Dr Alan Stewart and Prof Ramzi Ajjan (University of Leeds) have just been awarded a BHF PhD studentship grant of £108k for a project entitled “Plasma non-esterified fatty acids and fibrin clot formation in obesity – a relationship forged in zinc?“. The grant will provide funding for Stephen Hierons.

Zn²⁺ is an essential regulator of coagulation and its availability in plasma is fine-tuned through buffering by human serum albumin (HSA). Non-esterified fatty acids (NEFAs) transported by HSA reduce its ability to bind/buffer Zn²⁺. It is thought that this occurs through binding to HSA at a particular NEFA site called FA2. This dynamic is important as plasma NEFA levels are elevated in type-2 diabetes mellitus (T2DM), obesity and other disorders that associate with an increased risk of developing thrombotic complications. Through our previous work we found that only certain plasma NEFAs are elevated in T2DM/obese subjects (compared to leaner controls without diabetes) and their levels correlate with fibrin clot parameters.

Here we will identify the role of the FA2 site in mediating Zn²⁺-mishandling by HSA and will assess the degree to which individual NEFAs enhance Zn²⁺-dependent effects on fibrin clot formation and lysis. Finally we will examine whether bariatric surgery, which is known to lower plasma NEFA concentrations in obese individuals (by restricting calorie intake), beneficially influences fibrin clot formation and lysis in obese individuals. Collectively, the work will provide essential information relating to the interplay between plasma NEFAs and a key coagulatory pathway in obesity.

Dr Alan Stewart and BHF-sponsored PhD student, Jordan Marsh attended the British Heart Foundation Annual Parliamentary Reception on 5th Feb 2020. The event at the parliament each year, celebrates and raises awareness of great the work carried out by the charity. The event was sponsored by Alex Cole-Hamilton, MSP and featured talks by BHF UK’s Young Volunteer of the Year, Mohamad Najjar; newly appointed Head of BHF Scotland, James Jopling; and the Minister for Public Health, Sport and Wellbeing, Joe Fitzpatrick MSP.

On the 5th December the Metal Ions in Medicine Group held their inaugural away day in the Gateway Building. On the day there were talks from post-doctoral researchers, PhD students, MSc students and an undergraduate student. Research topics included:

1. The role of zinc in cardiac muscle contraction

2. Fetal and adult circulatory zinc transport

3. The role of cobalt in ALVAL (aseptic lymphocyte-dominated vasculitis-associated lesion)

4. Characterisation of mutations in ATP2C2, a calcium/manganese transporter implicated in dyslexia

5. Biomarker discovery in esophageal adenocarcinoma

Sam and Alan would like to thank all the attendees/speakers for making the day so much fun and also to Dr Juan Varela (School of Biology) for coming along to support!

Dr Alan Stewart and Dr Sam Pitt have just been awarded a BHF PhD studentship grant of £108k for a project entitled “Role of plasma fatty acid and zinc dynamics in platelet functioning: Implications for pathological clotting“.

Zinc is an essential micronutrient that is required for many biological processes including control of coagulation. When platelets become activated they release zinc, which in turn binds to plasma proteins and cell surface receptors to regulate clotting. Currently we do not understand how zinc gets into platelets, how it is stored or how these processes may be altered in diseases associated with abnormal clotting. Elevated plasma free fatty acid (FFA) levels are associated with conditions such as cancer, obesity and diabetes, which also increase the risk of developing thrombotic blood clots. Our studies suggest that high levels of FFAs disrupt zinc handling in the blood potentially leading to thrombotic complications.

The specific aims of this project are to:
1. Examine zinc storage, compartmentalisation and flux in platelets.
2. Identify the zinc homeostatic machinery in platelets.
3. Examine the effects of FFA-mediated dysregulation of plasma zinc on platelet functioning.

We are looking for enthusiastic candidates who hold a first or upper-second class degree (and/or an MSc/MRes degree) in Molecular or Cellular Biology, Biochemistry, Chemistry or a related subject from a recognised academic institution. Applicants with some degree of laboratory research experience are particularly encouraged to apply. To apply, please visit the University of St Andrews website and download the PhD application form. Full details on how to apply are given here: http://www.st-andrews.ac.uk/study/pg/apply/research/

Here we detail a new technique to trick bacteria into revealing hundreds of holes in their cell walls, opening the door for drugs that destroy bacterial cells. This interdisciplinary work shows for first time that MscL channels are kept closed by membrane lipids – specifically lipid chains- which are located within nano-pockets highly sensitive to tension, pressure and force. When access of these lipids is disrupted by molecular nano-guards engineered at the entrance of the nano-pockets, the channel mechanically responds and opens its pore. Targeting these pores may pave the way for new drugs that can destroy bacterial cells and could make current antibiotics more effective or allow for the development of antibiotic-free drugs that can use these openings.

Here is a link to our paper https://www.nature.com/articles/s41467-019-12591-x

3^rd year BHF-funded PhD student Amy Dorward (Pitt lab) and Dr Gavin Robertson (PDRA; Pitt lab) visited Prof Hiroshi Takeshima’s lab at the Graduate School of Pharmaceutical Science, Kyoto University, Japan between 9^th August – 14^th September 2019. During this time both Amy and Gavin carried out some exciting new experiments, which will contribute to an upcoming publication.

Whilst in Kyoto, Amy, Gavin and Dr Samantha Pitt attended the International Society for Zinc Biology (ISZB) 2019 conference. They would like to thank the organisers for an excellent meeting. Samantha gave an invited talk entitled “Intracellular Calcium and Zinc Dynamics are Intrinsically Coupled”. Amy and Gavin both presented posters. Gavin was awarded a Metallomics poster prize.

Amy was awarded travel grants by Russell Trust, Biochemical Society, British Society for Cell Biology (BSCB) and the School of Medicine. Gavin obtained funding from BSCB and the Physiological Society.

Dr Alan Stewart and Dr Swati Arya would like to thank the organisers of ICAP2019 for an excellent meeting in Lisbon. Alan presented our work on drusen proteomics using SWATH-MS in an invited talk entitled ‘Hydroxyapatite interactome in Age-related Macular Degeneration’. Whilst Swati scooped a poster prize with her poster entitled “Quantitative proteomic changes in LPS-activated monocyte-derived dendritic cells”.

The Pitt and Stewart labs would like to say a big congratulations to Dr Gavin Robertson and Dr Amelie Sobczak on their graduation, and would also like to say a big thank you to the BHF for funding these students. #Ever to Excel

Dr Alan Stewart, Dr Swati Arya and Dr Peter Caie have been awarded a £89,415 grant from Tenovus Scotland for a new project entitled “Assessment of the predictive value of plasma proteins in oesophageal adenocarcinoma treatment”. The funding will support a PhD studentship due to start later in the year. Applications are now open to candidates who are interested in applying for this studentship. They must hold a first or upper-second class degree (and/or an MSc/MRes degree) in Molecular & Cellular Biology, Biochemistry, Chemistry (Analytical) or a related subject from a recognised academic institution. Full details are available here.

Dr Alan Stewart has been appointed to the editorial board of the journal, Scientific Reports – an online open access “mega journal” from the publishers of Nature. The journal publishes scientifically valid primary research from all areas of the natural and clinical sciences. Alan will serve on the journal’s Chemical Biology board.