Bioscience Research Group Seminar Series

Delivered by Prof. Marta Filizola, Icahn School of Medicine at Mount Sinai, New York, USA

Prescription opioids such as oxycodone and morphine remain the gold standard for treating moderate to severe pain, notwithstanding the daunting number of unintentional opioid overdose fatalities mostly due to respiratory depression through the μ-opioid receptor (MOR), as well as their high potential for abuse liability. Since efforts to discover safer analgesics targeting MOR at the orthosteric site have encountered challenges, there is a need to discover potentially safer non-opioid alternatives while making opioid drugs safer to use. Molecular dynamics simulations leveraged by artificial intelligence-based methods have contributed an atomic-level understanding of how opioid drugs bind and activate this receptor, shedding light on the complexities of receptor pharmacology and thus informing the design of potentially improved opioid therapeutics. In this presentation, I will summarize recent efforts from my lab towards this goal.

Delivered by Dr Jonathan A. G. Cox, School of Biosciences, College of Health and Life Sciences, Aston University

Infections caused by Mycobacterium abscessus are increasing in prevalence in cystic fibrosis patients. This opportunistic pathogen′s intrinsic resistance to most antibiotics has perpetuated an urgent demand for new, more effective therapeutic interventions. In this talk, Dr Cox will explain what M. abscessus is and why it poses such a significant clinical challenge. He will then discuss his group’s progress in developing a new three-drug treatment for M. abscessus infection; increasing the susceptibility of the organism to amoxicillin, by repurposing the β-lactamase inhibitor, relebactam, in combination with the front line M. abscessus drug imipenem. He will explain how this synergy has been explored on a microbial and biochemical level, and talk about how these drugs are being clinically trialled in the UK as a last therapeutic option for patients where conventional treatment has proven unsuccessful.

Delivered by Dr Shoib Siddiqui, Clinical, Pharmaceutical & Biological Sciences University of Hertfordshire

Glycans (sugars/carbohydrates) are present on the surface of every cell. Sialoglycans (Sia) is the terminal sugar for the glycan chain present on the glycoproteins and glycolipids. Sia binds with a family of protein called Siglecs (Sialic Acid binding Immunoglobulin superfamily Lectins) and can modulate the immune responses. Siglecs can be immunoinhibitory or immune-activating in nature. We have recently shown that an engagement of Sia with inhibitory or activating Siglecs affect tumour growth (Stanczak, Siddiqui et al., JCI, 2018).

It has also been recently shown that the secretory protein HMGB1 is a Sia binding lectin and plays an important role in the pathogenesis of sepsis (Siddiqui et al., PNAS, 2021). Thus, using state of the art techniques, the Siglec-Sia axis and HMGB1-Sia axis have been shown to be emerging players in cancer and sepsis. In this seminar, I will talk about some of the ground-breaking discoveries in the field of sepsis and cancer and how to target Sialoglycans for the next generation therapeutic interventions.

Delivered by Dr Emmanouil Karteris, Division of Biomedical Sciences, Brunel University London

Delivered by Dr Eric Hill, School of Life & Health Sciences, Aston Research Centre for Healthy Ageing, Aston University

Alzheimer's disease (AD) is the most common form of dementia affecting around 36 million people worldwide. It is impossible to study such changes in the cells of living patients, and it is difficult to adequately study the disease in animals as they do not naturally develop the condition. A revolutionary technique now allows stem cells to be generated from the skin cells of individual patients. In this seminar Dr Hill will discuss the use of these induced pluripotent stem cells to generate functional brain models to study AD and how advancements in tissue engineering are allowing scientists to build complex neural circuits to study development and disease.

Delivered by Professor Peter Mullany, Microbial Diseases, UCL Eastman Dental Institute,
Faculty of Medical Sciences

Mobile genetic elements (MGEs) can spread genes between bacteria, sometimes even between very distantly related organisms. In this talk I will illustrate, using examples taken from my research, the different types of MGEs and the effect they can have on bacteria and consequently on humans.

As well as providing challenges for humans MGEs offer many opportunities in the field of biotechnology. Evolution has equipped them with the ability to cross bacterial cell walls and membranes, to enter and genetically manipulate bacterial genomes. These abilities have been utilised by molecular biologists for the last 60 years or so to make huge advances in biological sciences. Furthermore, the response of the host bacteria to protect themselves from MGEs such as production of restriction enzymes and CRISPR Cas systems has also been used by scientists to revolutionise molecular biology.

I will give a brief example of some of our current work using CRISPR Cas systems to target antibiotic resistance genes on MGEs.

Delivered by Dr Caroline Formstone, Department of Clinical, Pharmaceutical & Biological Science, University of Hertfordshire, UK

The skin provides a protective layer for the body against desiccation and external assault. How skin is built in the embryo has been long studied but little is known about how it encompasses the body. My research has shown that the skin emerges in mouse embryos just over half-way through gestation. The skin appears as a thickened tissue at the mid-flank of the embryo trunk which subsequently thins and spreads from the mid-flank towards the front of the embryo (ventral-side) and the back of the embryo (dorsal-side) eventually enclosing the embryo trunk 2-3 days later. I will provide evidence that skin enclosure of the embryo body requires both intrinsic and extrinsic processes. Overall, my research raises the hypothesis that failure to enclose the embryo body with skin may underlie some common birth defects of dorsal and ventral closure and importantly that extrinsic factors may reduce their prevalence.

Delivered by Prof. Ana-Nicoleta Bondar, Department of Physics, Freie Universität Berlin, Germany

The new SARS-CoV-2 virus is known to bind via the spike protein (protein S) to the human host ACE2 receptor followed by proteolytic activation of S. Structural signatures of conformations sampled by protein S were identified with graph-based algorithms in static structures and simulations of protein S. We found that the closed conformation of protein S has, at key functional sites, three-fold symmetrical H-bond clusters. Loss of three-fold symmetry as observed in open and closed conformations of the spike protein could facilitate conformational selection for receptor and protease interactions. Instead of discrete interaction pairs, the receptor-binding interface consists of an extensive interaction network that includes multiple groups from both protein S and ACE2, which could explain strong binding affinity and provide robustness.

Delivered by Dr. Bill Broadhurst, Department of Biochemistry, University of Cambridge

I will provide a brief introduction to protein dynamics on different timescales and ways of quantifying these processes, with a particular focus on NMR spectroscopy. I will then discuss an application to the conformational plasticity of ligand-bound ternary complexes of the beta1-adrenergic receptor, a model G-protein coupled receptor (Nature Communications (2020) 11, 669). After that I will describe some of my work on the dynamics of acyl carrier protein domains in modular polyketide synthase multienzyme complexes (Biochemical J (2016) 473, 1097-1110; Scientific Reports (2019) 9, 2325; Chemical Comm (2017) 53, 11457-11460).