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Biomedical subjects

D Sexton

Publications and source records attributed to D Sexton.

At least 19 recordsLinked to original sources
PubMed2005

A distinct strategy to generate high-affinity peptide binders to receptor tyrosine kinases.

We describe a novel and general way of generating high affinity peptide (HAP) binders to receptor tyrosine kinases (RTKs), using a multi-step process comprising phage-display selection, identification of peptide pairs suitable for hetero-dimerization (non-competitive and synergistic) and chemical synthesis of heterodimers. Using this strategy, we generated HAPs with K(D)s below 1 nM for VEGF receptor-2 (VEGFR-2) and c-Met. VEGFR-2 HAPs bound significantly better (6- to 500-fold) than either of the individual peptides that were used for heterodimer synthesis. Most significantly, HAPs were much better (150- to 800-fold) competitors than monomers of the natural ligand (VEGF) in various competitive binding and functional assays. In addition, we also found the binding of HAPs to be less sensitive to serum than their component peptides. We believe that this method may be applied to any protein for generating high affinity peptide (HAP) binders.

Dimerization↗
PubMed2005

Uncertainty in predictions of the climate response to rising levels of greenhouse gases.

The range of possibilities for future climate evolution needs to be taken into account when planning climate change mitigation and adaptation strategies. This requires ensembles of multi-decadal simulations to assess both chaotic climate variability and model response uncertainty. Statistical estimates of model response uncertainty, based on observations of recent climate change, admit climate sensitivities--defined as the equilibrium response of global mean temperature to doubling levels of atmospheric carbon dioxide--substantially greater than 5 K. But such strong responses are not used in ranges for future climate change because they have not been seen in general circulation models. Here we present results from the 'climateprediction.net' experiment, the first multi-thousand-member grand ensemble of simulations using a general circulation model and thereby explicitly resolving regional details. We find model versions as realistic as other state-of-the-art climate models but with climate sensitivities ranging from less than 2 K to more than 11 K. Models with such extreme sensitivities are critical for the study of the full range of possible responses of the climate system to rising greenhouse gas levels, and for assessing the risks associated with specific targets for stabilizing these levels.

Journal Article↗
PubMed2001

Strategy for protein isoform identification from expressed sequence tags and its application to peptide mass fingerprinting.

Expressed Sequence Tags (ESTs) are an invaluable resource for protein identification and characterisation in proteomics. They allow proteins to be identified in the absence of genome sequence data. When EST sequences are used for protein identification, they are usually first processed into contigs to reduce redundancy and generate longer sequences from the overlapping ESTs. However, the process of generating contigs may accidentally group biologically meaningful isoforms together. Here we report means of discovering isoforms in EST sequences and how to use this information in the framework of protein identification and characterisation with peptide mass fingerprinting. We illustrate our strategies with examples from the dbEST database as well as protein isoforms from two-dimensional polyacrylamide gels.

Amino Acid Sequence↗
PubMed2001

Proteomic analysis of a developmentally regulated secretory vesicle.

Secretion of spore coat proteins from the prespore secretory vesicles (PSVs) in Dictyostelium discoideum is a signal mediated event that underlies terminal cell differentiation, and represents an important case of developmentally regulated secretion. In order to study the biochemical mechanisms that govern the regulated fusion of the PSVs with the plasma membrane and the subsequent secretion of their cargo, we purified this organelle from prespore cells. Analysis of protein extracts of highly purified PSVs indicated that, in addition to the cargo of structural spore coat proteins, many more proteins are associated with the PSVs. Their identification is paramount to the understanding of the mechanism of regulated secretion in this system. In this study we have taken the first comprehensive proteomic approach to the analysis of an entire, previously uncharacterized, organelle, with the goal of identifying the major proteins associated with the PSVs. We show that in addition to the structural spore coat proteins, the PSVs contain the enzymes needed for proper spore coat assembly (thioredoxin 2 and 3), regulatory proteins which we predict receive and transduce the developmental signal for secretion (rab7 GTPase, PI-3 kinase, NDP kinase and the calcium binding proteins calfumirin-1 and calreticulin) as well as proteins that interact with the cytoskeleton to mediate movement of the PSVs to the plasma membrane (actin binding proteins coactosin and profilin 1). In addition, the results suggest that proteins can play multiple roles in the cell, and that protein function can be dictated in part by subcellular localization. The identification of the PSV proteins is allowing us to develop testable hypotheses about the roles of these proteins within the functional context of developmentally regulated secretion.

Animals↗
PubMed1997

Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor.

Mitogen-activated protein kinases function in signal transduction pathways that are involved in controlling key cellular processes in many organisms. A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-activated protein kinase. This mitogen-activated protein kinase pathway has been implicated in the signal transduction of cytokine- and stress-induced apoptosis in a variety of cell types. Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53. In addition, in a set of 88 human cancer cell lines prescreened for loss of heterozygosity, we detected two nonsense and three missense sequence variants of MKK4 in cancer cell lines derived from human pancreatic, breast, colon, and testis cells. In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase. Thus, the incidence of coding mutations of MKK4 in the set of cell lines is 6 of 213 (approximately 3%). These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells.

DNA, Neoplasm↗
PubMed1997

Localization of SMAD5 and its evaluation as a candidate myeloid tumor suppressor.

Acquired interstitial or complete losses of chromosome 5 are recurring anomalies associated with preleukemic myelodysplasia and acute myelogenous leukemia with a poor prognosis. Previous studies have delineated a potential myeloid tumor suppressor locus to a <2.4-Mb interval between the genes for IL9 and EGR1 on 5q31. In this report, we have localized the SMAD5 gene, a homologue of the tumor suppressor genes SMAD4/DPC-4 and SMAD2/JV18.1, to the minimal myeloid tumor suppressor locus and characterized its open reading frame and genomic organization. SMAD5 transcripts are readily detectable in hematolymphoid tissues and leukemic blasts. Absence of intragenic mutations in the remaining SMAD5 allele of leukemic patients and multiple solid tumor cell lines prescreened for loss of heterozygosity suggests that SMAD5 may not be a common target of somatic inactivation in malignancy.

Base Sequence↗
PubMed1997

Correlates of the quality of life of adults with severe or profound mental retardation.

To ensure quality of services for individuals with mental retardation/developmental disability, professionals must measure consumer outcomes related to lifestyle. In this study variables contributing to quality of life for 60 adults with severe or profound disabilities who resided in ICF/MR community-based homes for 4 to 5 persons were examined. Using the Quality of Life Index, we studied interrelations among personal lifestyle characteristics of adults and community-home program characteristics with quality of life factors. The R2 effect size (.571) involving total scores on the Quality of Life Index as the criterion variable was large and statistically significant.

Adult↗
PubMed1995

Cerebral phaeohyphomycosis complicated with brain abscess: a case report.

Cerebral phaeohyphomycosis is used to describe the rare clinical syndrome of cerebral infection caused by dematiaceous (i.e. pigmented olivaceous-brown) fungi. It usually presents as brain abscess. In view of the rarity of this fungal infection and its clinical importance, we report a case of cerebral phaeohyphomycosis caused by Xylohypha bantiana. The patient presented with a seizure attack. The MRI study revealed a ring-enhancing lesion with marked perifocal edema in right high frontoparietal junction of the brain. He underwent an initial craniotomy for removal of the lesion and a second craniotomy for recurrence of the lesion 3 months later. The diagnosis was based on successful cultivation of X. bantiana from the surgical specimen and on histopathology. The patient received antifungal drug therapy of 5-flucytosine and itraconazole. He has done well without any symptoms. We think complete surgical removal of the brain abscess combined with antifungal drug therapy is the best management for this rare fungal disease.

Brain Abscess↗
PubMed1994

Predicting child abuse potential across family types.

The present study was conducted to explore whether stress, family resources, and social support are correlates of the child abuse potential of mothers, and whether prediction functions differ across families with children with disabilities and families with no children with disabilities. The design and analyses were correlational. Statistically and practically significant relationships were found. Stress in family functioning appears to be an important predictor of child abuse potential, and it is suggested that interventions might be designed to target related features of family functioning.

Adult↗
PubMed1989

Measurement characteristics of a short form of the questionnaire on resources and stress.

The psychometric integrity of a short form of a measure of ecological stress was evaluated based on data provided by both fathers and mothers representing intact families, half of which included children with handicaps and half of which did not. Alpha reliability, factor structure, and construct validity analyses generally supported the conclusion that the short form of the Questionnaire on Resources and Stress is reasonably reliable and valid.

Adult↗