The postholder will advise University of Leicester staff on regulatory requirements and best practice for work with hazardous chemicals, biological agents and genetically modified organisms. Additional duties will include monitoring safety performance and providing training programmes. Candidates should be science graduates with relevant postgraduate experience and excellent interpersonal skills. Knowledge of genetic modification principles and procedures is essential.
The antiretroviral drug abacavir has helped to revolutionise HIV treatment, requiring many patients to take just two pills once a day, instead of following a complex regime often involving four to five different medications. Failure to comply by missing a dose can have devastating consequences for HIV patients, as the virus can quickly build up resistance to drugs which prevents them working. But the drug can cause a rare but potentially deadly side effect in around one in 20 patients called ‘hypersensitivity syndrome’, leading to a severe skin rash and swollen joints and in rare cases death. This has put a number of patients off the drug who could benefit. Now patients at Leicester’s infectious diseases unit are being offered gene testing as part of a research project which can accurately predict whether a patient will react through a simple blood test. Patients with the gene HLA B5701 are up to 100 times more likely to have an adverse reaction to the drug. Dr Martin Wiselka of Leicester University Medical School, says “The risk has put doctors and patients off trying the drug, but if we do a gene test before we start and identify the patients who will have a reaction we can use it more widely.” Leicestershire HIV patients are now being routinely gene tested before being considered for the treatment. Those found to be unsuitable can be offered a range of other effective treatments. “We strongly believe that the test will be useful”, added Dr Wiselka. “This is a first drug where we can test for a adverse reaction in advance of prescribing it. This would be useful for other medicines such as penicillin allergy.” The research was funded by Glaxo-Smith Kline and is known as the PREDICT study. There are approximately 700 HIV-positive patients in Leicestershire. The majority are on antiviral treatment. Antiviral treatment has revolutionised the outcome of HIV infection which used to be fatal in all cases. The treatment suppresses the virus but does not cure the disease. Patients are likely to require lifelong treatment but those on treatment remain well, are able to return to work in many cases and can look forward to a virtually normal life expectancy.
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This article first appeared in the June 2006 issue of the Scandinavian Life Sciences magazine.
Located at the heart of England’s East Midlands, the University of Leicester provides a powerful springboard into life sciences related R&D in the UK. In addition to discoveries of world-wide impact, the university has developed a number of commercial initiatives - bringing findings of laboratory investigation to the forefront of the public domain.
With an annual research income of £35m, the University of Leicester ranks among the UK’s top 20 institutions in terms of research income per full-time member of staff which is reflected in the work emanating from the field of biological sciences.
Research groups in biochemistry, biology, cardiovascular science, cell physiology and pharmacology, genetics, and infection/immunity are all acclaimed for their international excellence. In 2005 the University opened the new £20m Henry Wellcome biomedical research building.
Save money - eradicate polio
Getting close to eradication polio has cost more than $5 billion, and the WHO predicts that completely eradicating the virus will cost another $1.5 billion. Vaccinating enough people to keep the virus to its current low levels over the next 20 years would cost more than eradication. A low-cost control policy that relies only on routine immunisation for 20 years with costs of more than $3500 million could lead to roughly 200,000 paralytic poliomyelitis cases every year in low-income countries, whereas a low-case control policy that keeps the number of cases at about 1500 per year could cost around $10,000 million discounted over the 20 years.
HIV Rev protein enhances encapsidation The AIDS pandemic is still an important public health problem, particularly in developing countries. A comprehensive understanding of the HIV replication cycle might allow development of new therapeutics. Despite 20 years of extensive research, the intracellular fate of the different RNAs produced during virus replication is not fully understood. It is known that the viral regulatory protein Rev binds to large viral RNAs and shuttles them from the nucleus to the cytoplasm by a cellular export pathway. We now provide evidence for a more far-reaching role of Rev. We observed that Rev enhances packaging of viral RNA into viral particles to a much larger extent than its effect on viral RNA levels in the cytoplasm. Thus, an early nuclear event (binding of Rev to the viral RNA) seems to be intimately linked to RNA encapsidation occurring at a late step of the viral replication cycle. Since Rev is not part of the viral particles, Rev seems to act indirectly, possibly by targeting the viral RNA to a cytoplasmic compartment favourable for RNA encapsidation. Thus, further studies on the function of Rev might also advance our understanding of cytoplasmic RNA trafficking and subcytoplasmic compartmentalization.
Syntrophus aciditrophicus: Life at the thermodynamic limit of microbial growth
The bacterium Syntrophus aciditrophicus lives on a diet so austere that it exists on the brink of energetic death. The entire genome sequence of this bacterium provides clues as to how it survives, and might even improve the efficiency by which we can make hydrogen from waste materials: Biochemically, the syntrophic bacteria constitute the missing link in our understanding of anaerobic flow of carbon in the biosphere. The completed genome sequence of Syntrophus aciditrophicus provides a glimpse of the composition and architecture of the electron transfer and energy-transducing systems needed to exist on marginal energy economies of a syntrophic lifestyle. The genome contains 3,179,300 base pairs and 3,169 genes where 1,618 genes were assigned putative functions. Metabolic reconstruction of the gene inventory revealed that most biosynthetic pathways of a typical Gram-negative microbe were present. A distinctive feature of syntrophic metabolism is the need for reverse electron transport. Genomic analysis confirms the S. aciditrophicus metabolic and regulatory commitment to a nonconventional mode of life compared with our prevailing understanding of microbiology.
Cloning Microbial Metagenomes We have developed techniques to clone the entire microbial metagenome; viruses, prokaryotes and eukaryotes. Established approaches were used to isolate environmental DNA and make prokaryotic gene libraries. These libraries contain genes encoding enzymes; cellulases and esterases have been functionally expressed. PCR amplification of environmental DNA has been used to identify integron associated gene cassettes encoding unidentified ORFs. Sequence independent DNA amplification was used to make a faecal virus metagenomic library. Analysis of this library showed the presence of protein ORFS especially enzymes involved in nucleic acid metabolism. Most virus ORFs were unrelated to known sequences. Finally metagenomic microbial eukaryotic RNA was reverse transcribed to select for mRNA; the cDNA was used to make libraries containing many eukaryotic ORFs. International Symposium on Extremophiles and Their Applications, 2005.
vCJD from dental treatment?
Research suggests that between 1 in 1,400 and 1 in 20,000 people in the UK may be carrying variant CJD without showing any symptoms. Now UK dentists have been told not to re-use instruments for root canal work because of a possibility they could infect patients with vCJD. The government’s chief dental officer for England said there had been no cases of transmission, but research had shown a potential risk. The ban applies to instruments known as files and reamers used in endodontic procedures, most often to remove dead or damaged tissue from the root canal of a tooth. There are approximately one million NHS endodontic treatments every year in England and Wales (do the maths).
Dr Barry Cockcroft, the chief dental officer for England, said: “There are no reported definite or suspected cases of vCJD transmission arising from dental procedures. This new guidance to dentists is purely an extra precaution. The public should continue to attend their dentist as normal.”
Use of thermolysin in the diagnosis of prion diseases The molecular diagnosis of prion diseases almost always involves the use of a protease to distinguish PrPC from PrPSc and invariably the protease of choice is proteinase K. Here, we have applied the protease thermolysin to the diagnosis of animal prion diseases. This thermostable protease cleaves at the hydrophobic residues Leu, Ile, Phe, Val, Ala, and Met, residues that are absent from the protease accessible aminoterminal region of PrPSc. Therefore, although thermolysin readily digests PrPC into small protein fragments, full-length PrPSc is resistant to such proteolysis. This contrasts with proteinase K digestion where an aminoterminally truncated PrPSc species is produced, PrP27-30. Thermolysin was used in the diagnosis of ovine scrapie and bovine spongiform encephalopathy and produced comparable assay sensitivity to assays using proteinase K digestion. Furthermore, we demonstrated the concentration of thermolysin-resistant PrPSc using immobilized metal-affinity chromatography. The use of thermolysin to reveal a full-length PrPSc has application for the development of novel immunodiagnostics by exploiting the wide range of commercially available immunoreagents and metal affinity matrices that bind the amino-terminal region of PrP. In addition, thermolysin provides a complementary tool to proteinase K to allow the study of the contribution of the amino-terminal domain of PrPSc to disease pathogenesis.
A 25 nm virion may be the cause of transmissible spongiform encephalopathies? The transmissible spongiform encephalopathies (TSEs) such as endemic sheep scrapie, sporadic human Creutzfeldt-Jakob disease (CJD), and epidemic bovine spongiform encephalopathy (BSE) may all be caused by a unique class of “slow” viruses. This concept remains the most parsimonious explanation of the evidence to date, and correctly predicted the spread of the BSE agent to vastly divergent species. With the popularization of the prion (infectious protein) hypothesis, substantial data pointing to a TSE virus have been largely ignored. Yet no form of prion protein (PrP) fulfills Koch’s postulates for infection. Pathologic PrP is not proportional to, or necessary for infection, and recombinant and “amplified” prions have failed to produce significant infectivity. Moreover, the “wealth of data” claimed to support the existence of infectious PrP are increasingly contradicted by experimental observations, and cumbersome speculative notions, such as spontaneous PrP mutations and invisible strain-specific forms of “infectious PrP” are proposed to explain the incompatible data. The ability of many “slow” viruses to survive harsh environmental conditions and enzymatic assaults, their stealth invasion through protective host-immune defenses, and their ability to hide in the host and persist for many years, all fit nicely with the characteristics of TSE agents. Highly infectious preparations with negligible PrP contain nucleic acids of 1-5 kb, even after exhaustive nuclease digestion. Sedimentation as well as electron microscopic data also reveal spherical infectious particles of 25-35 nm in diameter. This particle size can accommodate a viral genome of 1-4 kb, sufficient to encode a protective nucleocapsid and/or an enzyme required for its replication. Host PrP acts as a cellular facilitator for infectious particles, and ultimately accrues pathological amyloid features. A most significant advance has been the development of tissue culture models that support the replication of many different strains of agent and can produce high levels of infectivity. These models provide new ways to rapidly identify intrinsic viral and strain-specific molecules so important for diagnosis, prevention, and fundamental understanding.J Cell Biochem 2007 100: 897-915
Hmmm - I’ll believe this when these mysterious “virions” are shown to fulfill Koch’s Postulates.
Experimental Officer University of Leicester, School of Medicine, Department of Infection, Immunity and Inflammation
Applications are invited for an Experimental Officer responsible for generating income as well as maintaining and expanding existing contracts. The group is involved in the development of microbiological contract work in water analysis, disinfectant and drug efficacy testing and would suit an applicant with a background in this area.
Downloadable application forms and further particulars are available from www.le.ac.uk/personnel/jobs , or in hardcopy from Personnel Services, tel: 0116 252 2422, fax: 0116 252 5140, email: recruitment2@le.ac.uk. Closing date: 29 March 2007
Technician University of Leicester, School of Medicine, Department of Infection, Immunity and Inflammation
An enthusiastic and well organised person with excellent interpersonal skills is sought to manage the day to day operation of the Category III containment suite. This will include monitoring of health and safety documentation, some financial management and to take responsibility for the training of all the users of the facility.
Downloadable application forms and further particulars are available from www.le.ac.uk/personnel/jobs , or in hardcopy from Personnel Services, tel: 0116 252 2422, fax: 0116 252 5140, email: recruitment2@le.ac.uk. Closing date: 3 April 2007
University of Leicester, School of Medicine, Department of Infection, Immunity and Inflammation.
Applicants must demonstrate a high level of research ability, an established track record with high quality publications. As a Reader you should additionally be able to demonstrate evidence of an international reputation, strong research leadership and the ability to build your own substantial research group.
Downloadable application forms and further particulars are available from www.le.ac.uk/personnel/jobs , or in hardcopy from Personnel Services, tel: 0116 252 2422, fax: 0116 252 5140, email: recruitment2@le.ac.uk.
Closing date: 6 April 2007
SV40 and human cancer
A few months ago, I recorded a podcast about whether there is a role for SV40 in human cancer. A paper just published again confirms the negative conclusion I reached. An unknown proportion of formalin-inactivated poliovirus vaccine lots administered to millions of US residents between 1955 and 1963 was contaminated with small amounts of infectious simian virus 40 (SV40), a polyomavirus of the rhesus macaque. It has been reported that mesothelioma, brain tumors, osteosarcoma and non-Hodgkin lymphoma (NHL) contain SV40 DNA sequences and that SV40 infection introduced into humans by the vaccine probably contributed to the development of these cancers. In summary, the most recent evidence does not support the notion that SV40 contributed to the development of human cancers.
Malaria mitochondria make DNA
Mitochondria act as a cell’s power plant, producing energy from oxygen taken in by respiration. Scientists looking at mitochondria in Plasmodium falciparum, the deadliest of the four types of the parasite that causes malaria in humans, found this parasite’s mitochondria do not generate energy but still consume oxygen. The mitochondrial electron transport chain of Plasmodium falciparum serves only one function, to manufacture ubiquinone which required for DNA biosynthesis. Many single-cell eukaryotes have lost their mitochondrial genomes during evolution, and P. falciparum seems to be close to that state. These findings also help explain how GlaxoSmithKline’s antimalarial drug Malarone, works. Malaria, a mosquito-borne disease caused by a parasite, occurs throughout tropical and sub-tropical regions of the world, killing at least a million people annually, most of them young children in sub-Saharan Africa.
Web2DNA takes a website, analyzes it, crunches it up and spit it out as a graphic representation of DNA. The brightness of the lines is determined by the importance of the tags in terms of structure:
H1 is brighter than H2, which is brighter than H3…
TABLE is brighter than TR, which is brighter than TD tags…
It’s a real buzz to work in a place which feels like it’s constantly moving science forward. Here are just few of the items which can across my desk (OK, screen) yesterday:
England’s top ranked University for teaching quality and overall satisfaction amongst universities teaching full time students - National Student Survey 2005 and 2006
One of just 19 UK universities to feature in world’s top 200- Shanghai Jiao Tong International Index, 2005 and 2006. Ranked as a Top 20 university by The Times Good University Guide.
Short listed Higher Education Institution of the Year - THES awards 2005 and 2006
Students’ Union of the Year award 2005, short listed 2006
Founded in 1921, the University of Leicester has 19,000 students from 120 countries. Teaching in 18 subject areas has been graded Excellent by the Quality Assurance Agency- including 14 successive scores - a consistent run of success matched by just one other UK University. Leicester is world renowned for the invention of DNA Fingerprinting by Professor Sir Alec Jeffreys and houses Europe’s biggest academic Space Research Centre. 90% of staff are actively engaged in high quality research and 13 subject areas have been awarded the highest rating of 5* and 5 for research quality, demonstrating excellence at an international level. The University’s research grant income places it among the top 20 UK research universities. The University employs over 3,000 people, has an annual turnover of £167.5m, covers an estate of 94 hectares and is engaged in a £300m investment programme- among the biggest of any UK university.
Crystal Structure of the SV40 T-Antigen Origin Binding Domain in Complex with DNA Summary: How DNA replicates is a critical question for understanding life. DNA replication remains difficult to investigate in eukaryotes, where it involves a complex, multi-protein apparatus which initiates replication at multiple poorly-defined DNA sequences. This process is far easier to study in viral systems, where the DNA sequences at the origin of replication are well-defined and only one or two proteins are required to initiate replication. In simian virus 40 (SV40), the large T-antigen protein (T-ag) is responsible for recognizing DNA sequences required to start replication, called the origin of replication. SV40 T-ag can also cause DNA to melt or unwind. We report here the crystal structure of the DNA-binding domain of SV40 T-ag on a DNA fragment derived from the viral origin of replication. The structure shows that although T-ag and its functionally analogous protein, papilloma virus E1, share no detectable sequence homology in this region, the two domains bind the DNA in similar ways. In both cases, DNA binding is thought to initiate assembly of a complex of the full-length proteins on DNA. Interestingly, SV40 T-ag DNA-binding domains do not interact with one another when bound to DNA. In addition to describing the molecular details of the DNA–protein interactions and the alterations in protein structure induced by DNA binding, we present a model describing the subsequent assembly events. Meinke, G. et al. PLoS Biol 5(2): e23
Video of RNAi in action
Kudos to Biosingularity for pointing to this excellent YouTube video of RNAi:
XDR-TB in South Africa: No Time for Denial or Complacency
Some months ago, I recorded a podcast about extreme drug resistant tuberculosis (XDR-TB). Now a paper in PLoS Medicine argues that the situation is so serious that affected patients should be forcibly isolated to stop the disease spreading.
The South African outbreak of the multi drug-resistant XDR-TB has killed at least 74 people in the past few months. South Africa is one of the world’s fastest growing tourist destinations, home to millions of migrant labourers from neighbouring countries, and its ports and roads service several other African countries. Seroprevalence rates for HIV in South Africa, and in adjoining nations such as Lesotho and Swaziland, are very high. Cumulatively, these factors make for a potentially explosive international health crisis.
“All reasonable attempts must be made to accommodate the interests of infected patients in a sensitive and humane manner, although, if necessary, the government must adopt a more robust approach towards uncooperative patients with MDR-TB and XDR-TB, which might necessitate favouring the interests of the wider public over that of the patient. Although such an approach might interfere with the patient’s right to autonomy and will undoubtedly have human rights implications, such measures are reasonable and justifiable, and must be seen in a utilitarian perspective. Ultimately in such crises, the interests of public health must prevail over the rights of the individual.”
Microscopy in focus Scientific American has an interesting article on Sidestepping microscopy’s limits: out-of-focus images made clear. Researchers have found a practical way to extract clear images from the parts of a sample illuminated by light above and below the focal plane. The new method may soon allow doctors to diagnose tumors without removing a piece of tissue from a patient.
Biological and Chemical Safety Officer
More than a quarter of U.S. women carry cervical cancer virus
Professor Sir Alec Jeffreys of the 
