Gastrointestinal cancers, including oesophagus, stomach and colon, are among the top ten cancers worldwide. Minimally invasive surgery of early gastrointestinal cancer and other digestive diseases offer important advantages compared to traditional open surgery in terms of reduced trauma and faster patient recovery. However, there are several limitations to current endoscopes including distal force transmission, triangulation of instruments, lack of bimanual tissue manipulations and visual-spatial orientation. Thus interventional endoscopy requires considerable experience and involves complex and time-consuming workflows. As a result, a sizeable amount of endoscopic interventions fail to reach the end of the colon and the small intestine because of their tortuous nature. Due to the current COVID-19 pandemic, endoscopy units nationwide have been struggling with capacity to perform gastrointestinal endoscopies resulting in a delay to diagnosis and treatment, impacting patient morbidity and mortality. Improving access to flexible endoscopy for diagnosis and treatment, and facilitating its deployment safely and affordably, should therefore be a priority and is a pressing clinical need. This research aims to transform early diagnosis and minimally invasive intervention of the gastrointestinal tract, including the small intestine. To this end we will develop the underlying technology necessary to achieve autonomous self-propelled locomotion for the next generation of soft robotic endoscopes. Departing from the conventional push-endoscopy paradigm will reduce the discomfort associated to early diagnosis and will allow endoscopists who are less skilled in therapeutic procedures, outside secondary or tertiary care, to perform endoluminal and potentially transluminal surgery. Our focus on affordability aims to address the growing demand for single-use medical devices driven by infectious diseases, and to reduce the financial barriers that are preventing the wider use of surgical robotics in low-income countries.

Red blood cell (RBC) diseases can result in chronic anaemia and are a major source of morbidity and mortality worldwide. Among these the thalassemia syndromes (alpha and beta thalassemia) and sickle cell disease (SCD) represent a significant global health problem and financial burden to health services with no drugs available for thalassemia and just 2 for SCD, but unsuitable for many patients. The mainstay therapy is RBC transfusion, with the only curative treatment bone marrow transplant. Thus, new cost-effective treatments are desperately required to deliver optimal therapies to the greatest number of people. However, studying these diseases is severely impeded by paucity of suitable and adequate quantities of material from patients, and lack of suitable cell lines that accurately mimic the disease state. Although erythroid cells can be generated in vitro from peripheral blood stem cells, the approach is severely limited by the restricted expansion potential of the cells and thus number of cells generated, with repeat collections required, a particularly unsuitable approach for anaemic patients. Mouse models of the diseases are therefore routinely used for both biological studies and drug evaluation, but fundamental differences exist between mouse and human erythropoiesis (the process of RBC production). New approaches and human systems for these disorders are therefore essential. We have recently developed methodology and generated 1) the first immortalised adult human erythroid cell line (BEL-A) that recapitulates normal adult erythropoiesis, with cells expressing normal levels of adult haemoglobin, undergoing normal development and expelling their nuclei to produce mature red cells, providing a sustainable supply of cells which we have extensively characterised; 2) a platform for introducing mutations into the BEL-A cells, creating sublines with single or multiple gene edits. We now have the unique opportunity to exploit these tools and technologies to create lines as human model cellular systems of RBC diseases, providing a sustainable and reproducible supply of cells for study. Disease mutations will be introduced into the genome of BEL-A cells. We plan to create eight beta thalassemia and five alpha thalassemia lines with mutations associated with different disease severity and with different mode of action, as well as a SCD line. The lines will provide the unique opportunity to study cell specific effects of human mutations and evaluate drugs and reagents in a human cellular context with a constant genetic background, removing the many experimental variables between patient samples. Furthermore, such a range of lines for a given disease will help determine variability in disease mechanisms, as well as evaluation of drugs etc across spectra of phenotypes. Lines will undergo extensive characterisation to validate disease phenotype and as a data resource to facilitate use of the lines by ourselves and others. Amongst the wide range of analyses performed we will include comparative proteomics both to validate known targets and to identify novel dysregulated proteins, for future studies. All data will be made available on a dedicated website. The lines will be a valuable resource for a wide range of applications including, i) further investigation into erythroid cell specific molecular mechanisms underlying the disease phenotypes, ii) clinically relevant screening tools for drug evaluation and analysis of mode of action, iii) analysing reagents for gene therapy strategies iv) insertion, verification and functional determination of mutations identified from genome-wide studies as potential modifiers of disease severity. In summary the aim of our proposal is to create not just much needed human cellular model systems of the thalassemia syndromes and SCD, but a compendium of associated and extensively characterised disease lines as a readily available resource for ourselves and the research community

Gastrointestinal cancers, affecting the oesophagus, stomach and colon, are among the top ten cancers worldwide. Minimally invasive surgery uses endoscopes to access the body and offers important advantages compared to traditional open surgery through a large cut, including less trauma and faster recovery. Surgeons who use flexible endoscopy to treat patients need to be very experienced. Endoscopies are complex and can take a long time to do. A large number of endoscopies fail to reach the end of the colon and the small intestine due to the number of tight bends in the gut. Incomplete removal of tumours leads to regrowth and complications. Improving access to flexible endoscopy for diagnosis and treatment is very important to patients and doctors. We also need to make sure that the procedure is safe, accurate and affordable for the NHS. This research aims to transform early diagnosis and treatment of gut cancers using flexible endoscopy. We will combine a soft robotic endoscope with a probe carrying a miniature surgical laser, and a powerful tissue analysis device. This will be easier to use than standard endoscopes and will allow endoscopists with less experience to perform the surgery. The ability to find and treat early tumours will reduce the number of patients requiring further surgery, reduce discomfort and lower the number of tumours that grow back. Automation of key steps of the test - including deployment of the instrument, detection of cancer, and laser surgery - will eventually allow cancer surgeries to be done in outpatient clinics or GP surgeries. In this programme, we are bringing together leading experts in robotics, medical imaging, control, engineering, surgery and cancer. This expertise will help us to design a device which will have a major healthcare impact and benefit the largest possible number of patients.

Rice is a mainstay of global food security. Drought stress is a primary limitation to rice yields and is projected to worsen in the future due to the effects of global climate change. The development of rice cultivars with better drought tolerance is therefore an important strategic goal for global food security. This project addresses this need by developing Rhizo-rice, new rice lines that have root traits that permit them to have both improved soil exploration and more efficient water capture under drought conditions. Rhizo-rice lines will have 1) steeper root growth angles, 2) fewer major roots, 3) greater root branching in deep soil, 4) increased formation of root air spaces (aerenchyma), which reduces the cost of root tissue, and 5) smaller water conductance vessels (xylem), which forces the plant to use soil water more sparingly. It is hypothesized that these traits will have much more value in combination than would be predicted from their isolated effects. This project will evaluate the benefits of Rhizo-rice lines in the field and computer simulation modelling and will discover genetic elements controlling Rhizo-rice root traits. Furthermore, we will evaluate these root traits in rice breeding lines in use in Thailand and will train Thai scientists in methods to incorporate root traits in rice breeding programs. This project integrates leading rice researchers and breeders in Thailand, leading crop physiologists in the UK and at the International Rice Research Institute in the Philippines, and leading root modelers in the UK. We will investigate how different root architectures and drought conditions affect rice growth by measuring features of the root system in rice plants grown in different conditions. By recording the number, length and angle of different types of roots and taking microscopy images of the root structures, we will test how these features affect drought tolerance. These measurements will be complemented by computational modelling, which will enable us to test many different root structures and drought conditions. We have previously developed computational models to simulate root growth in maize, barley, common bean, lupin and squash. We will adapt these models to simulate rice root growth, which will enable us to predict the best type of root growth to maximise water uptake in drought conditions. Finally, we will determine which genes are responsible for creating the desirable root structures. We will use recently developed techniques to analyse the genes and root structures in many different varieties of rice, which will enable us to identify suitable varieties for maximising drought tolerance. This project will generate several tools to facilitate the breeding of more drought tolerant rice lines. It will validate specific root traits as selection targets in rice breeding; will discover genetic markers for these traits; will identify sources for desirable root traits in rice germplasm, and will enhance the ability of Thai scientists to create a team for breeding rice lines with superior root traits.

Animal experimental design to study the role of phage therapy in acute-non typhoidal Salmonellosis Co-investigator: Dr. Parameth Thiennimitr, M.D.,Ph.D. Address: Department of Microbiology, Faculty of Medicine, Chiang Mai University Species of animal: 6-8 weeks old female mouse (Mus musculus) C57BL6 strain Protocol (in brief): C57BL/6 mice will be purchased from Nomura Siam International. Mice will be acclimatized for at least 1 week before the experiment day. 24 hour before Salmonella enterica Typhimurium (strain IR715) infection, mouse will be orally gavaged with 20 mg streptomycin sulphate to allow subsequent STM IR715 to establish a colitis. Streptomycin-treated mice will be orally infected with 100 microlitr of 109 cfu/ml STM IR715 solution. Then, 100 microlitr of Salmonella phage solution will be orally gavaged to the infected mice for consecutively 3 days. On day 4 post infection, mice will be euthanized by CO2 and cervical dislocation. Mouse colon content, colon, spleen will be collected for further analysis. Control group (no treatment) of mice will be orally fed with normal saline solution as used as a vehicle for the experimental (phage therapy) groups. Animal protocol approval committee: All animal experiments conduct at Chiang Mai University will be approved by the Chiang Mai University Animal Care and Use Committee (CMU-ACUC). All animal experiments will be performed in the AAALAC-certified biosafety level (BSL) 2 facility located in Chiang Mai University. Numbers of animal in each group is 7. [Calculated followed Bernard, R. (2000). Fundamentals of biostatistics (5th ed). Duxbery: Thomson learning, 308, level of significance = 0.05)]