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Search Results: 1 - 10 of 403476 matches for " Jacqueline M. Matthews "
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Contribution of DEAF1 Structural Domains to the Interaction with the Breast Cancer Oncogene LMO4
Liza Cubeddu, Soumya Joseph, Derek J. Richard, Jacqueline M. Matthews
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039218
Abstract: The proteins LMO4 and DEAF1 contribute to the proliferation of mammary epithelial cells. During breast cancer LMO4 is upregulated, affecting its interaction with other protein partners. This may set cells on a path to tumour formation. LMO4 and DEAF1 interact, but it is unknown how they cooperate to regulate cell proliferation. In this study, we identify a specific LMO4-binding domain in DEAF1. This domain contains an unstructured region that directly contacts LMO4, and a coiled coil that contains the DEAF1 nuclear export signal (NES). The coiled coil region can form tetramers and has the typical properties of a coiled coil domain. Using a simple cell-based assay, we show that LMO4 modulates the activity of the DEAF NES, causing nuclear accumulation of a construct containing the LMO4-interaction region of DEAF1.
The Importance of pH in Regulating the Function of the Fasciola hepatica Cathepsin L1 Cysteine Protease
Jonathan Lowther,Mark W. Robinson,Sheila M. Donnelly,Weibo Xu,Colin M. Stack,Jacqueline M. Matthews,John P. Dalton
PLOS Neglected Tropical Diseases , 2009, DOI: 10.1371/journal.pntd.0000369
Abstract: The helminth parasite Fasciola hepatica secretes cathepsin L cysteine proteases to invade its host, migrate through tissues and digest haemoglobin, its main source of amino acids. Here we investigated the importance of pH in regulating the activity and functions of the major cathepsin L protease FheCL1. The slightly acidic pH of the parasite gut facilitates the auto-catalytic activation of FheCL1 from its inactive proFheCL1 zymogen; this process was ~40-fold faster at pH 4.5 than at pH 7.0. Active mature FheCL1 is very stable at acidic and neutral conditions (the enzyme retained ~45% activity when incubated at 37°C and pH 4.5 for 10 days) and displayed a broad pH range for activity peptide substrates and the protein ovalbumin, peaking between pH 5.5 and pH 7.0. This pH profile likely reflects the need for FheCL1 to function both in the parasite gut and in the host tissues. FheCL1, however, could not cleave its natural substrate Hb in the pH range pH 5.5 and pH 7.0; digestion occurred only at pH≤4.5, which coincided with pH-induced dissociation of the Hb tetramer. Our studies indicate that the acidic pH of the parasite relaxes the Hb structure, making it susceptible to proteolysis by FheCL1. This process is enhanced by glutathione (GSH), the main reducing agent contained in red blood cells. Using mass spectrometry, we show that FheCL1 can degrade Hb to small peptides, predominantly of 4–14 residues, but cannot release free amino acids. Therefore, we suggest that Hb degradation is not completed in the gut lumen but that the resulting peptides are absorbed by the gut epithelial cells for further processing by intracellular di- and amino-peptidases to free amino acids that are distributed through the parasite tissue for protein anabolism.
Solution Structure of the LIM-Homeodomain Transcription Factor Complex Lhx3/Ldb1 and the Effects of a Pituitary Mutation on Key Lhx3 Interactions
Mugdha Bhati, Christopher Lee, Morgan S. Gadd, Cy M. Jeffries, Ann Kwan, Andrew E. Whitten, Jill Trewhella, Joel P. Mackay, Jacqueline M. Matthews
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040719
Abstract: Lhx3 is a LIM-homeodomain (LIM-HD) transcription factor that regulates neural cell subtype specification and pituitary development in vertebrates, and mutations in this protein cause combined pituitary hormone deficiency syndrome (CPHDS). The recently published structures of Lhx3 in complex with each of two key protein partners, Isl1 and Ldb1, provide an opportunity to understand the effect of mutations and posttranslational modifications on key protein-protein interactions. Here, we use small-angle X-ray scattering of an Ldb1-Lhx3 complex to confirm that in solution the protein is well represented by our previously determined NMR structure as an ensemble of conformers each comprising two well-defined halves (each made up of LIM domain from Lhx3 and the corresponding binding motif in Ldb1) with some flexibility between the two halves. NMR analysis of an Lhx3 mutant that causes CPHDS, Lhx3(Y114C), shows that the mutation does not alter the zinc-ligation properties of Lhx3, but appears to cause a structural rearrangement of the hydrophobic core of the LIM2 domain of Lhx3 that destabilises the domain and/or reduces the affinity of Lhx3 for both Ldb1 and Isl1. Thus the mutation would affect the formation of Lhx3-containing transcription factor complexes, particularly in the pituitary gland where these complexes are required for the production of multiple pituitary cell types and hormones.
Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation
Corrine J Porter, Jacqueline M Matthews, Joel P Mackay, Sharon E Pursglove, Jason W Schmidberger, Peter J Leedman, Stephanie C Pero, David N Krag, Matthew CJ Wilce, Jacqueline A Wilce
BMC Structural Biology , 2007, DOI: 10.1186/1472-6807-7-58
Abstract: As a first step towards understanding how Grb7 may be inhibited by G7-18NATE, we solved the crystal structure of the Grb7 SH2 domain to 2.1 ? resolution. We describe the details of the peptide binding site underlying target specificity, as well as the dimer interface of Grb 7 SH2. Dimer formation of Grb7 was determined to be in the μM range using analytical ultracentrifugation for both full-length Grb7 and the SH2 domain alone, suggesting the SH2 domain forms the basis of a physiological dimer. ITC measurements of the interaction of the G7-18NATE peptide with the Grb7 SH2 domain revealed that it binds with a binding affinity of Kd = ~35.7 μM and NMR spectroscopy titration experiments revealed that peptide binding causes perturbations to both the ligand binding surface of the Grb7 SH2 domain as well as to the dimer interface, suggesting that dimerisation of Grb7 is impacted on by peptide binding.Together the data allow us to propose a model of the Grb7 SH2 domain/G7-18NATE interaction and to rationalize the basis for the observed binding specificity and affinity. We propose that the current study will assist with the development of second generation Grb7 SH2 domain inhibitors, potentially leading to novel inhibitors of cancer cell migration and invasion.Tyrosine kinase signaling pathways play a major role in the regulation of cell growth, division and motility. It is unsurprising, therefore, that aberrations of these pathways can underlie cancerous phenotypes [1,2] and that tyrosine kinase pathways have been the targets of several successful anti-cancer agents [3]. These targets have included extracellular and cytoplasmic domains of receptor tyrosine kinases, but downstream binding partners may also prove to be important targets for new therapeutics [4,5].Grb7 is a member of a family of adapter proteins that includes Grb10 and Grb14, and serves to couple activated tyrosine kinases to downstream signaling pathways [6]. These proteins share a region with sequence homol
The Magnetic Field Morphology of the Class 0 Protostar L1157-mm
Ian W. Stephens,Leslie W. Looney,Woojin Kwon,Charles L. H. Hull,Richard L. Plambeck,Richard M. Crutcher,Nicholas Chapman,Giles Novak,Jacqueline Davidson,John E. Vaillancourt,Hiroko Shinnaga,Tristan Matthews
Physics , 2013, DOI: 10.1088/2041-8205/769/1/L15
Abstract: We present the first detection of polarization around the Class 0 low-mass protostar L1157-mm at two different wavelengths. We show polarimetric maps at large scales (10" resolution at 350 um) from the SHARC-II Polarimeter and at smaller scales (1.2"-4.5" at 1.3 mm) from the Combined Array for Research in Millimeter-wave Astronomy (CARMA). The observations are consistent with each other and show inferred magnetic field lines aligned with the outflow. The CARMA observations suggest a full hourglass magnetic field morphology centered about the core; this is only the second well-defined hourglass detected around a low-mass protostar to date. We apply two different methods to CARMA polarimetric observations to estimate the plane-of-sky magnetic field magnitude, finding values of 1.4 and 3.4 mG.
Mutations in MITF and PAX3 Cause “Splashed White” and Other White Spotting Phenotypes in Horses
Regula Hauswirth equal contributor,Bianca Haase equal contributor,Marlis Blatter,Samantha A. Brooks,Dominik Burger,Cord Dr?gemüller,Vincent Gerber,Diana Henke,Jozef Janda,Rony Jude,K. Gary Magdesian,Jacqueline M. Matthews,Pierre-André Poncet,Vilhjálmur Svansson,Teruaki Tozaki,Lorna Wilkinson-White,M. Cecilia T. Penedo,Stefan Rieder,Tosso Leeb
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002653
Abstract: During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The “splashed white” pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes.
Evidence for granulation in early A-type stars
Thomas Kallinger,Jaymie M. Matthews
Physics , 2010, DOI: 10.1088/2041-8205/711/1/L35
Abstract: Stars with spectral types earlier than about F0 on (or close) to the main sequence have long been believed to lack observable surface convection, although evolutionary models of A-type stars do predict very thin surface convective zones. We present evidence for granulation in two delta Scuti stars of spectral type A2: HD174936 and HD50844. Recent analyses of space-based CoRoT (Convection, Rotation, and planetary Transits) data revealed up to some 1000 frequencies in the photometry of these stars. The frequencies were interpreted as individual pulsation modes. If true, there must be large numbers of nonradial modes of very high degree l which should suffer cancellation effects in disk-integrated photometry (even of high space-based precision). The p-mode interpretation of all the frequencies in HD174936 and HD50844 depends on the assumption of white (frequency independent) noise. Our independent analyses of the data provide an alternative explanation: most of the peaks in the Fourier spectra are the signature of non-white granulation background noise, and less than about 100 of the frequencies are actual stellar p-modes in each star. We find granulation time scales which are consistent with scaling relations that describe cooler stars with known surface convection. If the granulation interpretation is correct, the hundreds of low-amplitude Fourier peaks reported in recent studies are falsely interpreted as independent pulsation modes and a significantly lower number of frequencies are associated with pulsation, consistent with only modes of low degree.
The Fat Controller: Adipocyte Development
Jacqueline M. Stephens
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1001436
Abstract: Obesity is a condition characterized by excess adipose tissue that results from positive energy balance and is the most common metabolic disorder in the industrialized world. The obesity epidemic shows no sign of slowing, and it is increasingly a global problem. Serious clinical problems associated with obesity include an increased risk for type 2 diabetes, atherosclerosis, and cancer. Hence, understanding the origin and development of adipocytes and adipose tissue will be critical to the analysis and treatment of metabolic diseases. Historically, albeit incorrectly, adipocytes were thought to be inert cells whose singular function was lipid storage. It is now known that adipocytes have other critical functions; the most important include sensitivity to insulin and the ability to produce and secrete adipocyte-specific endocrine hormones that regulate energy homeostasis in other tissues. Today, adipocytes are recognized as critical regulators of whole-body metabolism and known to be involved in the pathogenesis of a variety of metabolic diseases. All cells come from other cells and many cells arise from precursor cells. Adipocytes are not created from other adipocytes, but they arise from precursor cells. In the last two decades, scientists have discovered the function of many proteins that influence the ability of precursor cells to become adipocytes. If the expansion of the adipose tissue is the problem, it seems logical that adipocyte development inhibitors could be a viable anti-obesity therapeutic. However, factors that block adipocyte development and limit adipocyte expansion also impair metabolic health. This notion may be counterintuitive, but several lines of evidence support the idea that blocking adipocyte development is unhealthy. For this reason it is clear that we need a better understanding of adipocyte development.
Review: Michael Bloor, Jane Frankland, Michelle Thomas & Kate Robson (2001). Focus Groups in Social Research Review: Michael Bloor, Jane Frankland, Michelle Thomas & Kate Robson (2001). Focus Groups in Social Research Rese a: Michael Bloor, Jane Frankland, Michelle Thomas & Kate Robson (2001). Focus Groups in Social Research
Jacqueline M. Barnett
Forum : Qualitative Social Research , 2002,
Abstract: Dieses Buch versteht sich als eine Einführung, die zun chst Fokusgruppen im Kontext der Sozialwissenschaften verortet und dann grundlegende Richtlinien für die Vorbereitung und die Durchführung von Fokusgruppen sowie für die Datenanalyse vermittelt. Obwohl das Buch als Einführung für Forschende, die keine Erfahrung mit Untersuchungen mittels Fokusgruppen besitzen, angelegt ist, enth lt es keine eigenst ndige, umfassende Anleitung für diesen Bereich. Dennoch k nnten insbesondere Studierende eines Einführungsseminars sehr von diesem überblick über die Methode der Fokusgruppen profitieren. Da einige Schlüsselkonzepte zur Zusammenstellung und zum Einsatz von Fokusgruppen vollst ndig fehlen, sollte das Buch jedoch nicht als einzige Quelle zur Anleitung für Fokusgruppen verwendet werden. URN: urn:nbn:de:0114-fqs0204432 This book is an introductory text that situates focus groups within the social science context and provides basic guidelines for preparing and conducting focus groups as well as analyzing the data. This book is not meaty and should not be used as the sole means for focus group guidance. Moreover, there are some key concepts regarding sampling and uses for focus group research that are missing from this book. Therefore, while it provides functional information for the researcher new to focus group studies, this book is not a stand-alone guide. An undergraduate survey course in research methods, however, would benefit greatly from this overview on focus groups. URN: urn:nbn:de:0114-fqs0204432 Este libro es un texto introductorio que sitúa a la entrevista grupal (focus group) dentro del contexto de las ciencias sociales y ofrece guías básicas para preparar y conducir entrevistas grupales, así como también analizar los datos que se generen. Este libro no es un material suficiente para usarse sólo; más aún, hay algunos conceptos relacionados con el muestreo y los usos de la entrevista grupal que están ausentes en este libro. Por lo tanto, aunque es un material de lectura que ofrece información funcional para el investigador novel en la investigación basada en entrevista grupal, este libro no es una guía suficiente, tendría que complementarse con otros materiales. Sin embargo, un curso general de métodos de investigación en el nivel de licenciatura, podría beneficiarse grandemente de esta revisión panorámica de la entrevista grupal. URN: urn:nbn:de:0114-fqs0204432
Review: Benjamin Crabtree & William Miller (Hrsg.) (1999). Doing Qualitative Research (2. Auflage) Review: Benjamin Crabtree & William Miller (Eds.) (1999). Doing Qualitative Research (2nd edition) Rese a: Benjamin Crabtree & William Miller (Eds.) (1999). Doing Qualitative Research (segunda edición)
Jacqueline M. Barnett
Forum : Qualitative Social Research , 2002,
Abstract: Das Buch ist ein Muss für alle qualitativ Forschenden im Themenfeld Gesundheit. Den Lesenden wird ein überblick zu qualitativen Methoden geboten und unterschiedliche Erhebungsverfahren und Auswertungsstrategien werden zusammen mit einigen besonderen Forschungsdesigns vorgestellt. Besonders wertvoll sind die detaillierten Beispiele tats chlicher Forschungsprobleme und die angebotenen Vorschl ge zu deren L sung. In Anbetracht der Komplexit t der Verfahren und Forschungsdesigns, die vorgestellt werden, eignet sich der Band weniger als Einführungsbuch oder als Anleitung zur Nutzung qualitativer Methoden. Vielmehr richtet er sich an zumindest teilweise mit qualitativer Forschung bereits vertraute Personen; für diesen Kreis ist das Buch allerdings von gro em Wert. URN: urn:nbn:de:0114-fqs020432 This text is a must for the qualitative researcher whose work primarily lies in the field of healthcare. The reader is taken through an overview of qualitative methods and then shown various data collection techniques and data analysis strategies along with some exceptional research designs. The detailed exemplars of real research problems and suggestions for solutions are invaluable. The book should not be used for introduction to or survey of qualitative methods instruction because of the complexity of strategies and research designs. For the experienced or somewhat experienced researcher, however, this text is priceless. URN: urn:nbn:de:0114-fqs020432 Este texto es obligante para el investigador cualitativo cuyo trabajo se vincula primordialmente con el campo de la atención en salud. El lector es llevado a través de una revisión de métodos cualitativos y luego se le muestran varias técnicas de recolección de datos y de estrategias para el análisis de datos, conjuntamente con algunos dise os de investigación excepcionales. Los ejemplos detallados de problemas reales de investigación y de sugerencias para su solución son invalorables, Este libro no debería ser utilizado como introducción o encuesta sobre instrucción en métodos cualitativos debido a la complejidad de estrategias y dise os de investigación. No obstante para el investigador experimentado o algo experimentado, este texto es muy valioso. URN: urn:nbn:de:0114-fqs020432
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