Research Seminar: De Novo Protein Design: Faster, Better, Fitter

Professor Dek Woolfson, Schools of Chemistry and Biochemistry, & BrisSynBio, University of Bristol

Wednesday 26th November, 4.00 p.m., Stacey Lecture Theatre 1

We have developed a toolkit of de novo peptides (1). These can be used as building blocks for the rapid construction of new protein structures and supramolecular assemblies. This talk will demonstrate the utility of this approach to make nanoscale protein pores (2, 3), and peptide-based nanocages (4). Potential applications of these structures and materials span nanoscience, synthetic biology and biotechnology.

  1. A Basis Set of de Novo Coiled-Coil Peptide Oligomers for Rational Protein Design and Synthetic Biology. JM Fletcher, AL Boyle, M Bruning, GJ Bartlett, TL Vincent, NR Zaccai, CT Armstrong, EHC Bromley, PJ Booth, RL Brady, AR Thomson, and DN Woolfson.  ACS Synthetic Biology 6, 240-250 (2012)
  2. A de novo peptide hexamer with a mutable channel. NR Zaccai, B Chi, AR Thomson, AL Boyle, GJ Bartlett, M Bruning, N Linden, RB Sessions, PJ Booth, RL Brady and DN Woolfson. Nature Chemical Biology 7, 935-941 (2011)
  3. Computational design of water-soluble alpha-helical barrels. AR Thomson, CW Wood, AJ Burton, GJ Bartlett, RB Sessions, RL Brady and DN Woolfson. Science 346, 485-488 (2014)
  4. Self-assembling cages from coiled-coil peptide modules. JM Fletcher, RL Harniman, FRH Barnes, AL Boyle, A Collins, J Mantell, TH Sharp, Antognozzi, PJ Booth, N Linden, MJ Miles, RB Sessions, P Verkade, and DN Woolfson.  Science 340, 595-599 (2013)

Ageing expert Dr. Jennifer Tullet in podcast for “The Naked Scientists”

tulletDr. Jennifer Tullet recently contributed to the Naked Genetics podcast on “Genes, Ageing and Metabolism” for the popular “Naked Scientists” BBC radio show. The podcast explored Dr. Tullet’s use of the nematode worm C. elegans to understand the process of ageing and, in particular, how modifying the genetic make up of the organism alters metabolic processes that may influence the ageing process.

Dr. Tullet is a former undergraduate student from the School of Biosciences, and currently teaches metabolic regulation as part of our undergraduate degree programmes.

Research Seminar: Recombination in RNA viruses: Molecular mechanisms and honeybee diseases

Professor David Evans School of Life Sciences, University of Warwick

Wednesday 19th November, 4.00 p.m., Stacey Lecture Theatre 1

RNA viruses evolve rapidly, generating large populations of diverse progeny by the combined influence of error-prone polymerases and – in cells co-infected with two related viruses – recombinants possessing hybrid genomes. Recombination, presumably because it involves significant change in virus genotype, can readily generate viruses with a virulent phenotype. Using examples of poliovirus (humans) and deformed wing virus (DWV; honeybees) I will discuss recent novel insights into the molecular mechanism of recombination and the selection and evolution of virulent recombinant viruses in the host. Our studies demonstrate that recombination is a biphasic process, involving the generation of intermediates of greater than genome-length, potentially providing a mechanistic explanation for “evolution by duplication”. In honeybees, virulent recombinant forms of DWV are the primary cause of overwintering colony losses by beekeepers.

 

Research Seminar: Cell death and immunity

Professor Matthew  Albert Institut Pasteur, Paris, France

Wednesday 12th November, 4.00 p.m., Stacey Lecture Theatre 1

The danger model predicts that the way a cell dies influences the immune response, and in particular that necrotic cell death releases inflammatory damage-associated molecular patters (DAMPs) that are contained during programmed cell death (PCD). In the past decade, non-apoptotic forms of PCD have been defined, including necroptosis, a form of death morphologically similar to necrosis. Understanding how different forms of PCD influence the immune response has been hampered by the multiple programs intersecting at a molecular level, and as a result the heterogenous mixture of cell death phenotypes within a bulk cell population. We have used inducible forms of key apoptotic or necroptotic enzymes to specifically control cell death pathways, and test their impact in immunologically relevant settings. Our study demonstrates that necroptotic cells are superior in their ability to induce inflammation and recruitment of innate immune cells into the intra-peritoneal cavity. Moreover, we have shown that RIPK3-induced necroptotic cells can mediate efficient cross-priming of antigen by dendritic cells, in contrast to cells undergoing  Caspase-8 induced apoptosis. Additionally, vaccination with necroptotic cells induce protective immunity to tumor challenge. Surprisingly, secondary necrotic cells or primary freeze/thaw necrotic cells, despite release of DAMPs, did not induce such a potent CD8+ T cell response, indicating that programmed necrosis provide a unique set of signals that control the cross-priming.

Sky TV features expert commentary on Ebola by Dr. Jeremy Rossman

ebola virusA recent commentary article by Dr Jeremy Rossman, Lecturer in Virology at the School of Biosciences, he warns that the situation could change if the ‘exponential’ spread of the disease in West Africa is not halted soon.

He commented: ‘The situation in West Africa continues to worsen as the largest Ebola virus outbreak continues to spread. Over 8000 people have been infected and there are now isolated cases in the USA and Europe. Current trends show an exponential increase in cases, with almost 35% of the new cases arising in the past 21 days. In Sierra Leone it is estimated that there are five new cases every hour. Despite the efforts of many countries, resources and experienced medical practitioners are in short supply. Without additional resources it will be extremely difficult to stem the spread of the disease.

‘Despite the dire situation, there is still only limited cause for concern within the UK. There is heightened security and screening intended to keep infected people from leaving the Ebola region and the NHS has prepared treatment and quarantine facilities in the event that a case does arise in the UK. Unfortunately, Ebola has a long incubation period which means that an infected person may pass all screening tests before becoming sick.

‘As a result, it is not possible to completely prevent Ebola-infected individuals from entering the county, as was recently seen in the USA. However, hospitals and clinicians have been trained to recognize Ebola and to initiate preventive quarantine and disease surveillance. Even if an isolated outbreak did occur in the UK, it is unlikely that the disease would spread, given the current health care system and our available resources. However, this situation could change if the exponential spread of Ebola virus in West Africa is not halted soon.’

Dr Rossman was recently interviewed by Sky TV, see the full interview here:

http://mms.tveyes.com/PlaybackPortal.aspx?SavedEditID=f63263a5-6a91-4078-8bf6-4d7c3817bd68

 

Research Seminar: Getting to know the enemy: The dastardly and conniving alpha-synuclein oligomer

Professor Daniel Otzen

Interdisciplinary Nanoscience Research Center (iNANO), Aarhus University

Wednesday 5th November, 4.00 p.m., Stacey Lecture Theatre 1

The 140-residue protein alpha-synuclein (aSN) is a key player in the development of Parkinson’s Disease, characterized by the death of i.a. dopaminergic neurons. Although natively unfolded as a monomer in solution, aSN readily forms amyloid fibrils which accumulate as intracellular inclusions. It is however increasingly accepted that the cytotoxic species are smaller oligomeric (non-fibrillar) states, which can disrupt phospholipid vesicles in vitro. The role of the oligomer in the aggregation of aSN is unclear. We have recently demonstrated that aSN can form oligomers of at least two different size classes. The smaller oligomer has a mean size of 430 ± 88 kDa or 30±6 aSN monomers. It consists of a dense core and a more extended or unfolded shell which is unable to elongate fibrils, but rather inhibits amyloid formation in a concentration-dependent way, consistent with an off-pathway oligomer [1]. Hydrogen-deuterium exchange mass spectrometry reveals that this oligomer in fact consists of two co-existing oligomer populations with different hydrogen-bond protection patterns. The majority species (75-80%) is only protected in the central part of the sequence and is not in exchange with monomers, while the minority species is more protected but likely exchanges through the monomer. We suggest that the minority species is on-pathway and can form fibrils by incorporating monomers, while the majority species is the cytotoxic off-pathway species [2]. Cytotoxic membrane permeabilization is inhibited by the plant compound EGCG (epigallocatechin gallate) by a mechanism that is rather unexpected: there are no changes in overall oligomer structure or size but the C-terminal tail, which is otherwise mobile, becomes relatively immobilized and the affinity for membranes is highly diminished [3].

References:

1.Lorenzen, N. et al. & Otzen, D. E. (2014). The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation. J. Am. Chem. Soc. 136, 3859-68.

2.Paslawski, W. et al. & Otzen, D. E. (2014). Co-existence of two different α-synuclein oligomers with different core structures determined by  Hydrogen/Deuterium Exchange Mass Spectrometry. Angew Chem Int Ed Engl Apr 16 (Hot Paper), [Epub ahead of print].

3.Lorenzen, N. et al. & Otzen, D. E. (2014). How epigallogatechin gallate can inhibit α-synuclein oligomer toxicity in vitro. J. Biol. Chem. In press (Paper of the Week).

 

Research Seminar: Datamining of bioactive ligands

Dr. John Overington, BSc PhD MBCS FSB FRSC C.Chem.

European Molecular Biology Laboratory – European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge

Wednesday 29th October, 4.00 p.m., Stacey Lecture Theatre 1

The ChEMBL database contains data from many successful and failed drug discovery projects. By querying the data in specific ways and performing data-mining, it is possible to discover useful rules for the selection of drug targets, rules for lead optimisation, and also for understanding and anticipating attrition during clinical development. During the talk we outline a number of examples of useful and practical rules discovered from the ChEMBL data, covering attrition and polypharmacology, screening file enrichment, and finally how to discover tractable targets from genomic and clinical data.

Research Seminar: Challenging clonal, uniparental inheritance of animal mtDNA.

Dr. Emmanuel (Manolis) Ladoukasis Department of Biology, University of Crete

Wednesday 22nd October, 4.00 p.m., Stacey Lecture Theatre 1

During ’90s animal mitochondrial DNA (mtDNA) was described as short, maternally inherited, non-recombining genome. Two decades later there is enough evidence to challenge these assumptions. In this talk I will present data, which show that both the maternal inheritance and the non-recombination of mtDNA might not be as strict as was previously believed. I will also suggest a hypothesis which couples maternal inheritance of mtDNA with heteroplasmy and recombination.

Wain Medal Lecture: The Battle of the Sexes: how sex chromosomes influence human health and disease

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Dr. James Turner, Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London.

Wednesday 15th October, 5.00 p.m., Woolf Lecture Theatre, University of Kent

Free and open to all

Most people would readily accept that men and women are different. Although some of these differences, for example in anatomy and biochemistry, are obvious, others are less commonly appreciated. For instance, women suffer from rheumatoid arthritis more often than men, and conversely, men are more commonly diagnosed with autism than women. Why is this the case? The answer is that men and women differ fundamentally in their genetic make-up.

XY chromosomesGenes are carried on chromosomes, and most of these chromosomes are identical between the sexes. However, one particular pair of chromosomes, the aptly-termed “sex chromosomes” is not the same in men and women. Women have two copies of a long, gene rich chromosome called the X chromosome, while men have one X chromosome, and a second, gene-poor, wimpy chromosome called the Y chromosome. As well as influencing disease susceptibility, these sex chromosomes determine whether a human embryo will go on to develop as a boy or a girl, and they have an especially important role in male and female fertility during later life.

In this presentation, I will explain how and why sex chromosomes appeared in our ancestors, and the benefits and drawbacks that they have for human health. I will also discuss how research into sex chromosomes is represented in the popular media, and how cutting edge research on these unusual chromosomes is creating new potential disease treatments.

Biography:

James studied Medicine at University College London, during which he also carried out a PhD in sex chromosome genetics at the Medical Research Council National Institute for Medical Research, London with Paul Burgoyne. He subsequently worked as a junior physician at West Hertfordshire NHS Trust, before returning to NIMR London to continue his work on sex chromosome genetics as a postdoctoral scientist. He completed his postdoctoral training in the laboratories of Peter Warburton, Mount Sinai School of Medicine, and David Page, Whitehead Institute, USA, before starting his own research group at NIMR and becoming an honorary research associate at UCL in 2007. His research focuses on the evolution, cell biology and biochemistry of the sex chromosomes from a variety of organisms, including mammals, in order to understand how these chromosomes influence human health and disease.

Teaching Awards for staff in School of Biosciences

Staff in the School of Biosciences have been recognised at the University Teaching Awards ceremonyTeaching Prizes. Dr. Jeremy Rossman received the Sciences Faculty Teaching Prize from the Vice-Chancellor, Professor Dame Julia Goodfellow, for the development of novel approaches to teaching Virology. His work with final year students encourages them to engage with cutting edge literature, placing them at the centre of the discovery process and developing the critical evaluation skills that are essential in scientific research.

Capping an extraordinary year of achievement, Dr. Peter Klappa was presented with a special (and surprise!) award at the ceremony in recognition of his sustained excellence in teaching. As part of the 50th Anniversary celebrations that are commencing this academic year, Dr. Klappa was presented with the award by Pro-Vice-Chancellor Professor Chris Davies. It follows his award of a National Teaching Fellowship in July 2014.