117,693 research outputs found
Ruddock, Joan & Cooper, Jeff: transcript of a video interview (07-Jun-2016)
No full textInterview with Dame Joan Ruddock and Mr Jeff Cooper, conducted by Ms Lynda Finn, with additional questions by Mr Alan Yabsley, for the History of Modern Biomedicine Research Group, 07 June 2016, in the School of History, Queen Mary University of London. Transcribed by Mrs Debra Gee, and edited by Mr Alan Yabsley and Professor Tilli Tansey. The project management was undertaken by Mr Adam Wilkinson. Dame Joan Ruddock DBE BSc ARCS (b. 1943) was a Member of Parliament (MP) for Lewisham Deptford from 1987 to 2015. In 1989 she brought forward a Private Members’ Bill on fly-tipping that became the Control of Pollution Act 1989 and, in 2003, a Private Members’ Bill that became the Household Waste Recycling Act 2003. In 2007 she became Parliamentary Under Secretary in the Department for Environment, Food and Rural Affairs and requested the waste brief, serving as Minister for Biodiversity, Climate Change and Waste until she joined the newly created Department for Energy and Climate Change in October 2008. Dame Joan gave her final speech to the House of Commons on 26 March 2015. Mr Jeff Cooper MSc (b. 1949) became Waste Recycling Coordinator at the Greater London Council in 1982. He was subsequently appointed Waste Planner for the London Waste Regulation Authority (LWRA) where he also represented the International Solid Waste Association’s recycling working group as its Vice-Chair. He joined the newly-formed Environment Agency in 1996 on a project for the development of regulations for packaging waste. He was elected Junior Vice President of the Chartered Institution of Wastes Management in 2004, and served as President from 2007 to 2008. Since 2009 he has worked as an independent consultant and journalist.The History of Modern Biomedicine Research Group is funded by the Wellcome Trust, which is a registered charity (no. 210183). The current interview has been funded by the Wellcome Trust Strategic Award entitled “Makers of modern biomedicine: testimonies and legacy” (2012-2017; awarded to Professor Tilli Tansey)
Disulfidisidoksia sisältävien proteiinien laskostumisen uudet säätelymekanismit ja rakenteelliset ominaisuudet
No full textAbstractEfficient maturation of disulfide-containing proteins in the endoplasmic reticulum (ER) requires facilitated folding, aided by various folding catalysts and chaperones. As protein folding is a complex process, proteins may, even in the presence of endogenous folding factors, form misfolded states. Therefore, the cell has acquired several layers of quality control mechanisms to keep the folding load in the ER in balance with the folding capacity. The activity of folding catalysts is regulated to avoid stress connected to hyperoxidation. Other quality control mechanisms include the unfolded protein response (UPR) and ER-associated protein degradation (ERAD). The UPR consists of signaling cascades that sense unfolded protein stress and upregulate folding factors and other components to relieve the stress. ERAD directly removes non-native proteins.The main folding catalysts that introduce disulfide bonds to folding proteins in the ER are members of the ER oxidoreductin 1 (Ero1) family and protein disulfide isomerases (PDI). Ero1 is a sulfhydryl oxidase that reduces molecular oxygen to hydrogen peroxide to form disulfides. The newly generated disulfides are then transferred during the catalytic cycle to PDI which catalyzes disulfide formation in folding proteins. The Ero1-PDI pathway has been studied extensively by cell-based techniques, and its activity is regulated in a redox dependent manner by rearranging regulatory disulfides. However, the kinetic aspects of these regulatory functions have remained poorly characterized.In this study, we report comprehensive kinetic measurements for the Ero1-PDI pathway that reveal novel regulatory mechanisms for oxidative protein folding (OPF). These include a mechanism consisting of high affinity and apparent cooperativity for substrate oxygen to allow Ero1 to function efficiently at hypoxic conditions. We also show that different human Ero1 isoforms have differential dependence for substrate PDI with one of the isoforms, Ero1α, showing strong dependence for PDI for both redox activation as well as the catalytic cycle. This observation allowed us to describe a potential crosstalk between OPF and ERAD, in which OPF by the Ero1α-PDI pathway is downregulated, to potentially increase the efficiency of ERAD which requires reduced protein substrates. This work is concluded by a structural study of a novel chaperone, pERp1, that is crucial for our immunity, as it is involved in the folding of some immunoglobulins.Original papersOriginal papers are not included in the electronic version of the dissertation.Moilanen, A., Korhonen, K., Saaranen, M. J., & Ruddock, L. W. (2018). Molecular analysis of human Ero1 reveals novel regulatory mechanisms for oxidative protein folding. Life Science Alliance, 1(3), e201800090. https://doi.org/10.26508/lsa.201800090Self-archived versionMoilanen, A., & Ruddock, L. W. (2020). Non-native proteins inhibit the ER oxidoreductin 1 (Ero1)–protein disulfide-isomerase relay when protein folding capacity is exceeded. Journal of Biological Chemistry, 295(26), 8647–8655. https://doi.org/10.1074/jbc.ra119.011766Self-archived versionSowa, S. T., Moilanen, A., Biterova, E., Saaranen, M. J., Lehtiö, L., & Ruddock L. W. (2020). High-resolution crystal structure of human pERp1, a saposin-like protein crucial for IgA, IgM and integrin maturation in the endoplasmic reticulum. Manuscript submitted for publication. https://doi.org/10.1016/j.jmb.2021.166826Self-archived versionTiivistelmäDisulfidisidoksia sisältävien proteiinien laskostumista endoplasmakalvostossa avustavat erilaiset laskostumiskatalyytit ja kaperonit. Koska laskostuminen on monimutkaista, voivat proteiinit laskostumistekijöistä huolimatta laskostua väärin. Endoplasmakalvostoon onkin kehittynyt useita laadunvarmistusmekanismeja, jotka pitävät laskostumistaakan ja -kapasiteetin tasapainossa. Laskostumiskatalyyttien aktiivisuutta voidaan säädellä, minkä avulla vältetään ylihapettumiseen liittyvä stressi. Muihin laadunvarmistuskeinoihin kuuluvat UPR (unfolded protein response) ja ERAD (endoplasmic reticulum-associated degradation). UPR tunnistaa laskostumattomien proteiinien aiheuttaman stressin ja saa aikaan mm. laskostumistekijöiden lisätuotantoa stressin vähentämiseksi. ERAD poistaa suoraan laskostumattomia proteiineja hajottamalla niitä.Ero1- ja PDI-proteiiniperheiden jäsenet toimivat pääasiallisina laskostumiskatalyytteinä, jotka muodostavat disulfideja laskostuviin proteiineihin. Ero1 on sulfhydryylioksidaasi, joka pelkistää hapen veryperoksidiksi muodostaessaan disulfidin. Uuden disulfidin Ero1 siirtää sitten PDI:lle, joka puolestaan katalysoi disulfidien muodostuksen laskostuvissa proteiineissa. Ero1-PDI-systeemiä on tutkittu paljon solutasolla, ja sen aktiivisuutta voidaan säädellä järjestelemällä sen omia säätelydisulfideja. Tämän säätelyjärjestelmän entsyymikinetiikka tunnetaan kuitenkin huonosti.Tässä työssä esittelemme Ero1-PDI-systeemin laajat entsyymikinetiikan mittaukset, jotka paljastavat uusia säätelymenetelmiä proteiinien laskostumiseen. Näihin menetelmiin kuuluvat mm. tehokkuus hypoksisissa olosuhteissa ja erilaiset kineettiset ominaisuudet ihmisen Ero1-perheen jäsenten välillä. Tulokset osoittavat, että Ero1α vaatii korkeat pitoisuudet PDI-substraattia sekä aktivoituakseen että disulfidien siirtoon PDI:lle. Näiden tulosten perusteella havaitsimme mahdollisen laskostumisen ja ERAD:n välisen vuorovaikutuksen, jossa laskostumisen tehokkuutta lasketaan ERAD:n toiminnan tehostamiseksi. Lisäksi esittelemme kiderakenteen uudelle kaperonille, pERp1:lle, joka vasta-aineiden laskostumistekijänä on tärkeä immuniteetillemme.OsajulkaisutOsajulkaisut eivät sisälly väitöskirjan elektroniseen versioon.Moilanen, A., Korhonen, K., Saaranen, M. J., & Ruddock, L. W. (2018). Molecular analysis of human Ero1 reveals novel regulatory mechanisms for oxidative protein folding. Life Science Alliance, 1(3), e201800090. https://doi.org/10.26508/lsa.201800090Rinnakkaistallennettu versioMoilanen, A., & Ruddock, L. W. (2020). Non-native proteins inhibit the ER oxidoreductin 1 (Ero1)–protein disulfide-isomerase relay when protein folding capacity is exceeded. Journal of Biological Chemistry, 295(26), 8647–8655. https://doi.org/10.1074/jbc.ra119.011766Rinnakkaistallennettu versioSowa, S. T., Moilanen, A., Biterova, E., Saaranen, M. J., Lehtiö, L., & Ruddock L. W. (2020). High-resolution crystal structure of human pERp1, a saposin-like protein crucial for IgA, IgM and integrin maturation in the endoplasmic reticulum. Manuscript submitted for publication. https://doi.org/10.1016/j.jmb.2021.166826Rinnakkaistallennettu versioAcademic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in the Leena Palotie auditorium (101A) of the Faculty of Medicine (Aapistie 5 A), on 15 February 2021, at 12 noonAbstract
Efficient maturation of disulfide-containing proteins in the endoplasmic reticulum (ER) requires facilitated folding, aided by various folding catalysts and chaperones. As protein folding is a complex process, proteins may, even in the presence of endogenous folding factors, form misfolded states. Therefore, the cell has acquired several layers of quality control mechanisms to keep the folding load in the ER in balance with the folding capacity. The activity of folding catalysts is regulated to avoid stress connected to hyperoxidation. Other quality control mechanisms include the unfolded protein response (UPR) and ER-associated protein degradation (ERAD). The UPR consists of signaling cascades that sense unfolded protein stress and upregulate folding factors and other components to relieve the stress. ERAD directly removes non-native proteins.
The main folding catalysts that introduce disulfide bonds to folding proteins in the ER are members of the ER oxidoreductin 1 (Ero1) family and protein disulfide isomerases (PDI). Ero1 is a sulfhydryl oxidase that reduces molecular oxygen to hydrogen peroxide to form disulfides. The newly generated disulfides are then transferred during the catalytic cycle to PDI which catalyzes disulfide formation in folding proteins. The Ero1-PDI pathway has been studied extensively by cell-based techniques, and its activity is regulated in a redox dependent manner by rearranging regulatory disulfides. However, the kinetic aspects of these regulatory functions have remained poorly characterized.
In this study, we report comprehensive kinetic measurements for the Ero1-PDI pathway that reveal novel regulatory mechanisms for oxidative protein folding (OPF). These include a mechanism consisting of high affinity and apparent cooperativity for substrate oxygen to allow Ero1 to function efficiently at hypoxic conditions. We also show that different human Ero1 isoforms have differential dependence for substrate PDI with one of the isoforms, Ero1α, showing strong dependence for PDI for both redox activation as well as the catalytic cycle. This observation allowed us to describe a potential crosstalk between OPF and ERAD, in which OPF by the Ero1α-PDI pathway is downregulated, to potentially increase the efficiency of ERAD which requires reduced protein substrates. This work is concluded by a structural study of a novel chaperone, pERp1, that is crucial for our immunity, as it is involved in the folding of some immunoglobulins.Tiivistelmä
Disulfidisidoksia sisältävien proteiinien laskostumista endoplasmakalvostossa avustavat erilaiset laskostumiskatalyytit ja kaperonit. Koska laskostuminen on monimutkaista, voivat proteiinit laskostumistekijöistä huolimatta laskostua väärin. Endoplasmakalvostoon onkin kehittynyt useita laadunvarmistusmekanismeja, jotka pitävät laskostumistaakan ja -kapasiteetin tasapainossa. Laskostumiskatalyyttien aktiivisuutta voidaan säädellä, minkä avulla vältetään ylihapettumiseen liittyvä stressi. Muihin laadunvarmistuskeinoihin kuuluvat UPR (unfolded protein response) ja ERAD (endoplasmic reticulum-associated degradation). UPR tunnistaa laskostumattomien proteiinien aiheuttaman stressin ja saa aikaan mm. laskostumistekijöiden lisätuotantoa stressin vähentämiseksi. ERAD poistaa suoraan laskostumattomia proteiineja hajottamalla niitä.
Ero1- ja PDI-proteiiniperheiden jäsenet toimivat pääasiallisina laskostumiskatalyytteinä, jotka muodostavat disulfideja laskostuviin proteiineihin. Ero1 on sulfhydryylioksidaasi, joka pelkistää hapen veryperoksidiksi muodostaessaan disulfidin. Uuden disulfidin Ero1 siirtää sitten PDI:lle, joka puolestaan katalysoi disulfidien muodostuksen laskostuvissa proteiineissa. Ero1-PDI-systeemiä on tutkittu paljon solutasolla, ja sen aktiivisuutta voidaan säädellä järjestelemällä sen omia säätelydisulfideja. Tämän säätelyjärjestelmän entsyymikinetiikka tunnetaan kuitenkin huonosti.
Tässä työssä esittelemme Ero1-PDI-systeemin laajat entsyymikinetiikan mittaukset, jotka paljastavat uusia säätelymenetelmiä proteiinien laskostumiseen. Näihin menetelmiin kuuluvat mm. tehokkuus hypoksisissa olosuhteissa ja erilaiset kineettiset ominaisuudet ihmisen Ero1-perheen jäsenten välillä. Tulokset osoittavat, että Ero1α vaatii korkeat pitoisuudet PDI-substraattia sekä aktivoituakseen että disulfidien siirtoon PDI:lle. Näiden tulosten perusteella havaitsimme mahdollisen laskostumisen ja ERAD:n välisen vuorovaikutuksen, jossa laskostumisen tehokkuutta lasketaan ERAD:n toiminnan tehostamiseksi. Lisäksi esittelemme kiderakenteen uudelle kaperonille, pERp1:lle, joka vasta-aineiden laskostumistekijänä on tärkeä immuniteetillemme
The role of neural networks in early stage cost estimation in the 21st century
No full textThe impact of technology on all areas of science and industry in the latter half of the twentieth century has been enormous, and the building industry has been no exception. However, early stage cost estimation has been little affected by these advances in comparison to most of the rest of the industry, and is still largely based on a combination of simple models and professional judgement. This paper reports how research currently being undertaken at UMIST could change this practice significantly. A neural network model which is able to estimate the total cost of construction to the client is being developed. This model considers forty variables which define the project at this early stage. Some of these variables would not usually be considered within the estimation of the cost. Perhaps most significantly, by including procurement it is able to evaluate the cost of different procurement routes inclusive of the client’s administrative costs. How the neural network improves on existing modelling techniques by its use of existing project data is explained, and its role in early stage cost estimation in the 21st century outlined
The role of neural networks in early stage cost estimation in the 21st century
No full textThe impact of technology on all areas of science and industry in the latter half of the twentieth century has been enormous, and the building industry has been no exception. However, early stage cost estimation has been little affected by these advances in comparison to most of the rest of the industry, and is still largely based on a combination of simple models and professional judgement. This paper reports how research currently being undertaken at UMIST could change this practice significantly. A neural network model which is able to estimate the total cost of construction to the client is being developed. This model considers forty variables which define the project at this early stage. Some of these variables would not usually be considered within the estimation of the cost. Perhaps most significantly, by including procurement it is able to evaluate the cost of different procurement routes inclusive of the client’s administrative costs. How the neural network improves on existing modelling techniques by its use of existing project data is explained, and its role in early stage cost estimation in the 21st century outlined
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Scientific Theories
No full textThe aim ofthis chapter is to look briefly at theories in general, before concentrating on scientific theories - how they are used, structured, tested and verified. The research that usesthe kind of scientific theories we are concentrating on is often referred to as quantitative research but for the sake of completeness, we will also discuss theories in the so-called qualitative research. Theories are an absolutely essential part of our daily life. They help us to make sense of the enormous mass of information and perceptions we are bombarded with every day. Theories help us to recognise, identify and classify things and events, to understand, explain, relate and to make predictions. They give us context and hierarchy. In short, theories combine to make up our understanding of the world. We have theories for all purposes, theories that say that 'if you heat up a metal rod, it will expand' or 'the time required to make a decision is in inverse proportion to the money involved' or 'the earth is flat' or that 'if you sin, God will punish you
Solution structure of Oxidised ERp18
No full textPrimary Citation: Rowe, M.L.; Ruddock, L.W.; Kelly, G.; Schmidt, J.M.; Williamson, R.A.; Howard, M.J. "Solution structure and dynamics of ERp18, a small endoplasmic reticulum resident oxidoreductase." Journal: (2009) Biochemistry 48: 4596-4606. PubMed: 19361226. DOI: 10.1021/bi9003342.
Molecular Description: Classification: Oxidoreductase, Structure Weight: 17801.10 Da, Molecule: Thioredoxin domain-containing protein 12, Polymer: 1, Type: polypeptide(L), Length: 157, Chains: A, EC#: 1.8.4.2, Fragment: UNP residues 24-172. Source: Scientific Name: Homo sapiens, Common Name: Human, Expression System: Escherichia coli
Square Dancing with the Stars to Enhance Dynamic Hirschman Linkages?
No full textIn this Presidential Address, the author takes the reader on a reconnaissance of his life and time as a regional scientist. He points out scenery he found scintillating along the way, hoping that some may pick up the banner and chew on a few of the ideas for a while. He suggests a revisit to Albert O. Hirschman’s notion of key sectors and more empirical analysis related to Marcus Berliant’s and Masahisa Fujita’s notion of knowledge creation and transfer.Presidential Address, San Antonio, Texas, March 29, 2014 (53rd Meetings of the Southern Regional Science Association
Appropriate Similarity Measures for Author Cocitation Analysis
No full textWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Letter from unknown writer to Jesse L. Boyce
No full textLetter to Jesse L. Boyce from unknown author (possibly Jack) about the investigation into the powder magazine located in the Grand Canyon. Some personal news is included in the letter such as the writer's marriage to the daughter of C.A. Taylor, former Supervisor of Cochise County
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