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Biomedical subjects

Alan Williams

Publications and source records attributed to Alan Williams.

18 recordsLinked to original sources
PubMed2006

Alternative splicing and differential gene expression in colon cancer detected by a whole genome exon array.

BACKGROUND: Alternative splicing is a mechanism for increasing protein diversity by excluding or including exons during post-transcriptional processing. Alternatively spliced proteins are particularly relevant in oncology since they may contribute to the etiology of cancer, provide selective drug targets, or serve as a marker set for cancer diagnosis. While conventional identification of splice variants generally targets individual genes, we present here a new exon-centric array (GeneChip Human Exon 1.0 ST) that allows genome-wide identification of differential splice variation, and concurrently provides a flexible and inclusive analysis of gene expression. RESULTS: We analyzed 20 paired tumor-normal colon cancer samples using a microarray designed to detect over one million putative exons that can be virtually assembled into potential gene-level transcripts according to various levels of prior supporting evidence. Analysis of high confidence (empirically supported) transcripts identified 160 differentially expressed genes, with 42 genes occupying a network impacting cell proliferation and another twenty nine genes with unknown functions. A more speculative analysis, including transcripts based solely on computational prediction, produced another 160 differentially expressed genes, three-fourths of which have no previous annotation. We also present a comparison of gene signal estimations from the Exon 1.0 ST and the U133 Plus 2.0 arrays. Novel splicing events were predicted by experimental algorithms that compare the relative contribution of each exon to the cognate transcript intensity in each tissue. The resulting candidate splice variants were validated with RT-PCR. We found nine genes that were differentially spliced between colon tumors and normal colon tissues, several of which have not been previously implicated in cancer. Top scoring candidates from our analysis were also found to substantially overlap with EST-based bioinformatic predictions of alternative splicing in cancer. CONCLUSION: Differential expression of high confidence transcripts correlated extremely well with known cancer genes and pathways, suggesting that the more speculative transcripts, largely based solely on computational prediction and mostly with no previous annotation, might be novel targets in colon cancer. Five of the identified splicing events affect mediators of cytoskeletal organization (ACTN1, VCL, CALD1, CTTN, TPM1), two affect extracellular matrix proteins (FN1, COL6A3) and another participates in integrin signaling (SLC3A2). Altogether they form a pattern of colon-cancer specific alterations that may particularly impact cell motility.

Algorithms↗
PubMed2006

Effects of sensing behavior on a latency code.

Sensory information is often acquired through active exploration, yet relatively little is known about how neurons encode sensory stimuli in the context of natural patterns of sensing behavior. We examined the effects of sensing behavior on a spike latency code in the active electrosensory system of mormyrid fish. These fish actively probe their environment by emitting brief electric organ discharge (EOD) pulses. Nearby objects alter the spatial pattern of current flowing through the skin. These changes are encoded by small shifts in the latency of individual electroreceptor afferent spikes after the EOD. In nature, the temporal pattern of EOD intervals is highly structured and varies depending on the behavioral context. We performed experiments in which we varied both the EOD amplitude and the intervals between EODs to understand how sensing behavior affects afferent latency coding. We use white-noise stimuli and linear filter estimation methods to develop simple models characterizing the dependence of afferent spike latency on the preceding sequence of EOD intervals and amplitudes. Comparing the predictions of these models with actual afferent responses for natural patterns of EOD intervals and amplitudes reveals an unexpectedly rich interplay between sensing behavior and stimulus encoding. Implications of our results for how afferent spike latency is decoded at central stages of electrosensory processing are discussed.

Action Potentials↗
PubMed2006

Unusual intron conservation near tissue-regulated exons found by splicing microarrays.

Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe differential expression of RNA containing at least two alternative splice junctions for about 40% of the 6,216 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif that is strikingly similar to the branchpoint consensus but is located downstream of the 5' splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase genes reveals that each contains a paralogous tissue-regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Proteins exported via the PrsD-PrsE type I secretion system and the acidic exopolysaccharide are involved in biofilm formation by Rhizobium leguminosarum.

The type I protein secretion system of Rhizobium leguminosarum bv. viciae encoded by the prsD and prsE genes is responsible for secretion of the exopolysaccharide (EPS)-glycanases PlyA and PlyB. The formation of a ring of biofilm on the surface of the glass in shaken cultures by both the prsD and prsE secretion mutants was greatly affected. Confocal laser scanning microscopy analysis of green-fluorescent-protein-labeled bacteria showed that during growth in minimal medium, R. leguminosarum wild type developed microcolonies, which progress to a characteristic three-dimensional biofilm structure. However, the prsD and prsE secretion mutants were able to form only an immature biofilm structure. A mutant disrupted in the EPS-glycanase plyB gene showed altered timing of biofilm formation, and its structure was atypical. A mutation in an essential gene for EPS synthesis (pssA) or deletion of several other pss genes involved in EPS synthesis completely abolished the ability of R. leguminosarum to develop a biofilm. Extracellular complementation studies of mixed bacterial cultures confirmed the role of the EPS and the modulation of the biofilm structure by the PrsD-PrsE secreted proteins. Protein analysis identified several additional proteins secreted by the PrsD-PrsE secretion system, and N-terminal sequencing revealed peptides homologous to the N termini of proteins from the Rap family (Rhizobium adhering proteins), which could have roles in cellular adhesion in R. leguminosarum. We propose a model for R. leguminosarum in which synthesis of the EPS leads the formation of a biofilm and several PrsD-PrsE secreted proteins are involved in different aspects of biofilm maturation, such as modulation of the EPS length or mediating attachment between bacteria.

ATP-Binding Cassette Transporters↗
PubMed2005

Nova regulates brain-specific splicing to shape the synapse.

Alternative RNA splicing greatly increases proteome diversity and may thereby contribute to tissue-specific functions. We carried out genome-wide quantitative analysis of alternative splicing using a custom Affymetrix microarray to assess the role of the neuronal splicing factor Nova in the brain. We used a stringent algorithm to identify 591 exons that were differentially spliced in the brain relative to immune tissues, and 6.6% of these showed major splicing defects in the neocortex of Nova2-/- mice. We tested 49 exons with the largest predicted Nova-dependent splicing changes and validated all 49 by RT-PCR. We analyzed the encoded proteins and found that all those with defined brain functions acted in the synapse (34 of 40, including neurotransmitter receptors, cation channels, adhesion and scaffold proteins) or in axon guidance (8 of 40). Moreover, of the 35 proteins with known interaction partners, 74% (26) interact with each other. Validating a large set of Nova RNA targets has led us to identify a multi-tiered network in which Nova regulates the exon content of RNAs encoding proteins that interact in the synapse.

Alternative Splicing↗
PubMed2005

QALY maximisation and people's preferences: a methodological review of the literature.

In cost-utility analysis, the numbers of quality-adjusted life years (QALYs) gained are aggregated according to the sum-ranking (or QALY maximisation) rule. This requires that the social value from health improvements is a simple product of gains in quality of life, length of life and the number of persons treated. The results from a systematic review of the literature suggest that QALY maximisation is descriptively flawed. Rather than being linear in quality and length of life, it would seem that social value diminishes in marginal increments of both. And rather than being neutral to the characteristics of people other than their propensity to generate QALYs, the social value of a health improvement seems to be higher if the person has worse lifetime health prospects and higher if that person has dependents. In addition, there is a desire to reduce inequalities in health. However, there are some uncertainties surrounding the results, particularly in relation to what might be affecting the responses, and there is the need for more studies of the general public that attempt to highlight the relative importance of various key factors.

Age Factors↗
PubMed2005

From sparks to spikes: information processing in the electrosensory systems of fish.

Recent work on electrosensory systems in fish has combined traditional neuroethological approaches with quantitative methods for characterizing neural coding. These studies have shed light on general issues in sensory processing, including how peripheral sensory receptors encode external stimuli and how these representations are transformed at subsequent stages of processing.

Animals↗
PubMed2005

A "fair innings" between the sexes: are men being treated inequitably?

In most modern developed communities, women are known to live longer than men. A less known fact is that in many statistics reporting differences in life expectancy between socio-economic classes, on average women in the worst-off social class live as long as men in the best-off social class, if not longer. It is true that women tend to have higher morbidity, or lower health-related quality of life, especially at advanced age, but this female disadvantage does not offset the life expectancy advantage sufficiently to lead to the conclusion that men and women enjoy comparable lifetime health prospects in these communities. Although there is much public and policy discussion about the inequity of health inequalities between the social classes, there is relatively little discussion about such inequalities between the sexes. The paper first discusses the applicability of the fair innings argument to the issue of inequality in health between the sexes. It critically examines six arguments concerning why inequality in health between the sexes may or may not be an inequity. Next, special attention is given to the argument that it is wrong to judge the fairness or unfairness of health inequalities in isolation, but that this judgement should be made only after considering other inequalities relevant to overall human well-being, many of which are believed to work to the disadvantage of women. An analytical framework based on the Gender-related Development Index (a supplementary index to the Human Development Index) is taken as a starting point, to address the issue of health and overall well-being. But this is found wanting, and suggestions are made as to how its conceptual and empirical properties could be improved. Meanwhile we conclude that a prima facie case has been made that the current distribution of health in most countries does not give men a "fair innings", but the broader question about general well-being remains unresolved.

Attitude to Health↗
PubMed2005

ANOSVA: a statistical method for detecting splice variation from expression data.

MOTIVATION: Many or most mammalian genes undergo alternative splicing, generating a variety of transcripts from a single gene. New information on splice variation is becoming available through technology for measuring expression levels of several exons or splice junctions per gene. We have developed a statistical method, ANalysis Of Splice VAriation (ANOSVA) to detect alternative splicing from expression data. Since ANOSVA requires no transcript information, it can be applied when the level of annotation is poor. When validated against spiked clone data, it generated no false positives and few false negatives. We demonstrated ANOSVA with data from a prototype mouse alternative splicing array, run against normal adult tissues, yielding a set of genes with evidence of tissue-specific splice variation. AVAILABILITY: The results are available at the supplementary information site. SUPPLEMENTARY INFORMATION: The results are available at the supplementary information site https://bioinfo.affymetrix.com/Papers/ANOSVA/

Alternative Splicing↗
PubMed2005

Thinking about equity in health care.

Public health care systems such as the British National Health Service typically profess two principal objectives: to improve the health of the whole population; and to reduce inequalities in health within it. Given scarce resources, these objectives are often in conflict. Much attention has justifiably been paid, by health economists, to addressing the former objective with methods of economic appraisal. My intention is to focus on the more difficult issue of the pursuit of 'equity' in health care, specifically the desire to reduce inequalities in health. This raises philosophical and policy questions about what makes some people more deserving of care than others, and whether or not society should adopt a forgiving stance towards those who have compromised their health status in some way, and offer access to treatment. Also, decision-makers may need to distinguish between the goal of raising the level of those worse-off and reducing inequality across society as a whole. Moreover, it is important to clarify what we wish to be made less unequal within the realm of health care provision. Tough decisions like these are based on value judgements and trading off one priority against another. In the interests of equity, such decisions need to be transparent and based on the preferences of society as a whole rather than covert and capricious. No manager needs reminding that resources are limited or that if more favourable treatment is accorded to some, inevitably less favourable treatment is accorded to others. Policy-making for a whole unit requires a nurse manager to offer a perspective on multidisciplinary matters and engage in wider public policy issues facing the team. As circumstances change, existing practice may be challenged as unfair, inefficient, or failing to account for important patient characteristics which make them different. Here, thinking clearly about equity is very important, and nurse managers are important as clarifiers of the thinking about what should be considered when making these difficult decisions.

Attitude to Health↗
PubMed2004

Random walks for spike-timing-dependent plasticity.

Random walk methods are used to calculate the moments of negative image equilibrium distributions in synaptic weight dynamics governed by spike-timing-dependent plasticity. The neural architecture of the model is based on the electrosensory lateral line lobe of mormyrid electric fish, which forms a negative image of the reafferent signal from the fish's own electric discharge to optimize detection of sensory electric fields. Of particular behavioral importance to the fish is the variance of the equilibrium postsynaptic potential in the presence of noise, which is determined by the variance of the equilibrium weight distribution. Recurrence relations are derived for the moments of the equilibrium weight distribution, for arbitrary postsynaptic potential functions and arbitrary learning rules. For the case of homogeneous network parameters, explicit closed form solutions are developed for the covariances of the synaptic weight and postsynaptic potential distributions.

Action Potentials↗
PubMed2004

Enhancer trapping identifies TRI, an Arabidopsis gene up-regulated by pathogen infection.

Enhancer trap Arabidopsis thaliana plants were screened for genes up-regulated by virus infection. The plants carried T-DNA insertions comprising a minimal -60-bp Cauliflower mosaic virus 35S promoter fused to the beta-glucuronidase (GUS) reporter gene. Approximately 12,000 plants were assayed for GUS activity before and after rub-inoculation with Tobacco rattle virus (TRV) tagged with the green fluorescent protein (GFP). One plant and its progeny consistently showed upregulation of GUS activity in response to TRV-GFP infection, indicating that a virus-responsive enhancer element was "tagged" by the T-DNA in this line. Other viruses, bacteria, and oomycetes, but not wounding, up-regulated GUS activity in the enhancer trap line, indicating that the response was not specific to TRV-GFP infection. A pathogen-inducible, alternatively spliced gene was identified, which we have termed TRI for TRV-induced gene. A pathogen-responsive element was localized to a 1.1-kb region upstream of the T-DNA insertion, and two different cis-acting elements, both implicated in defense responses, were found in the sequence upstream of TRI. Sequence analyses revealed that TRI is similar to ACRE169, a gene that is up-regulated in Cf-9-expressing tobacco when treated with Avr-9, the Cladosporium fulvum elicitor of the Cf-9 resistance response.

Alternative Splicing↗
PubMed2004

The donor notification process from the donor's perspective.

BACKGROUND: Despite large numbers of blood donors being notified of abnormal infectious disease screening results, there has been little scientific study of the effects of this process. STUDY DESIGN AND METHODS: With a 28-item questionnaire, an anonymous mail survey was conducted of 4141 blood donors notified of 15 distinct categories of abnormal infectious disease screening and confirmatory test results. RESULTS: The survey had a 42 percent response rate, and 10 percent of the respondents did not recall being notified of their results. Of the 1556 respondents who recalled being notified, 27 percent contacted the blood center for further information, 60 percent discussed their results with a health care provider, and 73 percent of permanently or indefinitely deferred donors correctly understood their deferral status. Confusion and emotional upset were reported in 81 and 75 percent of notified donors, respectively. CONCLUSIONS: The notification process appears to achieve most of its aims in the majority of donors. Nevertheless, some donors did not understand that they were ineligible for future donation, and many donors were confused and upset. These data indicate that the adverse impact of notifying donors about abnormal test results needs to be considered when new blood donor screening tests and confirmatory algorithms are being licensed and implemented. Further studies of the effectiveness of newer revised donor notification materials are needed.

Adult↗
PubMed2003

Stability of negative-image equilibria in spike-timing-dependent plasticity.

We investigate the stability of negative image equilibria in mean synaptic weight dynamics governed by spike-timing-dependent plasticity (STDP). The model architecture closely follows the anatomy and physiology of the electrosensory lateral line lobe (ELL) of mormyrid electric fish. The ELL uses a spike-timing-dependent learning rule to form a negative image of the reafferent signal from the fish's own electric discharge, thus improving detectability of external electric fields. We derive sufficient conditions for existence of the negative image and necessary and sufficient conditions for stability, for arbitrary postsynaptic potential functions and arbitrary learning rules. This significantly generalizes earlier investigations. We then apply the general result to several examples of biological interest, including a class of learning rules consistent with the rule observed experimentally in the mormyrid ELL.

Action Potentials↗
PubMed2003

Logical inconsistencies in survey respondents' health state valuations -- a methodological challenge for estimating social tariffs.

Logical inconsistencies in survey respondents' valuations of hypothetical health states - represented by the EQ-5D, for example - present a conundrum as to whether or not their responses ought to be included for estimating social 'tariffs'. A 'logical inconsistency' occurs when a state that 'in logical terms' is unambiguously less severe than another is assigned a lower value. Excluding such responses is defensible on data quality grounds but puts at risk the representativeness of the estimated tariff, given it is meant to represent the preferences of 'society'. This paper explores the rationale for and effect of excluding, to varying degrees, responses distinguished by the number of pairwise inconsistencies they contain, and reports equations for two tariffs that arise from contrasting approaches. The data are from a random sample of adult New Zealanders whose visual analogue scale valuations for a selection of EQ-5D states were collected in 1999 via a postal survey to which 1360 people responded (a 50% response rate). We conclude that there is no simple, generalisable 'rule' to guide exclusions and therefore researchers ought to explore the sensitivity of their estimated tariffs (and ultimately QALY estimates) to alternative treatments of logically inconsistent responses.

Adolescent↗