Biomedical subjects

Valerie Wilson

Publications and source records attributed to Valerie Wilson.

18 recordsLinked to original sources

PubMed2026

Brachyury expression levels predict lineage potential and axis-forming ability of in vitro-derived neuromesodermal progenitors.

Neuromesodermal progenitors (NMPs) produce the spinal cord and musculoskeleton in the elongating anterior-posterior axis. In vivo, NMPs possess dual potency, coinciding with regions co-expressing SOX2 and Brachyury (TBXT). In vitro, SOX2/TBXT co-expressing cells can be produced from pluripotent cells and, like their in vivo counterparts, can produce neural tube and somitic mesoderm. However, the functional characteristics of in vitro SOX2/TBXT co-expressing cells remain unclear, confounding comparisons with in vivo data. To address this, we developed a dual Sox2/Tbxt reporter mouse ESC line. SOX2/TBXT reporter-positive cells emerge in vitro from pluripotent populations with dynamics that mirror their appearance in the embryo. Purified SOX2/TBXT co-expressing populations can differentiate towards neurectoderm or mesoderm, including lateral mesoderm upon BMP stimulation. In gastruloids, quantitative live imaging shows that WNT or NOTCH inhibition rapidly leads to downregulation of TBXT expression and diminished axial extension. We show that clonally plated SOX2/TBXT co-expressing cells are bipotent NMPs that can also self-propagate. By combining clonal analysis with mathematical inference, we identify two thresholds of TBXT and/or SOX2 expression, switching clonal output from neural- to mesoderm-biased, and from mesoderm-biased to mesoderm-specified. Image analysis of embryonic NMPs supports a model whereby SOX2 and TBXT independently influence neuromesodermal differentiation. Thus, this Sox2/Tbxt double reporter cell line highlights unsuspected heterogeneity in NMPs, and together with image analysis of embryonic SOX2/TBXT levels, challenges the assumption that neuromesodermal fate choice is primarily governed by mutual antagonism between SOX2/TBXT.

Animals↗

PubMed2025

NANOG is repurposed after implantation to repress Sox2 and begin pluripotency extinction.

Loss of pluripotency is an essential step in post-implantation development that facilitates the emergence of somatic cell identities essential for gastrulation. Before implantation, pluripotent cell identity is governed by a gene regulatory network that includes the key transcription factors SOX2 and NANOG. However, it is unclear how the pluripotency gene regulatory network is dissolved to enable lineage restriction. Here, we show that SOX2 is required for post-implantation pluripotent identity in the mouse, and cells that lose SOX2 expression in the posterior epiblast are no longer pluripotent. Using in vitro and in vivo analyses, we demonstrate anticorrelated expression of NANOG and SOX2 preceding gastrulation, culminating in an early disappearance of pluripotent identity from posterior NANOGhigh/SOX2low epiblast. Surprisingly, Sox2 expression is repressed by NANOG and embryos with post-implantation deletion of Nanog maintain posterior SOX2 expression. Our results demonstrate that the distinctive features of post-implantation pluripotency are underpinned by altered functionality of pluripotency transcription factors, ensuring correct spatio-temporal loss of embryonic pluripotency.

Animals↗

PubMed2006

Critical realism as emancipatory action: the case for realistic evaluation in practice development.

To provide rigour when preparing a research design, the researcher needs to carefully consider not only the methodology but also the philosophical intent of the study. This, however, is often absent from reported research and provides the reader with little evidence by which to judge the merits of the chosen methodology and its influence on the study. The purpose of this paper is to set out the case for critical realism as a framework to guide appropriate action in practice development and realistic evaluation for understanding the consequences of those actions. It is evident that critical realism and critical social science share common ground. Emancipatory practice development (ePD) is based on the philosophy of critical social science and therefore by virtue is linked to the tenets of critical realism. Until now, the evaluation of ePD programme has been well served by 4th-generation evaluation. However, this paper outlines the need for a different approach to evaluation, one that is based on critical realism, that is concerned with emancipation, and that can be used in the ever-changing environment of clinical practice. Realistic evaluation not only links strongly to ePD programmes, but also serves as the basis for effective research questions that will test the outcomes of the research and inform the transferability of ePD mechanisms into differing contexts.

Attitude of Health Personnel↗

PubMed2006

Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population.

Regulatory T lymphocytes play a crucial role in modulating potentially self-reactive clones, and dysfunction of this cell type contributes to autoimmune disease. FOXP3 is a critical determinant of CD(4+)CD(25+)T regulatory (T(reg)) cell development and function. The aim of this study was to investigate whether genetic polymorphisms at the FOXP3 locus predispose to autoimmune endocrinopathies. Five single nucleotide polymorphisms (SNPs) and two microsatellite polymorphisms were genotyped in our Caucasian cohorts of 633 unrelated Graves' disease (GD) subjects, 104 autoimmune Addison's disease (AAD) subjects and 528 healthy controls. SNP genotyping was performed by either restriction enzyme digestion or by primer-extension-MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) assay. Microsatellites were analysed using fluorescent PCR. Case-control analysis was performed using chi(2) testing on contingency tables for allele frequency. Haplotype analysis was performed using the UNPHASED package. No evidence for disease association was found with any of the seven polymorphisms in either of the GD or AAD subjects as compared with controls (P = 0.26-0.94). Haplotype analysis found a weak evidence for the association of a minor haplotype with GD; this was not significant when corrected for multiple testing. This study has found no robust evidence that FOXP3 gene polymorphism contributes to the susceptibility to GD or AAD in the UK population.

Addison Disease↗

PubMed2005

Large, consistent estimates of the heritability of cognitive ability in two entire populations of 11-year-old twins from Scottish mental surveys of 1932 and 1947.

Twin studies provide estimates of genetic and environmental contributions to cognitive ability differences, but could be based on biased samples. Here we report whole-population estimates using twins from unique mental surveys in Scotland. The Scottish Mental Surveys of 1st June 1932 (SMS1932) and 4th June 1947 (SMS1947), respectively, administered the same validated verbal reasoning test to almost everyone born in 1921 or 1936 and attending school in Scotland. There were 572 twin pairs from the SMS1932, and 517 pairs from the SMS1947. Information on zygosity was unavailable. A novel application of a mixture distribution was used to estimate genetic and environmental components of verbal reasoning variation by maximum likelihood. We found consistent heritability (approximately 0.70) and shared environment (approximately 0.21) estimates. The estimates did not change substantially when additional quantitative traits (height and weight) were added in a multivariate analysis. More generally for studies in genetics, the methodological innovation developed here implies that large (national) data collections can provide sufficient information on twin pairs to estimate genetic parameters, even without zygosity.

Analysis of Variance↗

PubMed2005

Anonymous versus confidential HIV testing: client and provider decision making under uncertainty.

Six intensive observational studies of HIV testing sites were undertaken in order to improve understanding of confidential and anonymous testing. Three sites offered only confidential testing (a large health maintenance organization's Urgent Care clinic, the same organization's HIV clinic, and a private medical practitioner's office), one offered only anonymous testing (a free clinic), and two offered a choice of confidential or anonymous testing (a thrift shop alternate testing site and a mobile testing unit). Multiple data collection strategies were used including direct field observation, semistructured interviews with clients and providers, and document and policy analysis. Using an organizational/interactional uncertainty framework, this study found that the choice between anonymous and confidential testing is a central aspect of the HIV testing process, that some clients are unclear about the differences between anonymous and confidential testing, that alternate testing sites' providers play a significant role in encouraging confidential rather than anonymous testing in order to further their organization's resource needs and public health goals, and that testing counselors' may consider that some clients prefer anonymous testing because of fear of stigma, discrimination, or loss of privacy.

AIDS Serodiagnosis↗

PubMed2005

No association of the codon 55 methionine to valine polymorphism in the SUMO4 gene with Graves' disease.

OBJECTIVE: A functional polymorphism at codon 55 of the small ubiquitin-like modifier-4 (SUMO4) gene (methionine to valine; M55V) has recently been associated with type 1 diabetes mellitus (T1D). We aimed to establish whether this locus also contributes towards the genetic susceptibility to Graves' disease (GD) and autoimmune Addison's disease. DESIGN: A case-control analysis was performed using genomic DNA samples from 595 unrelated white GD subjects, 104 white autoimmune Addison's disease subjects and 467 healthy white control subjects. The SUMO4 M55V single nucleotide polymorphism (SNP) was genotyped using polymerase chain reaction (PCR) amplification followed by digestion with the restriction enzyme MseI. RESULTS: There was no association of the SUMO4 M55V alleles with either GD, thyroid-associated orbitopathy or autoimmune Addison's disease when compared to controls; P = 0.28, 0.46 and 0.91, respectively, by chi2 testing. CONCLUSION: We cannot confirm a generalized role for SUMO4 in autoimmune endocrinopathy. The SUMO4 codon 55 methionine to valine polymorphism may be exclusively associated with susceptibility to T1D, or the effect of the locus in GD and Addison's disease may be much less than that found in T1D patients.

Addison Disease↗

PubMed2005

Childhood IQ and social factors on smoking behaviour, lung function and smoking-related outcomes in adulthood: linking the Scottish Mental Survey 1932 and the Midspan studies.

OBJECTIVE: To investigate the associations of childhood IQ and adult social factors, and smoking behaviour, lung function (forced expiratory volume in one second; FEV(1)), and smoking-related outcomes in adulthood. DESIGN: Retrospective cohort study. METHOD: Participants were from the Midspan prospective studies conducted on Scottish adults in the 1970s. The sample consisted of 938 Midspan participants born in 1921 who were successfully matched with their cognitive ability test results on the Scottish Mental Survey 1932. RESULTS: Structural equation modelling showed that age 11 IQ was not directly associated with smoking consumption, but that IQ and adult social class had indirect effects on smoking consumption via deprivation category. The influence of IQ on FEV(1) was partly indirect via social class. Gender influenced smoking consumption and also IQ and social class. There was a 21% higher risk of having a smoking-related hospital admission, cancer, or death during 25 years of follow-up for each standard deviation disadvantage in IQ. Adjustment for adult social class, deprivation category, and smoking reduced the association to 10%. CONCLUSION: Childhood IQ was associated with social factors which influenced lung function in adulthood, but was not associated directly with smoking consumption. In future studies, it is important to consider other pathways which may account for variance in the link between childhood IQ and health in later life.

Adult↗

PubMed2005

The cognitive cost of being a twin: two whole-population surveys.

Do twins have a lower mean IQ score than singletons? Previous studies have not examined whole populations and are likely to be biased. Twin data from two whole-population surveys of IQ at age 11 years were examined: the Scottish Mental Surveys of 1932 and 1947. Additional variables from childhood were examined as possible mediating effects. There were 1080 twins from the 1932 survey, and 949 from the 1947 survey. In both surveys twins scored lower on the Moray House Test of verbal reasoning, equivalent to a deficit of about 5 IQ points. In the Scottish Mental Survey of 1947 the whole-population group of twins was compared in detail with a representative population sample. The same mental ability difference of about 5 IQ points was found, and was not accounted for by father's occupation, overcrowding in the childhood home, childhood height, school attendance or the number of people in the family.

Child↗

PubMed2004

New semidominant mutations that affect mouse development.

Dominantly acting mutations that produce visible phenotypes are frequently recovered, either during routine maintenance of colonies or from mutagenesis experiments. We have studied 12 dominant mouse mutations that cause a tail dysmorphology, a coat spotting phenotype, or a combination of these. The majority of these mutations act in a semidominant manner with the homozygous state associated with embryonic lethality and a visible phenotype at or before midgestation. The homozygous phenotypes include axis truncation and neural crest cell defects, as may be expected from the heterozygous phenotypes. The majority of mutations, however, also produced other phenotypes that include neural tube closure defects and aberrant heart looping. In one coat spotting mutant the homozygous condition is lethal before neural crest cell production commences. The mutated genes often function in processes additional to those alluded to by the heterozygous phenotype.

Alkylating Agents↗

PubMed2004

Role of the CD40 locus in Graves' disease.

The genetic basis for Graves' disease remains largely unknown, but significant linkage to microsatellite markers on 20q11 suggests that this region harbors a susceptibility gene. One obvious candidate gene at this 20q11 locus is CD40, which encodes a B-cell-surface receptor that is involved in T-cell to B-cell signaling and is implicated in control of T-cell autoreactivity. In addition, an allele of a single nucleotide polymorphism (SNP) in the Kozak consensus sequence of the 5' untranslated region of CD40 exon 1 has been reported to show modest evidence for association with Graves' disease. We have investigated the role of this 5' untranslated region (5' UTR) in Graves' disease susceptibility in our cohort of 451 unrelated white subjects with Graves' disease and 446 healthy controls. The CD40 5'UTR SNP (C --> T, position -1) was polymerase chain reaction (PCR)amplified and genotyped using the restriction enzyme NcoI. The frequency of the C allele was 74.8% in Graves' probands compared to 75.1% in controls (not significant [NS]). We find no evidence to support allelic association with Graves' disease at this CD40 SNP, despite the adequate power of the study. We are unable to confirm a role for CD40 in Graves' disease pathogenesis in our U.K. population, however, further studies involving larger patient cohorts and a saturated SNP marker map are required to resolve this issue.

5' Untranslated Regions↗

PubMed2004

Childhood mental ability and blood pressure at midlife: linking the Scottish Mental Survey 1932 and the Midspan studies.

OBJECTIVES: To establish the relationship between childhood mental ability and adult hypertension. DESIGN: Retrospective cohort study. SETTING: Community. PARTICIPANTS: Non-clinical sample of people born in 1921 who participated in both the Scottish Mental Survey 1932 and the Midspan studies. Nine hundred and thirty-eight people were participants in both studies. MAIN OUTCOME MEASURES: Mid-life systolic and diastolic blood pressure, intelligence quotient (IQ) at age 11 years, sex, social class, height and weight. RESULTS: After adjustment for age, sex, social class, body mass index, height, cholesterol level and smoking, there remained a 3.15 mmHg decrease in systolic blood pressure and a 1.5 mmHg decrease in diastolic blood pressure for each standard deviation increase in childhood IQ. CONCLUSIONS: The association between hypertension and lower cognitive function in adulthood is partly accounted for by individual differences in childhood IQ.

Blood Pressure↗

PubMed2003

A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study.

AIM: The association of cholesteryl ester transfer protein (CETP) gene polymorphisms with risk of a cardiovascular event and whether any association was explained by an influence on high-density lipoprotein (HDL) levels or low-density lipoprotein (LDL) size was tested in the West of Scotland Coronary Prevention Study (WOSCOPS). Gene-smoking and gene-treatment interactions were investigated. METHODS AND RESULTS: Cases (n=498) and controls (n=1108) were typed for TaqIB, C(-631)A, C(-629)A, I405V and D442G CETP polymorphisms. Homozygotes for the TaqIB2 allele (B2B2) had a 30% reduced risk of a cardiovascular event (odds ratio [OR] 0.70, CI(95)0.51-0.96, P=0.03) compared to B1B1 homozygotes. Inclusion of HDL or LDL diameter in multivariate analysis only marginally attenuated the relationships. Non-smokers, but not smokers, showed a dose-dependent association of risk with TaqIB genotype. Treatment benefit was not significantly different in B1B1 (OR 0.71, pravastatin vs placebo), B1B2 (OR 0.68) and B2B2 (OR 0.61) individuals. The other CETP polymorphisms studied had no significant association with cardiovascular risk. Haplotype analysis did not add to the information given by the individual polymorphisms. CONCLUSION: The association between CETP TaqIB genotype and cardiovascular risk is primarily in non-smokers, is not fully explained by effects on HDL levels or LDL size, and the benefit of pravastatin treatment was not influenced by this polymorphism.

Aged↗

PubMed2003

Putting the action into learning: the experience of an action learning set.

As part of a practice development initiative the nursing staff of a special care nursery unit chose to begin an action learning set. The set was established to enable nursing staff to participate in a learning activity which focused on personal as well as team development. This was facilitated by a practice development nurse (researcher) who although not part of the nursing team, worked within the unit on a supernumerary basis throughout the study period. The set members identified and explored issues from clinical practice through a process of questioning, reflection, and challenging one another with an aim to improving the care delivered to patients and their families. This paper describes the process involved in establishing the set and the journey the set has taken since its inception in May 2002. The main areas covered in this paper include an overview of the practice development initiative, a brief outline of action learning including the processes involved, how the set was established, what it is like to be a set member, the development of skills and knowledge, the personal growth that has resulted from participation, and how the set is being evaluated.

Australia↗

PubMed2003

Identification of Jade1, a gene encoding a PHD zinc finger protein, in a gene trap mutagenesis screen for genes involved in anteroposterior axis development.

In a gene trap screen for genes expressed in the primitive streak and tail bud during mouse embryogenesis, we isolated a mutation in Jade1, a gene encoding a PHD zinc finger protein previously shown to interact with the tumor suppressor pVHL. Expressed sequence tag analysis indicates that Jade1 is subject to posttranscriptional regulation, resulting in multiple transcripts and at least two protein isoforms. The fusion Jade1-beta-galactosidase reporter produced by the gene trap allele exhibits a regulated expression during embryogenesis and localizes to the nucleus and/or cytoplasm of different cell types. In addition to the primitive streak and tail bud, beta-galactosidase activity was found in other embryonic regions where pluripotent or tissue-specific progenitors are known to reside, including the early gastrulation epiblast and the ventricular zone of the cerebral cortex. Prominent reporter expression was also seen in the extraembryonic tissues as well as other differentiated cell types in the embryo, in particular the developing musculature. We show that the gene trap mutation produces a null allele. However, homozygotes for the gene trap integration are viable and fertile. Database searches identified a family of Jade proteins conserved through vertebrates. This raises the possibility that the absence of phenotype is due to a functional compensation by other family members.

Amino Acid Sequence↗

PubMed2002

Axial progenitors with extensive potency are localised to the mouse chordoneural hinge.

Elongation of the mouse anteroposterior axis depends on a small population of progenitors initially located in the primitive streak and later in the tail bud. Gene expression and lineage tracing have shown that there are many features common to these progenitor tissues throughout axial elongation. However, the identity and location of the progenitors is unclear. We show by lineage tracing that the descendants of 8.5 d.p.c. node and anterior primitive streak which remain in the tail bud are located in distinct territories: (1) ventral node descendants are located in the widened posterior end of the notochord; and (2) descendants of anterior streak are located in both the tail bud mesoderm, and in the posterior end of the neurectoderm. We show that cells from the posterior neurectoderm are fated to give rise to mesoderm even after posterior neuropore closure. The posterior end of the notochord, together with the ventral neurectoderm above it, is thus topologically equivalent to the chordoneural hinge region defined in Xenopus and chick. A stem cell model has been proposed for progenitors of two of the axial tissues, the myotome and spinal cord. Because it was possible that labelled cells in the tail bud represented stem cells, tail bud mesoderm and chordoneural hinge were grafted to 8.5 d.p.c. primitive streak to compare their developmental potency. This revealed that cells from the bulk of the tail bud mesoderm are disadvantaged in such heterochronic grafts from incorporating into the axis and even when they do so, they tend to contribute to short stretches of somites suggesting that tail bud mesoderm is restricted in potency. By contrast, cells from the chordoneural hinge of up to 12.5 d.p.c. embryos contribute efficiently to regions of the axis formed after grafting to 8.5 d.p.c. embryos, and also repopulate the tail bud. These cells were additionally capable of serial passage through three successive generations of embryos in culture without apparent loss of potency. This potential for self-renewal in chordoneural hinge cells strongly suggests that stem cells are located in this region.

Animals↗

PubMed2002

Visualization of whole-mount skeletal expression patterns of LacZ reporters using a tissue clearing protocol.

Gene targeting or trapping constructs that utilize the lacZ gene encoding beta-galactosidase activity to trap promoter expression have become an increasingly important way to disrupt gene function and monitor gene expression. A number of genes targeted in this way have revealed both expected and unexpected developmental abnormalities of the skeleton. The use of X-gal staining to monitor gene expression in developing skeletal structures is hampered in these mutants because, during the critical latter stages of mouse embryonic development, visualization is hindered by the opacity of overlying soft tissue. Here, we report the development of a reliable method to clear exogenous tissue in late-stage embryos and neonates that still preserves skeletal X-gal staining patterns. This protocol reveals (i) specific cell staining in localized regions of developing bone and cartilage in two different genetic models and (ii) that the intensity of X-gal staining is consistent with the level of expression of lacZ. We conclude that this protocol accurately reflects both the specificity and intensity of expression and will facilitate the analysis of mouse skeletal development.

Animals↗

PubMedDate not supplied

Childhood IQ, social class, deprivation, and their relationships with mortality and morbidity risk in later life: prospective observational study linking the Scottish Mental Survey 1932 and the Midspan studies.

OBJECTIVE: To investigate how childhood mental ability (IQ) is related to mortality and morbidity risk, when socioeconomic factors are also considered. METHODS: Participants were from the Midspan studies conducted on adults in the 1970s; 938 Midspan participants were successfully matched with the Scottish Mental Survey 1932 in which children born in 1921 and attending Scottish schools on June 1, 1932, took a cognitive ability test. Mortality, hospital admissions, and cancer incidence in the 25 years after the Midspan screening were investigated in relation to childhood IQ, social class, and deprivation. RESULTS: The risk of dying in 25 years was 17% higher for each standard deviation disadvantage in childhood IQ. Adjustment for social class and deprivation category accounted for some, but not all, of this higher risk, reducing it to 12%. Analysis by IQ quartile showed a substantial increased risk of death for the lowest-scoring quarter only. Structural equation modeling indicated that the effect of childhood IQ on mortality was partly indirectly influenced by social factors. Cause-specific mortality or hospital admission showed that lower IQ was associated with higher risks for all cardiovascular disease and coronary heart disease. Cause-specific mortality or cancer incidence risk was higher with decreasing IQ for lung cancer. CONCLUSIONS: Lower childhood IQ was related to higher mortality risk and some specific causes of death or morbidity. Childhood IQ may be considered as a marker for risk of death or illness in later life in similar and complementary ways to social class or deprivation category.

Adult↗