 normal-weight fathers. We will determine if obesity-associated epigenetic marks identified by others in published reports are also evident in the 1000 obese fathers. This will generate a validated list of 'obesity-associated' epigenetic changes. We will next determine the relative contribution of validated obesity-associated epigenetic marks from the obese father on the birth weight of their offspring in a study of newly pregnant women. We will study 250 pregnancies fathered by obese men compared with 250 pregnancies fathered by normal weight men. We will determine whether obese fathers are more likely to father low birth weight babies. We will take into account the influence of mothers' size and genes from both parents. We will determine whether placentae (genetically half paternal) from pregnancies fathered by obese men function differently to placentae from pregnancies fathered by normal weight men. Finally, in a separate study of 15 obese men, we will determine whether dramatic weight loss through bariatric surgery (by-pass of the stomach), is associated with reversal of obesity-associated epigenetic marks in DNA from their blood and sperm. EXPECTED RESULTS: The results of this project are of both scientific and public health interest. If obesity-associated epigenetic marks are evident in sperm of obese fathers and their low birth weight babies, we would have discovered a potential mechanism through which acquired paternal obesity perpetuates a vulnerability to obesity in a future generation. If weight loss eliminates these epigenetic marks, then we will have established a scientific rationale for a future study to investigate whether pre-conception paternal weight loss improves fetal growth and potentially improves the long-term health of the next generation.

SUMMARY One of the main hallmarks of Mycobacterium tuberculosis (MTB) pathogenesis is its ability to manipulate the timing of the immune response to its own advantage by changing expression of its antigens to avoid early recognition and destruction. MTB has capacity for infection of a wide range of tissues [Fanning A, 1999] with extrapulmonary TB representing approximately 15% of newly reported cases and 20-30% of relapsed cases [Global Tuberculosis Report 2017, WHO] and while macrophages constitute its main primary host, other cell types, such as professional phagocytes (i.e. dendritic cells) and non-professional antigen presenting cells (APCs) i.e. epithelial cells are submissive to the pathogen [Mvubu NE 2016, Harrif MJ, 2014, Lerner TR 2016] and can process and present MTB antigens [Flyer DC 2002, Penn BH 2018]. Cross-presentation of foreign antigens by host is a critical part of the process and in MTB infection this predominantly involves MHC-I receptors associated with short peptides derived via the intracellular proteasome-focused processing pathway [Adiko AC, 2015; Chen H, 2016; Ivanyi J, 2014]. Understanding and being able to influence this system is a fundamental part of next generation vaccine design. HYPOTHESIS The leading project hypothesis is that stimulation of Mtb antigens cross-presentation pathways may translate in identification of new protective antigens for next generation of vaccines. AIMS Objective 1. To examine BCG and MTB presentation upon in vitro infection in various mouse organs grouped as follows: Primary and secondary lymphoid organs Urinary system Respiratory system Cardiac system Differentiated bone marrow cells Objective 2. To ascertain antigenic changes in BCG and MTB presentation upon cross-presentation pathways stimulation METHODS AND TECHNIQUES - organ collection for in vitro infection assays and tissue culture - extraction and purification of immunogenic complexes - antigen(s) identification via mass spectrometry (collaborative work) FUTURE PROSPECTS Any new identified antigens / methods enhancing their presentation may be included into the current TB vaccination strategies to improve their efficacy REFERENCES 1. https://www.who.int/tb/publications/global_report/gtbr2017_main_text.pdf 2. Adiko AC et al. 'Intracellular transport routes for MHC I and their relevance for antigen crosspresentation' Front Immunol. 2015 Jul 2;6:335. doi: 10.3389/fimmu.2015.00335. eCollection 2015. Page 1 of 2 3. Fanning A. Tuberculosis: 6. Extrapulmonary disease; CMAJ. 1999 Jun 1;160(11):1597-603; PMID: 10374005 4. Flyer DC et al. Identification by mass spectrometry of CD8(+)-T-cell Mycobacterium tuberculosis epitopes within the Rv0341 gene product' Infect Immun. 2002 Jun;70(6):292632. 5. Harriff MJ et al. 'Human lung epithelial cells contain Mycobacterium tuberculosis in a late endosomal vacuole and are efficiently recognized by CD8 T cells' PLoS One. 2014 May 14;9(5):e97515. doi: 10.1371/journal.pone.0097515. eCollection 2014. 6. Ivanyj J 'Function and potentials of M.tuberculosis epitopes' Front Immunol. 2014 Mar 24;5:107. doi: 10.3389/fimmu.2014.00107. eCollection 2014. 7. Keller Ch et al. 'Genetically determined susceptibility to tuberculosis in mice causally involves accelerated and enhanced recruitment of granulocytes' Infect Immun. 2006 Jul;74(7):4295-309. 8. Lerner TR et al. Lymphatic endothelial cells are a replicative niche for Mycobacterium tuberculosis J Clin Invest. 2016 Mar 1;126(3):1093-108. doi: 10.1172/JCI83379. Epub 2016 Feb 22. 9. Mvubu NE et al. 'Mycobacterium tuberculosis strains exhibit differential and strain-specific molecular signatures in pulmonary epithelial cells' Dev Comp Immunol. 2016 Dec;65:321329. doi: 10.1016/j.dci.2016.07.022. Epub 2016 Aug 3. 10. Penn BH et al. 'An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses' Mol Cell. 2018 Aug 16;71(4):637-648.e5.

The project aims to address methods for creating a computational system for design efficiency of the Higher Education (HE) campuses in the North-West. With new developments in technology, like generative design processes, autonomous systems and self-aware bots, the AEC industry is bound to be affected at a global scale. But how would Artificial Intelligence (AI) augment the architectural design and what are the possibilities for architects working with these technological advancements? The case study will run as a collaboration with an experienced industrial partner that has been involved in designing and building school campuses in the UK. More specifically, the project's main focus is to identify improvement strategies for energy consumption in university campus buildings. A university campus usually occupies large areas in a city's fabric. The urge to create additional campuses or to further develop the existing ones continues as contracts that reach £2 billion are planned between 2017 and 2020, according to Barbour ABI, the construction analysts. Similarly, the Financial Times report that, in 2016, British universities have increased their budget on new buildings by 43 per cent in six months. However a campus is a complex structure that hosts various activities. These activities change continuously over time. Thus, the development or expansion of a campus is characterized by complexity. This complexity requires an approach different from the terraced houses construction style that was applied during the UK's rapid urbanization. The mere repetitive construction approach wouldn't respond efficiently since the overall behavior of a campus changes and it happens on a procedural level. Therefore, the approach should consider the flexibility of an adaptive system in the early stages of their design. During this project, the benefits of combining Human and Artificial Intelligence will be explored. Through the use of data from the campus, the goal is to realize which factor is the biggest contributor for the energy consumption. The data will relate to the design of the campus, as well as its' energy performance, and post-occupancy information & insights. By embracing this type of data with computation in the early stages of the design process, the project will investigate improvements in the workflow and output of the architectural practice for HE campuses. Based on The Clean Growth Strategy paper, the majority of buildings including campuses, heating creates around 32 per cent of total UK emissions. However the design of an efficient HE campus in energy consumption may not only reduce the emissions but help to drive growth. According to Terence Fox, a director in the finance department at Edinburgh University, new buildings can prove decisive. "If a student [comes] from the US, Australia or China, they need to come here because we've got not just the best students, but the best facilities. If the choice is Manchester or Edinburgh, and Manchester has new buildings, they'll probably go to Manchester." From a research aspect, the applications of the respective methodology could extend beyond the energy planning of higher education campuses. While the energy factor is becoming ever more critical within the AEC practice, further equally important design variables could be revisited and explored. People's flow in a building or the exterior view maximization are examples of such variables. In this manner, the architect's professional boundaries could be transcended. This application of Artificial Intelligence for design decision-making however is its' infancy even for large international firms. As more and more practices create specialist groups to embrace this technological development the benefits will become more tangible. And the AEC industry will be enhanced by embedding new ways of tackling design challenges; ways that would be impossible without the implementation of computational modelling systems.

Experimental demonstration of superposition states of massive systems, often referred to as Schrödinger cat states, has been an exciting research line of several fields in quantum physics. There have been many impressive experiments with a variety of different systems over the past years and research along these lines is still highly popular. While the field of optomechanics, which is based on massive mechanical oscillators coupled to optical fields through the radiation pressure force, is ideally positioned to realize such measurements and hence test the boundaries between classical and quantum theory, in this proposal we want to take one step beyond purely curiosity-driven exploration of quantum states of large systems. In particular, we will perform experiments using optomechanical systems that are not only of interest for testing the foundations of quantum physics, but will actually have a real potential application in quantum information processing: we are proposing to realize an entangled state between two micro-fabricated, on-chip mechanical resonators that are coupled to laser light at telecommunications wavelengths. Such a system will be directly applicable to realizing quantum memories with truly tailorable properties that can distribute quantum information over large distances. The basic idea is to initialize two mechanical resonators in their quantum ground state and to create entanglement through Raman scattering and single-photon post-selection. The quantum state will be verified through a standard entanglement measure, as well as by violating a Bell inequality with this massive, entangled state. The exact technique, as well as advanced experiments, is discussed in detail in this proposal.