Conway Focus Issue 13 March 2011

Elaine QuinnCommunications & Education Officer

UCD Conway Institute of Biomolecular & Biomedical ResearchUniversity College Dublin

Belfield, Dublin 4Ireland

E: [email protected]: (+353-1) 716 6706F: (+353-1) 716 6701

W: www.ucd.ie/conway

Investing in Your Future

septem

ber2

007

Issue1

Research by Conway Fellow, Dr OliverBlacque has revealed new informationabout a gene implicated in Joubertsyndrome and related cerebellar disorders(JSRDs), characterised by blindness, boneabnormalities, cystic kidneys,developmental delay and loss of muscletone and control. The findings of thisresearch, funded through a ScienceFoundation Ireland President of IrelandYoung Researcher Award (PIYRA) to OliverBlacque, were recently published in theJournal of Cell Biology.

One of seven genes associated with JSRDs,Arl13b codes for a protein already known toplay roles in the formation and/or functionof cilia, which are hair-like projectionsextending from the surface of the cell.However, the precise molecular details ofwhat exactly Arl13b is doing in cilia haveremained unclear.

Blacque’s team studied the gene in the ciliaof tiny worms (Caenorhabditis elegans)while collaborators in the University ofTokyo conducted parallel experiments incultured human cells. Together, theyconfirmed that Arl13b proteins uses lipidanchors to associate with the ciliarymembrane.

Much of the work on the project was carriedout by UCD doctoral candidate, SebihaCevik. She and her colleagues went on todemonstrate in C. elegans how disrupting

the function of worm Arl13b causes theciliary membrane to bulge and becomemisshapen as well as affecting the ability ofother proteins to properly distribute withinthe ciliary membrane.

They also found that a fully functionalArl13b protein is needed for the normalfunctioning of a protein transport system incilia. This intraflagellar transport system(IFT) makes contact with the ciliarymembrane. Based on these results, theyproposed a new working model for Arl13b,where it functions at the ciliary membraneto regulate important ciliary membraneproperties such as shape, transmembraneprotein distributions and IFT.

Up to only 20 years ago, many believedmost cilia to be redundant cellularorganelles that have fallen victim tomammalian evolution - a type of cellularappendix. We now know that these cellularantennae present on nearly all of our cellsand serve fundamental roles in manymotility and sensory functions, includingsignalling pathways critical to development.

It is now not surprising that defects incilium structure and function are associatedwith an ever expanding range of humandiseases and syndromes, collectively calledciliopathies, which have overlapping clinicalfeatures such as polycystic kidneys andlivers, retinal degeneration, boneabnormalities, hydrocephalus, as well as

complex traits including obesity, diabetes,mental retardation and even cancer.

Dr Oliver Blacque hopes that these findingswill ultimately lead to a greaterunderstanding not only of JSRDs, but alsoof closely related ciliopathies such asMeckel Gruber and Bardet-Biedl syndrome,as well as perhaps more commonphenotypes associated with ciliumdysfunction such as mental retardation andobesity.

He notes “That Arl13b associates with ciliarymembranes and is required for ciliumstructure/function in both worms andmammals demonstrates the remarkableevolutionary conservation of how this smallG-protein functions.”

ReferenceJoubert syndrome Arl13b functions at ciliarymembranes and stabilizes protein transport inCaenorhabditis elegans. Cevik S, Hori Y, Kaplan OI,Kida K, Toivenon T, Foley-Fisher C, Cottell D, Katada T,Kontani K, Blacque OE. J Cell Biol. 2010 Mar 22;188(6):953-69

May2010Issue10

I am delighted to welcome you to theConway Focus and look forward to workingwith you in the coming months!

As an institute with an increasinglyinterdisciplinary research focus andexpertise in specialist technology platforms,we are uniquely placed to participate in theeducation and training of the nextgeneration of research scientists. The newlylaunched PhD programme in Bioinformaticsand Systems Biology recently attracted 80EU and 120 non-EU applicants for up to 15studentships.

We introduced 4 new advanced coretechnology modules on a pilot basis thisacademic year; those covering principlesand practical aspects of imaging and appliedproteomics began in late March and will rununtil mid-June with a further two modules ingenomics and flow cytometry taking placeover week-long periods during the summermonths.

We hope to determine from this pilot ifdemand for training from within UCD as wellas from external academic centres andindustry will dictate stand-alone delivery ofthese advanced modules or inclusion within

larger programmes such as the new MSc inImaging commencing in September 2010.

I hope that a number of new initiatives,including the early-stage researcher forumdescribed in this issue, will not onlystrengthen the community of Conwayresearchers and forge new interdisciplinarylinks but will celebrate and heightenawareness of our research and innovationsuccesses.

Professor Walter KolchDirector, UCD Conway Institute

Director’s Message

Worm research reveals cilia disease gene function

UCD CONWAY INSTITUTE OF BIOMOLECULAR & BIOMEDICAL RESEARCH

Arl13b at ciliary membrane

Centre of Excellence hosts international workshop

As a European Centre of Excellence, theDepartment of Rheumatology in St Vincent’sUniversity Hospital was chosen to host aninternational two-day workshop on March26th & 27th 2010. Sponsored by RochePharma, the Participate workshop gavetwenty rheumatologists from centres inEurope and Australia the opportunity towitness the care of patients with rheumatoidarthritis (RA) at St Vincent’s.

The Participate programme focused onadvanced treatment regimens for RA in theclinic, including practical aspects of biologictherapy carried out in the accredited infusionsuite that provides optimal care for RApatients. In addition to lectures from ConwayFellows, Professors Oliver FitzGerald andDouglas Veale, delegates heard from clinicalnurse specialists about patient education,screening and monitoring of biologicaltherapies.

Addressing the international guests, Ms MaryDuff, Director of Nursing and Ms. KayConnolly, Assistant Director of Nursing for theBone & Joint Unit expressed their hope thatthe experience of the multidisciplinary teamfrom St Vincent’s would provide a template fordelegates to reproduce similar care andfacilities for the management of RA patients intheir respective countries.

Launch of Conway postdoctoral & graduate forum

A new fortnightly forum for Conway graduateand postdoctoral researchers will be launchedin May 2010. This initiative will give early-stage researchers the opportunity to talk aboutscience and issues that concern them in aninformal environment with refreshmentsprovided! Content for the forum will be

decided by the members but it is envisagedthat it will include a mix of technologyoverviews, informal and formal researchseminars, PhD viva rehearsals and careerdevelopment talks from within and beyondacademia. Forum committee members, PhDstudent Mr Thomas Schwarzl

([email protected] ) and postdoctoralresearchers, Dr David Gomez([email protected]) and Dr Craig Slattery([email protected] ) invite suggestions forthe forum schedule.

Frog peptide structure selected for journal cover

An image of the frog peptide structure centralto the work of a UCD Conway research teamwas selected as the front cover image for theApril 2010 edition of the scientific journal,Biochimica et Biophysica Acta (BBA);Proteins & Proteomics.

Peptides in the skin of many species of froghave anti-bacterial and anti-fungal propertiesas well as the ability to lyse or rupturemammalian cells. This innate immunityprotects it from attack. These properties offrog skin peptides are exciting from theprospect of being developed intotherapeutically valuable anti-infective and anti-cancer agents.

Conway Fellow, Dr Chandralal Hewage and histeam carried out molecular modelling of theXT-7 peptide and its analogue [G4K]XT-7 in a

variety of solutions in order to understand thestructural basis for the difference in biologicalactivity.

This particular XT-7 peptide, isolated from theskin of Silurana tropicalis, shows potential fordrug development as it has impressive activityagainst the growth of bacteria and Candidaalbicans. However, this potential as an anti-infective agent is restricted by its haemolyticactivity.

A change to the amino acid structure of theXT-7 peptide can create an analogue thatretains anti-infective properties but without thecomplicating haemolytic activity. The singleamino acid substitution (glycine replaced bylysine) improves the therapeutic potential ofthis naturally occurring peptide.

Cover of April 2010 edition of Biochimica et BiophysicaActa (BBA); Proteins & Proteomics.

May 2010.qxd:Layout 1 copy 07/05/2010 13:12 Page 1

Irish biopharmaceutical developmentcompany, Sigmoid Pharma recently scoopedthe overall Innovation of the Year award atthe inaugural Irish Times All-IslandInnovation Awards. The life-science SME,founded by UCD pharmacology graduate, DrIvan Coulter, has actively collaborated withConway Fellow, Professor Cormac Taylorsince being granted a Science FoundationIreland industry research partnership awardin 2004.

The Irish Times award recognises the stellarinnovative performance of Sigmoid Pharma intheir application of research and development.The company has developed two new drugtechnologies, LEDDS™ and SmPill™, which notonly enhance the solubility and permeability ofthe drug but can deliver it to targeted locationsin the gastrointestinal tract, including thecolon.

The Sigmoid Pharma-Taylor collaboration isfacilitating the development of a newtherapeutic approach for the treatment ofinflammatory bowel disease (IBD) by bringingtogether the research methodology of theTaylor group with the proprietaryliquid/emulsion drug delivery system,LEDDS®, developed by Sigmoid Pharma.

Commenting on the award, Professor Taylorsaid, “We are delighted for Dr Coulter and histeam and indeed it reflects well on ourpartnership. A key driver of successfulscientific research in 2010 is meaningfulinteraction of academia with industry that

results in both academic outputs and theapplication of research toward clinical productdevelopment with indigenous companies.”

Commenting on the Taylor collaboration, DrCoulter said, “The collaboration with the Taylorlaboratory clearly demonstrates the potentialthat can be realised through focusedapplication of basic research. The developmentof a smart economy will depend on like-mindedcollaborative partners identifying opportunitiesand realising basic and applied researchsynergies. This collaboration, initiated througha SFI research supplement, highlights thepotential that innovative indigenous companiesworking with academia can realise.”

Taylor’s collaboration with Sigmoid Pharma hascertainly been successful by these metrics withthree co-authored publications to date in two ofthe highest ranking scientific journals in thefield, Gastroenterology and Proceeding of theNational Academy of Sciences, as well as thegeneration of proprietary innovative productsand the creation of high-skilled jobs.

More than 15,000 people in Ireland andmillions of people worldwide are living with thesymptoms IBD today. Current therapeuticoptions for this chronic debilitating disease arevery limited with surgery often being the onlyviable option. The Sigmoid product, currentlyin a phase II clinical study, uniquely enablesoral delivery of a powerful drug withoutcausing systemic side-effects.

Under normal conditions, the gastrointestinal

tract is lined with cells that block the contentsof the gut from leaking into the intestine. In anIBD patient, this barrier is broken and thecontents of the gut leak out into surroundingareas. The research team in UCD Conway useda model of IBD and, by applying a new class ofdrugs known as hydroxylase inhibitors, wereable to almost completely reverse thesymptoms of the disease.

“When we applied these new drugs to our IBDmodel, the gut was tricked into thinking that itwas being deprived of oxygen. This activatedprotective pathways, which in turn preventedthe death of the cells that line thegastrointestinal tract,” explained ProfessorTaylor. “Our pre-clinical trial data can nowinform the next phase Sigmoid Pharma productdevelopment pipeline”.

In addition to the product that is currently inphase II clinical studies, Sigmoid Pharma isdeveloping a LEDDS™-enabled formulation ofthe hydroxylase inhibitordimethyloxaloylglycine (DMOG) to bring abouteffective, safe and targeted delivery of thispotential therapeutic agent.

Conway collaborator scoops Irish Times Innovation Award

Conway researchers led by Dr. TaraMcMorrow and Professor Michael Ryan havesuccessfully secured €485,500 in funding aspart of an overall award to the SystemsBiology towards Novel Chronic KidneyDisease Diagnosis and Treatment (SysKid)consortium under the European Union FP7programme.

Syskid (www.SysKid.eu) was established tofurther our understanding of chronic kidney

disease (CKD) and improve patient treatment,with particular focus on CKD arising fromdiabetes and hypertension. The multi-disciplinary research consortium has 25partners (16 universities, 9 industry partners)from 15 countries and the project is due to runfor five years.

The UCD Conway team, including postdoctoralresearchers Dr. Craig Slattery and Dr. NataliaMartin, will utilise cell culture and animal

models to identify processes involved in earlyCKD progression and investigate novelstrategies for preventing and slowing theprogression of the disease. These studies willbe integrated with clinical and epidemiologicalstudies across the consortium using systemsbiology methodologies in order to develop newdiagnostic strategies and treatment options toprevent CKD development. [email protected] for details of a PhDposition currently available.

Success in EU FP7 call

Bioinformatic analysis of HIV progression studies

Meta-analysis by UCD researchers led byConway Fellow, Professor Denis Shields hasdetermined that there is no clear evidencethat particular defective viral sequences inthe HIV-1 nef gene or certain regions of theprotein play a significant role in diseaseprogression.

HIV-infected patients can be categorised onthe basis of the number of years it takes forthem to progress to AIDS. Some patientsmaintain stable CD4 lymphocyte counts anddo not go on to develop AIDS even after morethan 10 years of infection.

Scientists are curious as to why these long-term, non- progressor (LTNP) patients do notdevelop AIDS. This may reflect differences inthe host, viral genetics or environmentalfactors that could potentially be exploited forthe treatment of the disease.

Studies in model organisms have shown thatinfection with nef-deficient virus shows anattenuated course of infection and some

studies in humans have shown that nonprogression was associated with grossdeletions in the nef gene.

However, much of the research in the area todate has been based on observational or casestudies rather than rigorous, systematicscientific evaluation. This work by doctoralcandidate Ravindra Pushker set out todetermine in a substantially larger sample setif any association exists between diseaseprogression and particular amino aciddifferences or deletions within the nef gene.

On a per patient basis, there was no excess ofLTNP patients with one or more defective nefsequences when compared to progressors.While the high frequency of amino acidreplacement at particular residues is indicativeof rapid evolvement, permutation testingshowed that residues with more replacementsthan expected were not statistically significant.

The researchers conclude that current dataprovides no evidence that individual residues

of HIV nef are critical in determining the rateof disease progression. Professor DenisShields believes that searches for modifiers ofprogression rates should now focus on otherhost and viral factors. “Systematic evaluationof large quantities of data by bioinformaticscan be just as important in refutinghypotheses that are current in the literature, asit is in discovering unknown patterns”, he said.

This research was funded through ScienceFoundation Ireland and University CollegeDublin.

Reference:Meta-analysis to test the association of HIV-1 nef aminoacid differences and deletions with disease progression.Ravindra Pushker, Jean-Marc Jacquē, Denis C. Shields.Journal of Virology, Apr 2010 p3644-3653

GlycoExtractor advances glycan data manipulation

Glycomics needs the supporting frameworkof extensive, well-curated databases andflexible analytical tools. Currently, this fieldof study lacks the established,comprehensive and centralised datacollections, standards and informationreporting protocols that exist withingenomics and proteomics.

Researchers, Dr Natalia Artemenko and DrMatthew Campbell from the National Instituteof Bioprocessing Research & Training (NIBRT)led by Conway Fellow, Professor Pauline Ruddhave developed an open access, web-basedinterface that facilitates extraction, queryingand sharing of HPLC-glycan data generated inhigh throughput processes.

Glycosylation is the most common andstructurally diverse post-translationalmodification of proteins. More than half of allgene products have been shown to beglycosylated. With many specific glycans orglycoforms showing potential as cancerbiomarkers, there is an increasing need todevelop high throughput, highly sensitive androbust strategies that detail the glycome of

cells, tissues and fluids.

Commercial packages that support HPLCinstruments cannot facilitate the extraction oflarge quantities of data. In an effort to alleviatethis bottleneck within high-throughputglycomic projects, the NIBRT team havedeveloped a web-based tool that interfaceswith the Waters chromatography softwarepackage to improve and automate the exportof data to various file formats for subsequentanalysis. The modular architecture of the toolalso facilitates the manipulation of data fromother data management systems.

The NIBRT team are now working to integrateGlycoExtractor with the EUROCarbDBframework to provide a comprehensive high-throughput HPLC data analysis platform forthe storage and annotation of experimentaldata. The integration of next generationbioinformatic tools will further thedevelopment of unified approaches forhandling large scale glycomics data initiativeswith applications in biomarker discovery

This research was partially supported by

EUROCarbDB, a research infrastructure designstudy funded by the EU 6th FrameworkProgramme. Prospective users can access theGlycoExtractor tool onhttp://glycobase.nibrt.ie:8080/DemoGlycoExtractor/mainPage.ReferenceGlycoExtractor: A web-based interface for highthroughput processing of HPLC-Glycan dataNatalia V. Artemenko, Matthew P. Campbell, and PaulineM. Rudd Journal of Proteome Research, 2010, 9 (4), pp2037–2041

NIBRT researchers Dr Matthew Campbell and Dr NataliaArtemenko who developed GlycoExtractor

Zebrafish model gives insights into diabetic blindness

New research led by Conway Fellow DrBreandán Kennedy indicates that treatmentof diabetic blindness should look atprotecting the neurons responsible for colourvision in the eye and not just targeting theblood vessels as is currently the practice.

Nearly 2.5 million people worldwide are blinddue to diabetic retinopathy. This secondarycomplication of diabetes activates the growthof new leaky blood vessels in the eye and isresponsible for the death of photoreceptors,the neurons that send visual messages to ourbrain.

Until now, it was unclear if the changes tovessels and neurons occurred independently ofone other and which type of retinal neuron is

most likely to die as a result of the raisedglucose levels seen in diabetes.

Dr Kennedy and his team found that new bloodvessels and the neuronal cell death in diabeticretinopathy can arise independently of eachother. In addition, they identified that conephotoreceptor neurons, those involved incolour vision and used in daylight, are mostaffected by the high glucose levels.

The research team made their observationsusing a novel zebrafish model of diabetes,which resembles the early stages of diabeticretinopathy in humans. It is an excitingdevelopment for the group who now hope tofurther extend their research and establish amodel of late stage diabetic disease.

Commenting on the research, Dr Kennedysaid, “By establishing a robust model for earlyand late stage diabetic retinopathy, we wouldhope to better understand the progression ofthe disease and pave the way for identifyingnew drug targets for its successful treatment”.

The research was funded through ScienceFoundation Ireland and the Health ResearchBoard.

Reference:

Predominant cone photoreceptor dysfunction in ahyperglycaemic model of non-proliferative diabeticretinopathy. Yolanda Alvarez, Jenneth Chen, AlisonReynolds, Nore Waghorne, John J. O’Connor, BreandanKennedy. Disease Models & Mechanisms (2010)




















































Reference:





















































Reference:



Towards personalised nutritionAs the latest addition to the ‘omic’ field of science, metabolomics shows potential in the area of nutrition research. New research led by Conway Fellow, Dr Lorraine Brennan is making strides in developing the use of metabolomics to discover potential dietary biomarkers and in identifying groups of people who respond to specific dietary interventions.

The link between diet, lifestyle, genetics and risk factors for chronic diseases is now a focus of international research. With diet being a major contributory factor to the increase in metabolic diseases such as obesity, diabetes and cardiovascular disease, a reliable dietary assessment method is crucial to understanding this link.

The small molecules or metabolites that result from complex processes within the cell are influenced both by endogenous factors (such as age, sex, genes and disease) and exogenous factors (such as diet and drugs). Using nuclear magnetic resonance (NMR) and mass spectrometry, multivariate analysis of metabolites can provide a chemical profile of activity within cells.

New findings by this team show that metabolic profiling of urine can reflect dietary patterns of individuals. The study, published recently in the American Journal Clinical Nutrition, identified two novel

biomarkers for red meat and vegetable intake.

Using biofluids and food diaries from 160 individuals, researchers were able to identify metabolites associated with different dietary patterns from 33 different food groups. Several of the metabolites were linked to specific food groups. In particular, O-acetlycarnitine was associated with red meat intake and phenylacetylglutamine with vegetable intake.

Commenting on these findings, Dr Brennan says, “By identifying these biomarkers, we are taking a significant step forward in developing the novel concept of nutritype. The ability to produce a metabolic profile that reflects patterns of dietary intake could be extremely valuable as part of dietary assessment in the clinical setting”.

As well as gaining insight into the habitual dietary patterns of individuals, this research group have also used metabolomic profiling to monitor specific dietary interventions.

There is evidence to suggest that vitamin D status may play a role in the development of diseases related to the metabolic syndrome. This syndrome is the collective name for a group of risk factors that occur together and increase risk of stroke, cardiovascular disease and type II diabetes. Research findings by groups working in this area suggest that low

serum levels of vitamin D are associated with markers of disturbed glucose metabolism and cardiovascular disease.

“We have developed a method to identify people who respond to supplementation with vitamin D with respect to the markers of the metabolic syndrome. This new method is a move towards personalised nutrition and being in a position to advise specific groups of people based on their metabolic phenotype rather than more generic , ‘one size fits all’ approach.”

Lorraine Brennan, and her colleagues in the UCD Institute of Food & Health and University College Cork, are now in the process of expanding both of these studies to assess applicability in larger cohorts and, in respect of the latter study, to other dietary interventions. This work has been funded by the Irish Department of Agriculture, Food and Fisheries.

Director’s MessageI am delighted to welcome Dr Ian Barwick, Business Development Manager for the Conway, Systems Biology Ireland & Charles Institute to the directorate team. Ian will be pivotal in driving our strategic innovation agenda and maximising the impact of our relationships with industrial partners. Specifically, he aims to attract new collaborative research funds and identify opportunities for new product/process development with industry partners.

With a background in chemistry and over 18 years experience in the pharmaceutical industry, Ian comes to UCD from Bangor University, Wales where he spent 4 years as Technical Director for Intellectual Property and Commercialisation.

Congratulations to Professors Geraldine Butler and Denis Shields as they launch the Wellcome Trust UCD PhD programme in Computational Infection Biology. Their success in securing such competitive

funding is testament not only to the scientific credentials of the investigators involved but also to the collaborative strength that manifests with cross-institutional interactions.

Professor Walter Kolch Director

A number of Conway graduate and postdoctoral researchers have recently been recognised for outstanding research in national and international competitions.

Dr. Patricia McGowan won the 8th St Luke’s Young Investigators Award for her presentation on ‘ADAMs: new players in breast cancer progression’. A senior postdoctoral researcher working in the Education & Research Centre, St Vincent’s University Hospital with Professor Joe Duffy, Dr McGowan received the Royal Academy of Medicine in Ireland bronze medal and €1000.

Brian Morrissey, PhD student with Professors Stephen Pennington and John Armstrong (St Luke’s Hospital) won the Waters postgraduate symposium competition for demonstrating innovative, analytical ideas through his proteomic research.

As part of his €20,000 prize, Brian will spend a week in Waters laboratories in Manchester where their high value mass spectrometry equipment and specialist advice will be at his disposal.

Dr Judith Conroy, postgraduate researcher with Drs Sean Ennis and Sally Ann Lynch in UCD School of Medicine & Medical Science was one of three scientists awarded KnomeDISCOVERY™ exome sequencing and comparative analysis packages.

Judith will use KnomeDISCOVERY™ in her research on facio-audio-symphalangism (FAS), a rare developmental syndrome. Working with two Irish families each with a set of triplets where only two children are ‘identical’ twins and both have FAS, she hopes to identify distinctive spelling variants that could cause the disease

and establish if there is any link to the process of twinning.

Mar

ch 2

011

Issu

e 13

Reference

O’Sullivan A, Gibney MJ, Brennan L. Dietary intake patterns are reflected in metabolomic profiles: potential role in dietary assessment studies. American Journal Clinical Nutrition 2011 93:314-321. In press

O’Sullivan A, Gibney MJ, O Connor A, Mion B, Kaluskar S, Cashman KD, Flynn A, Shanahan F, Brennan L. (2010) Biochemical and Metabolomic Phenotyping in the Identification of a Vitamin D Responsive Metabotype for Markers of the Metabolic Syndrome.Molecular Nutrition and Food Research.In press DOI 10.1002/mnfr.201000458

Recognising excellence in research



















































Reference:



PhD student, Kalyana Venneti and Conway Fellow, Dr Chandralal Hewage have determined the 3-dimensional solution structure of glucagon-like peptide-2 (GLP-2) for the first time using nuclear magnetic resonance and molecular modelling. This visual was selected as the cover image of the current issue of the biochemical journal, FEBS Letters.

Acting as an intestinal growth promoting agent in the small and large bowel, GLP-2 promotes the expansion of the epithelial mucosa and, consequently, better absorption of nutrients. It does this by stimulating crypt cell proliferation and preventing cell death in the gut epithelium.

Glucagon-like peptide-2 (GLP-2)

is a therapeutic target used in the treatment of short bowel syndrome, where nutrients are not being correctly absorbed either due to severe intestinal disease or surgical resection of a large portion of the intestine.

“These results provide a valuable insight into the structural and functional properties of GLP-2 and its receptor interactions, which could help in the design of novel therapeutic drugs that may be active at the GLP-2 receptor”, says Dr Hewage.

Reference Conformational and molecular interaction studies of glucagon-like peptide-2 with its N-terminal extracellular receptor domain. Kalyana C. Venneti, Chandralal Hewage. FEBS Letters volume 585 issue 2 21 January 2011

New 3-D visual of intestinal growth promoting peptide

Solution structure of glucagon-like peptide-2 as the cover image of FEBS Letters, January 2011



















































Reference:



Conway Fellow, Professor J. Paul G. Malthouse has developed three iPhone applications intended as experimental planning aids for researchers and revision aids for undergraduate and postgraduate students. EnzymeQA, AminoAcidQA and NMRQA contain a series of questions and answers on the topics of enzymology, amino acid

metabolism and 1- dimensional nuclear magnetic resonance (NMR).

Scientists using NMR in their research can avail of practical tips on setting up experiments such as parameters and signal processing, interacting with NMR operators and even basic NMR facts. Those researchers considering

New biochemistry applications for iTunes storeusing single substrate enzyme catalysis can check on appropriate experimental conditions for determining catalytic constants using EnzymeQA. The applications can be found on http://itunes.apple.com/us/app/enzymeqa/id412649030?mt=8

Back row (L-R): Dr John O’Connor, Gen Sec RAMI and UCD SBBS and Conway Institute; Dr Patrick Buckley, RCSI, finalist; Dr Patricia McGowan, UCD SBBS and Conway Institute, winner 8th St Luke’s Young Investigators Award; Dr Antoinette Powell, TCD, finalist; Mr Tom Walsh, President RAMI. Front row (L-R): Prof Donal Hollywood, Professor Clinical Oncology TCD; Dr Catriona O’Sullivan, Medical Director St Luke’s Hospital; Dr Claire Donohoe, TCD, finalist.



















































Reference:



First Welcome Trust funding for Irish based PhD ProgrammeIrish biopharmaceutical developmentcompany, Sigmoid Pharma recently scoopedthe overall Innovation of the Year award atthe inaugural Irish Times All-IslandInnovation Awards. The life-science SME,founded by UCD pharmacology graduate, DrIvan Coulter, has actively collaborated withConway Fellow, Professor Cormac Taylorsince being granted a Science FoundationIreland industry research partnership awardin 2004.


















































Reference:



For the first time in its history, the Welcome Trust has awarded funding for an Irish based PhD programme. The UK charitable foundation will provide upwards of €3 million towards a four-year structured UCD PhD programme in Computational Infection Biology.

The UCD PhD Programme will contribute to one of the Wellcome Trust’s major research challenges, namely to understand the emergence, transmission, pathogenesis and control of acute and chronic infectious diseases at the global level.

“The research programme will investigate the basis of pathogenicity and virulence in infectious organisms ranging from viruses (such as human immunodeficiency virus (HIV), hepatitis B, and influenza) to bacteria causing malaria, TB and other major diseases, and fungi, which grow on indwelling medical devices,” says programme director, Professor Geraldine Butler, UCD School of Biomolecular & Biomedical Science and UCD Conway Institute.

“The areas of investigation will include the host response to infection, identifying therapeutic targets and

developing novel drugs. One aspect unique to University College Dublin is that the programme will investigate pathogenesis in both animals and man, addressing the ‘One World, One Health’ initiative, linking human, animal and environmental health.”

Advances in the development of new high-throughput scientific techniques have generated enormous amounts of data relevant to infectious disease research that is currently under-utilised, due to a lack of methodologies and suitably trained scientists.

The new UCD PhD programme aims to address this by equipping students with the skills necessary to negotiate the cultural and linguistic barriers that currently separate biological and computational research disciplines.

The PhD programme will draw on expertise from across five UCD Schools, the UCD Conway Institute, and the UCD Complex and Adaptive Systems Laboratory (CASL) and will train scientists to integrate computational methods with biological research focused on infectious diseases.

It will build on the success of the UCD

PhD programme in Bioinformatics and Systems Biology funded by the Irish Research Council for Science, Engineering & Technology (IRCSET) since 2007, and also on individual research projects on infectious disease and bioinformatics funded by Science Foundation Ireland grants to participating investigators.

Professor Denis Shields, UCD School of Medicine & Medical Science, UCD Conway Institute & UCD CASL is the deputy director of the programme and many Conway Fellows will be involved in aspects of delivery. More details on the programme and application process are available on: http://bioinfo-casl.ucd.ie/cib. The deadline for the 2011/2012 academic year is 18th March 2011.

Ribbon representation of human hepatitis B virus core protein (HBc) dimers as found within recombinant capsids



















































Reference:



Proteomics underpinning research across diverse disciplines

of screening of the NP surface by the corona may impact on cell-particle interactions.

Taking two compositionally different nanoparticles, polystyrene and silica, in different plasma concentrations, protein adsorption studies showed that the hard corona can evolve quite significantly in different plasma concentrations.

The findings have implications for experimental design and in vitro – in vivo extrapolations given the varying protein concentrations in each type of study.



















































Reference:



Novel regulator of photoreceptor gene expression Conway Fellow, Dr Breandan Kennedy and his team, in collaboration with scientists in the University of Washington, Seattle, have identified a transcriptional regulator that is sufficient to enhance the initiation of photoreceptor specific gene expression.

Photoreceptors are the sensory neurons that capture images of the world around us. Although the two types of photoreceptor appear structurally similar grossly, they are functionally distinct with cone photoreceptors enabling colour vision and rods adapted to function in low light.

The morphological and functional development of photoreceptors depends on regulated gene transcription but very few cis-regulatory elements have been identified to date.

Using a zebrafish model, this study focused on expression in the cone transducin gene (TαC), which is required for colour vision. Mutations in this gene in humans cause

total colour blindness and cone-based blindness in zebrafish.

The team identified photoreceptor regulatory element 1 (PRE-1), a 41 base pair sequence that specifically binds eye nuclear protein. It has a number of unique characteristics when compared to other cis-regulators of photoreceptor expression.

Commenting on the recent publication of this research in BMC Developmental Biology, Dr Breandan Kennedy said, “It is only by deciphering the molecular mechanisms responsible for development and functionality in such complex systems that we can hope to engineer appropriate gene expression responses in the future”.

Science Foundation Ireland funded this research. The Kennedy group hope to further expand this study to identify elements acting with PRE-1 to regulate cone-specific expression.

Reference PRE-1, a cis element sufficient to enhance cone- and rod- specific expression in differentiating zebrafish photoreceptors. Maria E. Morrissey, Sara Shelton, Susan E. Brockerhoff, James B. Hurley and Breandán N. Kennedy. BMC Developmental Biology 2011, 11:3 doi:10.1186/1471-213X-11-3



















































Reference:



IDDN announce new industrial partnership with Arch Therapeutics

The Irish Drug Delivery Network (IDDN), a strategic research cluster funded by Science Foundation Ireland, has announced that it will collaborate with Boston-based Arch Therapeutics to optimise the development of novel products for surgery and trauma.

Arch Therapeutics has developed a clear liquid that forms a barrier when topically applied to a wound. The barrier promptly stops bleeding and seals leaking. The material has no effect on the coagulation process and is biocompatible. The underlying technology platform was licensed from the Massachusetts Institute of Technology.

Welcoming the announcement, Professor David Brayden, IDDN Director and Conway Fellow, said, “We look forward to working with Dr Terence Norchi, CEO Arch Therapeutics to help optimise the polymer formulation process and characterise the material at all stages of the synthetic process for this product. Our aim is to ensure a reproducible process for effective application of the product in surgery. ”

IDDN scientists are based in four academic centres; UCD, TCD, RCSI and UCC. This project will involve Prof. David Brayden, Dr Marc Devocelle (RCSI) and postdoctoral scientists based at Centre

for Synthesis & Chemical Biology (UCD) and the Peptide Synthesis Laboratory (RCSI). Dr Abina Crean (UCC) will work to optimise certain aspects of the manufacturing process and look at peptide secondary structure.

Arch Therapeutics was co-founded by a group of Irish-Americans in Massachusetts, USA and named after the iconic Spanish Arch in Galway.

The UCD Conway Mass Spectrometry Resource (MSR) instrumentation and expertise are being utilised in a diverse range of projects that aim to identify proteins and their modifications implicated in fundamental biology in health and disease.

Two recent examples of publications involving the MSR highlight the fact that proteomics as a core technology platform is underpinning research across scientific disciplines from agriculture to nanotechnology.

Currently, a major challenge for the swine industry is to improve the water holding capacity (WHC) of pork and reduce the incidence of meat with poor appearance, texture and a reduced shelf life.

Dr Giuliano Elia, MSR Director worked with collaborators in Teagasc Food Research Centre and NUI Galway to identify potential biomarkers for the early prediction of meat quality in an industrial setting.

The study detailed 44 proteins recovered in exudates from muscle tissue. There were several significant associations between the protein fragment band volumes that can be related to WHC or post mortem degradation.

A number of peptides from the heat shock protein (HSP) family involved in protecting cells from stress were identified. HSP interact with damaged proteins in an effort to restore function. The team believe that HSP70 may have potential as a biomarker for moderate to good WHC.

Working with Professor Kenneth Dawson, Centre for Bio-Nano Interactions (CBNI), the MSR were involved in a project to initiate a framework for the study of the protein corona surrounding nanoparticles in biological media.

This durable, stabilising protein coating on the bare surface of nanoparticle (NP) monomers is now thought to be a primary defining element of nanoscale objects in biological media. The extent

Reference :Physical-Chemical Aspects of Protein Corona: Relevance to in Vitro and in Vivo Biological Impacts of Nanoparticles. Marco P. Monopoli, Dorota Walczyk,Abigail Campbell,Giuliano Elia,Iseult Lynch, Francesca Baldelli Bombelli, and Kenneth A. Dawson. J. Am. Chem. Soc. 2011 In press dx.doi.org/10.1021/ja107583h

Centrifugal drip is an accessible source for protein indicators of pork ageing and water-holding capacity. Alessio Di Luca, Anne Maria Mullen, Giuliano Elia, Grace Davey, Ruth M. Hamill. Meat Science 2010 doi:10.1016/j.meatsci.2010.12.033

Highlighted for mention by BMC Developmental Biology. Confocal micrographs of retinal sections from 5 dpf zebrafish embryos injected with the (3x PRE-1)-1.2 kb ZOP-EGFP construct shows co-localisation with a marker for rod photoreceptors. Staining shows enhanced green fluorescent protein EGFP (green), rod photoreceptors (4C12; red) and nuclei (DAPI; blue)

Specific effect of cigarette smoke on innate immune cells UCD researchers in the obesity immunology research group led by Conway Fellow, Professor Donal O’Shea have demonstrated for the first time that cigarette smoke extract (CSE) has a specific effect on a minor subset of immune cells and this may contribute to the role of cigarette smoke in the development of cancer.

Carginogens in cigarette smoke can lead directly to lung cancer and have been implicated in several other malignancies. In addition, cigarette smokers have an increased susceptibility to type II diabetes, infections and autoimmune disorders such as rheumatoid arthritis.

Invariant natural killer T (iNKT) cells are immune regulators that play an important role in mounting anti-tumour

responses with the early production of potent cytokines. Many studies have already shown that iNKT cells are defective in certain cancers.

This study compared the number and function of iNKT cells in a group of healthy individuals who smoke 20 cigarettes each day to those in non-smoking individuals of the same age group.

The recently published findings showed reduced iNKT cell numbers in cigarette smokers and also significant defects in the ability of iNKT cells to produce cytokines and kill target cells.

Commenting on the work, postdoctoral researcher and first author on this publication, Dr Andrew Hogan said,

“It would seem that cigarette smoke has multiple negative effects on innate immune cells that are important in tumour surveillance and protection against infection. In addition to increasing your risk of developing cancer, it appears that smoking also impairs your body’s ability to fight the disease effectively”. This research was funded through a Sanofi Aventis Newman scholarship to Dr Hogan.



















































Reference:



Reference Andrew. E. Hogan, Michelle. A. Corrigan, Vincent O’Reilly, Gadintshware Gaoatswe, Jean O’Connell, Derek. G. Doherty, Lydia Lynch, Donal O’Shea, Cigarette smoke alters invariant natural killer T cell function and may inhibit anti-tumour responses, Clinical Immunology (2011), doi:10.1016/j.clim.2011.01.011

Documents

Conway Focus Issue 13 March 2011