1,634 research outputs found
Efficient poultry housing, G. J. Simmonds; illustrated with plans, drawings and photographs by the author.
No full text25 p.
Detection of genome-scale ordered RNA structure (GORS) in genomes of positive-stranded RNA viruses:Implications for virus evolution and host persistence
No full textDiscrete RNA secondary and higher-order structures, typically local in extent, play a fundamental role in RNA virus replication. Using new bioinformatics analysis methods, we have identified genome-scale ordered RNA structure (GORS) in many genera and families of positive-strand animal and plant RNA viruses. There was remarkably variability between genera that possess this characteristic; for example, hepaciviruses in the family Flaviviridae show evidence for extensive internal base-pairing throughout their coding sequences that was absent in both the related pestivirus and flavivirus genera. Similar genus-associated variability was observed in the Picornaviridae, the Caliciviridae, and many plant virus families. The similarity in replication strategies between genera in each of these families rules out a role for GORS in a fundamentally conserved aspect of this aspect of the virus life cycle. However, in the Picornaviridae, Flaviviridae, and Caliciviridae, the existence of GORS correlated strongly with the ability of each genus to persist in their natural hosts. This raises the intriguing possibility of a role for GORS in the modulation of innate intracellular defense mechanisms (and secondarily, the acquired immune system) triggered by double-stranded RNA, analogous in function to the expression of structured RNA transcripts by large DNA viruses. Irrespective of function, the observed evolutionary conservation of GORS in many viruses imposes a considerable constraint on genome plasticity and the consequent narrowing of sequence space in which neutral drift can occur. These findings potentially reconcile the rapid evolution of RNA viruses over short periods with the documented examples of extreme conservatism evident from their intimate coevolution with their hosts
Evolutionary history, cross-species transmission and host adaptation of human viruses and their primate homologues
No full textAt present the origins of major human pathogens associated with hepatic disease are
poorly understood. The absence of such information pertaining to the evolutionary history
of hepatitis B virus (HBV) and hepatitis C virus (HCV) and its genetically related viruses
impacts upon the development of vaccines and effective eradication strategies. Studies are
currently limited by the absence of historical samples from which to date the emergence of
human infections and therefore the evolution of human hepatic viruses relies on
epidemiological studies and genetic analysis of contemporary virus populations
worldwide.
Approximately one third of the world’s population is infected with HBV, and despite the
availability of a vaccine, the virus is attributed with over 1 million deaths per year through
liver disease. HBV variants infecting humans show genetic and antigenic heterogeneity
and are currently classified into 8 genotypes A-H with nucleotide divergence of between
9-13%. In addition to these variants, recombination has been detected between genotypes
A and D, and B and C, which can generate novel variants. The past 10 years has seen the
detection of HBV in chimpanzees, gorillas and other non-human primates (NHPs) at
frequencies comparable to those observed in regions of endemic human HBV infection.
Despite the genetic divergence between human and NHP HBV variants the detection of
recombination between human genotype C and chimpanzee and gibbon variants suggests
that HBV can share hosts in nature. The evolutionary process that may have given rise to
the distinct species-specific variants of NHP HBV within overlapping geographical
regions has not been reconciled, with evidence supporting both allopatric speciation and
co-speciation.
HCV a member of the Flaviviridae family currently infects approximately 3% of the
world’s population and is one of the major causes of chronic liver disease, hepatocellular
carcinoma and liver cirrhosis. Human pegivirus (HPgV) a member of the Pegivirus genus
of the Flaviviridae family infects approximately 5% of the world’s population, although it
is of unknown disease association. Very recently, several studies of wild rodent and bat
populations have revealed much greater viral diversity of members of both Hepacivirus
and Pegivirus genera. Homologues of HCV have been detected in a range of species
including domestic dogs (canine hepacivirus [CHV]) and horses (non-primate
hepaciviruses [NPHV]). Similarly, several new pegiviruses have been described in horses
(equine pegivirus, [EPgV] and Theiler’s Disease Associated Virus [TDAV]), several
species of rodents (rodent pegivirus [RPgV]), and further species of bats (bat pegivirus,
[BPgV]). Despite the differences in pathogenicity between HCV and HPgV
infections, they share similar genomic organisation and are capable of establishing
persistent infections in humans. Studies into bat, horse and rodent homologs of HCV
and HPgV have yet to determine disease associations, transmission routes and
seroprevalence.
Studies presented within this thesis broaden our understanding of the clinical
presentations and host range of NPHV and EPgV. Screening to determine the level
of active and past infection to both viruses provides novel insight into infection
frequencies, host range, disease progression and examines the correlation between
infections and the presence or absence of hepatic disease. Research examining HBV
variants circulating in NHPs in Cameroon provides novel evidence for the
occurrence of recombination and cross species transmission between NHP variants
of HBV and examines the role these findings play in expanding our understanding of
the evolution of HBV
The influence of genetic variation in thirty selected genes on the clinical characteristics of early onset breast cancer
No full textIntroduction: common variants that alter breast cancer risk are being discovered. Here, we determine how these variants influence breast cancer prognosis, risk and tumour characteristics.Methods: we selected 1,001 women with early onset nonfamilial invasive breast cancer from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort and genotyped 206 single nucleotide polymorphisms (SNPs) across 30 candidate genes. After quality control, 899 cases and 133 SNPs remained. Survival analyses were used to identify SNPs associated with prognosis and determine their interdependency with recognized prognostic factors. To identify SNPs that alter breast cancer risk, association tests were used to compare cases with controls from the Wellcome Trust Case Control Consortium. To search for SNPs affecting tumour biology, cases were stratified into subgroups according to oestrogen receptor (ER) status and grade and tested for association.Results: we confirmed previous associations between increased breast cancer risk and SNPs in CASP8, TOX3 (previously known as TNRC9) and ESR1. Analysis of prognosis identified eight SNPs in six genes (MAP3K1, DAPK1, LSP1, MMP7, TOX3 and ESR1) and one region without genes on 8q24 that are associated with survival. For MMP7, TOX3 and MAP3K1 the effects on survival are independent of the main recognized clinical prognostic factors. The SNP in 8q24 is more weakly associated with independent effects on survival. Once grade and pathological nodal status (pN stage) were taken into account, SNPs in ESR1 and LSP1 showed no independent survival difference, whereas the effects of the DAPK1 SNP were removed when correcting for ER status. Interestingly, effects on survival for SNPs in ESR1 were most significant when only ER-positive tumours were examined. Stratifying POSH cases by tumour characteristics identified SNPs in FGFR2 and TOX3 associated with ER-positive disease and SNPs in ATM associated with ER-negative disease.Conclusions: we have demonstrated that several SNPs are associated with survival. In some cases this appears to be due to an effect on tumour characteristics known to have a bearing on prognosis; in other cases the effect appears to be independent of these prognostic factors. These findings require validatation by further studies in similar patient group
Prospective study of outcomes in Sporadic versus hereditary breast cancer (POSH): study protocol
No full textBackground: young women presenting with breast cancer are more likely to have a genetic predisposition to the disease than breast cancer patients in general. A genetic predisposition is known to increase the risk of new primary breast (and other) cancers. It is unclear from the literature whether genetic status should be taken into consideration when planning adjuvant treatment in a young woman presenting with a first primary breast cancer. The primary aim of the POSH study is to establish whether genetic status influences the prognosis of primary breast cancer independently of known prognostic factors. Methods/design: the study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period. Discussion: power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforwar
Contribution of newly discovered and emerging viruses to human disease
No full textAccording to the World Health Organization, over 200 infectious diseases in humans
originate from animals (zoonoses), posing significant threats to human health.
Zoonotic agents account for the majority of emerging and re-emerging pathogens. The
human-animal interface has been recognised as an important risk factor that facilitates
viruses to cross the species barrier and establish infection in humans. This indicates a
need to perform surveillance of human populations who are at high risk of zoonotic
infection due to their frequent contact with animals, together with the animals to which
humans are exposed. The VIZIONS (Vietnam Initiative on Zoonotic Infections) has
been conducted to directly respond to that need.
The large virus family Picornaviridae include known emerging pathogens that have
major impacts on the economies and human and animal health (e.g. foot-and-mouth
disease virus, hand foot and mouth disease virus). Some enteroviruses (EVs) and
parechoviruses in this family have been shown to be able to infect both humans and
animals while a number of new picornaviruses (new EV variants, cosaviruses,
cardioviruses, hunniviruses) with unknown pathogenicity and zoonotic potential have
been discovered. This thesis, as part of VIZIONS, hopes to address the following gaps
in our knowledge of such viruses in six genera (Enterovirus, Parechovirus, Cosavirus,
Cardiovirus, Kobuvirus and Hunnivirus) of the family Picornaviridae:
1) The prevalence and genetic diversity of picornaviruses in studied samples
2) The epidemiology and disease association of the identified viruses
3) The overlaps (if any) of picornaviruses circulating in animals and humans
4) Possible animal sources of picornavirus infections in humans
In order to do that, over 2,000 faecal samples collected from a wide range of hosts
(pigs, rats, bamboo rats, shrews, bats, chickens, ducks, boars, civets, porcupines,
monkeys and humans) were screened for picornaviruses by nested PCR and real-time
PCR assays. Detection frequencies varied between viruses and sample origins with
kobuvirus as the most commonly detected virus, followed by EV, cardiovirus and
hunnivirus. Parechovirus and cosavirus were not detected.
Comparison of detection frequencies of viruses infecting pigs revealed a disease
(diarrhoea) association with porcine kobuvirus (PKV) but not EV infections. However,
differences in PKV viral loads between diarrhoeic and non-diarrhoeic pigs were not
statistically significant (p = 0.22). In addition, the PKV VP1 sequences from the two
pig categories were not phylogenetically distinct. EV VP1 sequences obtained from
pigs and boars showed high genetic diversity with four previously known types and
nine new types (EV-G8 to -G16). Analyses of complete genome sequences of two new
EV types provided evidence for inter-type recombination with a putative breakpoint
in the 2A coding region.
Similarly, study on samples from monkeys showed endemic infection of EV but no
overlap with EV variants in humans was observed. The majority of EV detected in
monkeys were novel with evidence for chimeric genomes and putative recombination
breakpoints in the 2A region. New criteria for the classification of EV were
additionally proposed.
Characterization by sequencing of VP4/VP2 and VP1 regions or complete genomes of
picornaviruses in rats and bamboo rats also showed relatively high genetic diversity.
While these viruses can infect different species of rats, they were again genetically
different from viruses detected in the studied human populations.
In summary, studies in this thesis provide substantial new information on the
prevalence, genetic diversity and disease association of picornaviruses in the studied
populations. However, picornaviruses detected from animals were consistently
separate from those found in humans, consistent with a relatively limited zoonotic
potential of members of the virus family
Clinical correlates and epidemiology of respiratory viruses
No full textThe introduction of the polymerase chain reaction (PCR) into the diagnostic
setting has provided unprecedented opportunities in the field of respiratory medicine, not
only because pathogens need no longer be cultivable for detection but also through
improved sensitivity, specificity and turnaround time compared with traditional methods.
The recent discovery of several novel respiratory viruses, such as human
metapneumovirus (HMPV), human bocavirus and human coronaviruses (HCoVs) NL63
and HKU1 has nevertheless created significant challenges in respiratory diagnostics, as
identification of which pathogens should be tested for is increasingly difficult.
The recent discovery of two novel respiratory coronaviruses (HCoV-HKU1 and
HCoV-NL63) presented the opportunity to undertake large scale clinical and
epidemiologic study of these alongside two previously known respiratory coronaviruses,
HCoV-229E and HCoV-OC43. Over 12,000 samples collected over three years were
screened using a novel four-way multiplex real-time reverse transcription-PCR (RTPCR).
Clinically, coronaviruses were similar to viruses currently included in routine
diagnostics, with the exception of HCoV-229E which was identified as an opportunistic
pathogen in immunocompromised hosts. Variability in detection frequencies of HCoVHKU1
and HCoV-OC43 was evident. The low detection frequencies of HCoVs,
comparable to those of parainfluenza viruses 1 and 2 (which are included in the routine
diagnostic screening panel) indicate a borderline case for inclusion of these pathogens in
routine respiratory diagnostics.
To investigate the epidemiology and clinical correlates of HMPV in Edinburgh,
large scale retrospective screening of over 7000 respiratory samples collected over two
years was conducted. Nucleotide sequencing of HMPV-positive samples was undertaken
to determine phylogenetic relationships of circulating HMPV strains. HMPV comprises
two genotypes, A and B. Comparisons of the clinical presentations of the two genotypes
revealed little difference, with only the observation that sub-genotype B2 was more
frequently associated with infection of immunocompromised patients. Detection frequencies and symptomatology associated with HMPV infections were comparable to
respiratory viruses currently included in the routine diagnostic panel, mandating its
inclusion in future diagnostic screening.
A switch of the predominantly circulating genotype of HMPV was observed
between respiratory seasons. This is a phenomenon more widely reported for the closely
related respiratory syncytial virus (HRSV), which also comprises two circulating groups.
To further investigate subtype (HRSV)/ genotype (HMPV) switching, evolutionary
analyses of nucleotide sequence data generated from isolates collected from
geographically disparate referral centres was undertaken. The fusion and attachment (G)
genes were targeted, as these encode major surface proteins and are immunogenic.
Analyses were by MCMC analyses using Bayesian Evolutionary Analyses of Sampling
Trees (BEAST) software. Identification of positively selected sites was performed using
Phylogenetic Analysis Maximum Likelihood (PAML). Switching of the predominantly
circulating lineage does not arise for either virus due to emergence of novel strains, but
through fluctuating circulation frequencies of pre-existing lineages which have been
circulating for several decades, indicated by the time since the most recent common
ancestor. Two HRSV-A lineages comprising genotypes undergoing turnover and
replacement were identified. This finding is agreeable with serologic studies of the 1970s
which reported three HRSV serogroups, two within HRSV-A and one within HRSV-B.
HMPV and HRSV have similar mutation rates. Positively selected sites identified within
the HRSV G gene were incongruent with those identified in a previous study, generating
the hypothesis that immune evasion occurs within linear epitopes rather than at specific
sites.
A great deal of clinical and epidemiologic data was generated through this work,
parallel studies of other respiratory viruses and through diagnostic screening results. To
provide a robust indication of where resources should be diverted in terms of diagnostics,
therapeutics and vaccine development, and to inform infection control measures and
public health policy planning, quantification of the relative disease burden attributable to
the most commonly detected respiratory viruses was calculated using the World Health Organization- endorsed Disability Adjusted Life Year (DALY) model. Relative disease
burden was calculated in an age stratified manner to reflect the differences in sampling in
different age groups. HRSV and influenza A were consistently one of the greatest causes
of disease regardless of sampled population, although HRSV caused more disease in
children under 5 than influenza A and B combined. Rhinoviruses and PIV-3 were
significant pathogens in all groups except those aged 16-64 years; rhinoviruses were the
leading cause of disease in the immunocompromised patient group. The potential for
patient-specific diagnostic screening and guidance of interventions such as patient
cohorting were clear
Aspects of the New Commonwealth immigration question and its impacts: a study in policy making and elite politics, 1968-1981
No full text[Author's synopsis]:This thesis offers an analysis of policy making on aspects of the New Commonwealth immigration issue in Britain between 1968 and 1981. It concerns three formally distinct but profoundly interlocking issues: immigration control itself, the development of race relations policy and the pursuit of nationality law reform.I argue that a populist critique of prevailing bipartisanship on the subject grew up around the notion that immigration policy, and the notion of multiracial Britain itself, was subject to a profound shortfall in political legitimacy. These arguments were introduced by Enoch Powell in 1968, but remained too controversially wedded to race issues to achieve purchase in the mainstream. A limited form of bipartisanship therefore survived this early assault, to be rephrased by Edward Heath as a managerial compromise that sought to accept stronger immigration controls (and, significantly, the reform of nationality law), justifiable in the national interest, and to remove the issues from the political sphere through strong administration and wide governmental discretion.This compromise was subsequently weakened by threats to the governing competence that underlay it in the form of problems in the control system highlighted by officials (some of which became public knowledge), the possibility of a deterioration in race relations and an increase in immigration perceived to originate in policy defects and a more liberal management of entry by the Labour government. These perceived failures permitted a restatement of the political legitimacy critique by individuals within the Conservative Party. In seeking to repudiate ideas of 'consensus' more broadly, the party under Margaret Thatcher's leadership reincorporated the populist idea that high minded and elitist bipartisanship was a failed form of governance, emphasising the redress of putatively valid public grievances through a strengthened system of immigration control, designed to cure systematic weaknesses in regulating what had become largely secondary (family) migration, and through the realisation of the 1981 British Nationality Act, intended to close off the period of post-colonial migration
- …
