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Biomedical subjects

Keith Johnson

Publications and source records attributed to Keith Johnson.

7 recordsLinked to original sources
PubMed2006

So many studies, too few subjects: establishing functional relevance of genetic polymorphisms on pharmacokinetics.

Based on current literature, greater clarity in defining the magnitude of polymorphism effects on pharmacokinetics can be achieved by addressing key components of study design, including adequate subject numbers per study group. Convincing evidence of functional relevance exists for polymorphisms in genes such as CYP2D6 and UGT1A1, whereas the published evidence for similar effects for CYP3A5, OATP1B1, and ABCB1 is still emerging or equivocal. Polymorphism-associated differences in pharmacokinetic parameters were simulated to incorporate (1) the ratio of group mean parameter values for homozygous wild-type subjects versus homozygous variants, (2) pharmacokinetic variability, and (3) sample size needed to achieve 80% power, assuming 69% coefficient of variation. Subject selection by genotype and choice of probe substrate are also considered. Simulation results and literature examples are incorporated to define key recommendations for future investigations. This will allow for more definitive statements in publications regarding genotype influence on pharmacokinetics.

Biotransformation↗
PubMed2006

Race and ethnicity in the era of emerging pharmacogenomics.

Race and ethnicity are terms that are commonly used to categorize subjects in medical research. Advances in genetics and the emerging discipline of pharmacogenomics have brought these terms under scrutiny, with arguments either for the continued use or for the abandonment of these terms generating strong views. As pharmacogenomics research develops, we may find that more accurate and specific descriptions of relevant variation in genes will reduce the value that these imprecise descriptors have in predicting how people will respond to drug therapies.

Biomedical Research↗
PubMed2005

Characterisation of the transcription factor, SIX5, using a new panel of monoclonal antibodies.

SIX5 is a member of the human SIX family of transcription factors, many of which are involved in eye development. However, SIX5 transcripts are known to be present at very low levels in cells and no study has yet convincingly demonstrated detection of endogenous SIX5 protein by Western blotting or immunolocalisation. We have produced a new panel of 18 monoclonal antibodies (mAbs) that recognise at least four different epitopes in order to identify authentic human SIX5 protein in cells and tissues. Phage-displayed peptide libraries were used to identify individual amino-acids important for antibody binding within each epitope. Endogenous SIX5 migrated in SDS-PAGE with an apparent M(r) of 100 kDa and was present at similar levels in all foetal tissues and cell lines tested. In HeLa cells, it was located in the nucleoplasm with a granular distribution. An mRNA for a shorter splicing isoform of SIX5, with an altered carboxy-terminus, has been described, but further mAbs specific for this isoform did not detect any endogenous protein. We conclude that the full-length isoform is the major functional protein in vivo while the putative shorter protein is undetectable and may not be expressed at all.

Alternative Splicing↗
PubMed2005

Pharmacogenomics: integration into drug discovery and development.

To deliver on the promise of personalized medicine requires the integration of pharmacogenomics into the discovery and development of medicines. Over the last few years the pharmaceutical industry has been building considerable resources to achieve that. However, this requires new skill sets, capabilities and infrastructures which have not been a traditional part of the industry's efforts. In this article we describe how the integration of genetics and pharmacogenomics data has begun to deliver success and illustrate the challenges that the new science and technologies bring and how these challenges can be addressed in order to deliver on the promise.

Drug Design↗
PubMed2004

The decline and fate of an iron-induced subarctic phytoplankton bloom.

Iron supply has a key role in stimulating phytoplankton blooms in high-nitrate low-chlorophyll oceanic waters. However, the fate of the carbon fixed by these blooms, and how efficiently it is exported into the ocean's interior, remains largely unknown. Here we report on the decline and fate of an iron-stimulated diatom bloom in the Gulf of Alaska. The bloom terminated on day 18, following the depletion of iron and then silicic acid, after which mixed-layer particulate organic carbon (POC) concentrations declined over six days. Increased particulate silica export via sinking diatoms was recorded in sediment traps at depths between 50 and 125 m from day 21, yet increased POC export was not evident until day 24. Only a small proportion of the mixed-layer POC was intercepted by the traps, with more than half of the mixed-layer POC deficit attributable to bacterial remineralization and mesozooplankton grazing. The depletion of silicic acid and the inefficient transfer of iron-increased POC below the permanent thermocline have major implications both for the biogeochemical interpretation of times of greater iron supply in the geological past, and also for proposed geo-engineering schemes to increase oceanic carbon sequestration.

Alaska↗
PubMed2004

Syllable onset intervals as an indicator of discourse and syntactic boundaries in Taiwan Mandarin.

This study looks at the syllable onset interval (SOI) patterning in Taiwan Mandarin spontaneous speech and its relationship to discourse and syntactic units. Monologs were elicited by asking readers to tell stories depicted in comic strips and were transcribed and segmented into Discourse Segment Units (Grosz & Sidner, 1986), clauses, and phrases. Results showed that the degree of final lengthening was modulated by boundary types. Lengthening before discourse boundaries was longer than that before clausal boundaries, which was in turn longer than that before phrasal boundaries. Final SOI lengthening also seemed to reflect cognitive load. At the discourse and clausal levels, the degree of lengthening is modulated by narration order. First narrations tended to have longer final SOIs than second narrations. In addition, there was also a mild lengthening effect in nonfinal SOIs, as was evidenced by the length differences in initial and medial SOIs and the differential lengthening effect regarding the positioning of phrases in a clause.

Adult↗