Differences in collagen prolyl 4-hydroxylase assembly between two Caenorhabditis nematode species despite high amino acid sequence identity of the enzyme subunits

The collagen prolyl 4-hydroxylases (P4Hs) are essential for proper extracellular matrix formation in multicellular organisms. The vertebrate enzymes are α2β2 tetramers, in which the β subunits are identical to protein disulfide isomerase (PDI). Unique P4H forms have been shown to assemble from the <i>Caenorhabditis</i> <i>elegans</i> catalytic α subunit isoforms PHY-1 and PHY-2 and the β subunit PDI-2. A mixed PHY-1/PHY-2/(PDI-2)<sub>2</sub> tetramer is the major form, while PHY-1/PDI- 2 and PHY-2/PDI-2 dimers are also assembled but less efficiently. Cloning and characterization of the orthologous subunits from the closely related nematode <i>Caenorhabditis</i> <i>briggsae</i> revealed distinct differences in the assembly of active P4H forms in spite of the extremely high amino acid sequence identity (92-97%) between the <i>C. briggsae</i> and <i>C. elegans</i> subunits. In addition to a PHY-1/PHY-2(PDI-2)<sub>2</sub> tetramer and a PHY-1/PDI-2 dimer, an active (PHY- 2)<sub>2</sub>(PDI-2)<sub>2</sub> tetramer was formed in <i>C. briggsae</i> instead of a PHY-2/PDI-2 dimer. Site-directed mutagenesis studies and generation of inter-species hybrid polypeptides showed that the N-terminal halves of the <i>Caenorhabditis</i> PHY-2 polypeptides determine their assembly properties. Genetic disruption of <i>C. briggsae phy-1</i> (<i>Cb-dpy-18</i>) via a <i>Mos1</i> insertion resulted a small (short) phenotype that is less severe than the dumpy (short and fat) phenotype of the corresponding <i>C. elegans</i> mutants (<i>Ce-dpy-18</i>). <i>C. briggsae</i> <i>phy-2</i> RNA interference produced no visible phenotype in the wild type nematodes but produced a severe dumpy phenotype and larval arrest in <i>phy-1</i> mutants. Genetic complementation of the <i>C. briggsae</i> and <i>C. elegans</i> <i>phy-1</i> mutants was achieved by injection of a wild type <i>phy-1</i> gene from either species

Adiponectin Upregulates Prolyl-4-Hydroxylase α1 Expression in Interleukin 6-Stimulated Human Aortic Smooth Muscle Cells by Regulating ERK 1/2 and Sp1

Adiponectin is an anti-atherogenic adipokine that inhibits the development of plaque by mechanisms that are not completely understood. Extracellular matrix (ECM) may have a role in the pathogenesis of atherosclerosis. We explored the effect and mechanisms of adiponectin on the synthesis of prolyl-4-hydroxylase (P4H) in interleukin 6 (IL-6)-stimulated human aortic smooth muscle cells (HASMCs). P4Hα1 mRNA level was quantified by RT-PCR, the protein levels of phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and P4Hα1 were quantified by western blot analysis, and activation of specific protein 1 (Sp1) was determined by electrophoretic mobility shift assay and subcellular localization of Sp1 by immunofluorescence analysis. Adiponectin significantly increased P4Hα1 mRNA and protein levels in IL-6-stimulated HASMCs in a dose- and time-dependent manner. As well, ERK1/2 and Sp1 played a crucial role in the effect of adiponectin upregulating P4Hα1 expression in IL-6-stimulated HASMCs. Adiponectin abrogated the effects of IL-6 on collagen III level, which may indicate that P4Hα1 is essential for folding the procollagen polypeptide chains into stabilized collagen. Adiponectin attenuates IL-6–inhibited P4Hα1 synthesis and stabilizes collagen formation in HASMCs through a Sp1-ERK1/2-P4Hα1-dependent pathway

Association between promoter -1607 polymorphism of MMP1 and Lumbar Disc Disease in Southern Chinese

<p>Abstract</p> <p>Background</p> <p>Matrix metalloproteinases (MMPs) are involved in the degradation of the extracellular matrix of the intervertebral disc. A SNP for guanine insertion/deletion (G/D), the -1607 promoter polymorphism, of the <it>MMP1 </it>gene was found significantly affecting promoter activity and corresponding transcription level. Hence it is a good candidate for genetic studies in DDD.</p> <p>Methods</p> <p>Southern Chinese volunteers between 18 and 55 years were recruited from the population. DDD in the lumbar spine was defined by MRI using Schneiderman's classification. Genomic DNA was isolated from the leukocytes and genotyping was performed using the Sequenom^®platform. Association and Hardy-Weinberg equilibrium checking were assessed by Chi-square test and Mann-Whitney U test.</p> <p>Results</p> <p>Our results showed substantial evidence of association between -1607 promoter polymorphism of <it>MMP1 </it>and DDD in the Southern Chinese subjects. D allelic was significantly associated with DDD (p value = 0.027, odds ratio = 1.41 with 95% CI = 1.04–1.90) while Genotypic association on the presence of D allele was also significantly associated with DDD (p value = 0.046, odds ratio = 1.50 with 95% CI = 1.01–2.24). Further age stratification showed significant genotypic as well as allelic association in the group of over 40 years (genotypic: p value = 0.035, odds ratio = 1.617 with 95% CI = 1.033–2.529; allelic: p value = 0.033, odds ratio = 1.445 with 95% CI = 1.029–2.029). Disc bulge, annular tears and the Schmorl's nodes were not associated with the D allele.</p> <p>Conclusion</p> <p>We demonstrated that individuals with the presence of D allele for the -1607 promoter polymorphism of <it>MMP1 </it>are about 1.5 times more susceptible to develop DDD when compared with those having G allele only. Further association was identified in individuals over 40 years of age. Disc bulge, annular tear as well as Schmorl's nodes were not associated with this polymorphism.</p

Genetic susceptibility of intervertebral disc degeneration among young Finnish adults

<p>Abstract</p> <p>Background</p> <p>Disc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD.</p> <p>Methods</p> <p>We investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging.</p> <p>Results</p> <p>Of the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of <it>IL6 </it>SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of <it>IL6 </it>was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, <it>SKT </it>rs16924573 (OR 0.27 95% CI 0.07-0.96) and <it>CILP </it>rs2073711 in women (OR 2.04, 95% CI 1.07-3.89).</p> <p>Conclusion</p> <p>Our results indicate that <it>IL6</it>, <it>SKT </it>and <it>CILP </it>are involved in the etiology of DD among young adults.</p

Industrialization in construction:a process model for capability creation

Abstract Productivity improvement in the construction industry has been modest for decades. Problems with the schedules and costs of construction projects are well documented, as are the quality problems affecting buildings. There are several reasons behind this situation, but one of the main challenges has its roots in the fragmentation of the industry, which causes several problems between different construction stakeholders—but especially between different construction projects and project phases. Furthermore, the absence of product-based thinking and process management practices causes challenges in continuous improvement between projects. The objective of this dissertation is to boost productivity improvement by proposing an industrial operation model (IOM) for the construction industry. This dissertation presents capability creation practices—which have not been studied previously in the context of the construction industry—as a component of the IOM. This research uses qualitative interviews to study elements of the proposed IOM and capability creation practices for sales, production, and maintenance processes to create a basis for capability creation in these three operative business processes. The results of this dissertation include preconditions and steps for construction companies to implement the IOM. As part of the IOM, the capability creation processes, roles, and practices are described for sales, production, and maintenance. Capability creation practices take the requirements of the later phases of construction projects into account during the early design phase while simultaneously improving the design itself, enhancing the preplanning of sales, production, and maintenance, and preventing many known problems across the building lifecycle. In addition, capability creation practices enable the creation of more innovative solutions for the end customer.Tiivistelmä Rakennusteollisuuden tuottavuuskehitys on ollut vaatimatonta jo 1970-luvulta lähtien. Ongelmat rakennushankkeiden aikatauluissa ja kustannuksissa ovat varsin tuttuja, heikentäen samalla myös asiakkaalle myytävien tuotteiden eli rakennusten laatua. Syitä ongelmiin on monia, mutta yksi keskeisimmistä on alan pirstaloituminen, mikä aiheuttaa ongelmia sekä alan eri toimijoiden, että etenkin rakennushankkeen eri vaiheiden välillä. Samoin teollisen tuote- ja prosessiajattelun puuttuessa jatkuva parantaminen ja toiminnan tehostaminen eri projektien välillä jää vaillinaiseksi. Tämän väitöstutkimuksen tarkoitus on edistää rakennusalan tuottavuuskehitystä kuvaamalla teollinen toimintamalli alan yritysten toiminnan tehostamiseksi. Väitöstutkimuksessa esitellään eri liiketoimintaprosessien kyvykkyyksien luomisen menetelmät, joita ei ole aiemmin tutkittu rakennusteollisuudessa. Tutkimuksessa on käytetty laadullisia haastatteluja, joilla on tutkittu teollisen toimintamallin osatekijöitä sekä kyvykkyyksien luomisen mallia myynnin, rakentamisen ja ylläpidon liiketoimintaprosessien näkökulmista, kehittäen samalla tutkittavien yritysten avulla kyvykkyyksien luomisen perusteet kaikille kolmelle liiketoimintaprosessille. Väitöstutkimuksen tuloksena esitetään esivaatimukset ja menetelmät teollisen toimintamallin käyttöönotolle. Lisäksi kuvataan prosessit, roolit ja toimintatavat, joilla rakennusteollisuus voi huomioida myynnin, rakentamisen ja ylläpitovaiheen vaatimukset jo suunnitteluvaiheessa. Samalla suunnittelusta tulee tehokkaampaa, parannetaan myynnin, rakentamisen ja ylläpidon tehokkuutta sekä luodaan myös innovatiivisempia ratkaisuja asiakkaalle. Ja mikä tärkeintä, vältetään lukuisia ongelmia koko rakennushankkeen ja rakennuksen elinkaaren ajan

Industrial operation model for the construction industry

Abstract For decades, the construction industry has been searching for avenues to improve productivity. One potential direction for improvement is industrialisation, which involves repetitive and modular products and standardised processes to achieve economies of scale. This article describes an industrial operation model (IOM) based on the literature and uses empirical studies to find the emerging elements of the IOM in the construction industry. We employed qualitative and inductive approaches to build the general IOM framework. We determined the main challenges for the IOM through semi-structured interviews with 11 companies. The current state of the analysed IOM elements was perceived as inconstant and generally weak. In any case, we were able to describe several challenges in the main areas of the IOM. In this study, six preconditions for the IOM were defined as critical: defined target markets and products, effective product portfolio management, product and process data availability, efficient operative business processes, systematic continuous improvement, and governance and owners of the main IOM elements. The IOM framework and the proposed preconditions can be used as bases for future productivity development in the construction industry

Production capability creation (PCC) for collaborative construction projects:a qualitative study from Finland

Abstract The construction industry has been suffering from modest productivity development in recent decades. To address the recognized problems, collaborative delivery methods are replacing traditional project delivery models, especially in large and complex projects. The aim of this research is to describe the production capability creation (PCC) process as a solution for planning the production phase. The PCC process should be implemented parallel to the design phase and owned by the production. A qualitative and inductive approach, based primarily on case company interviews, is applied to identify the twelve most important challenges for preplanning in the design phase from a group of different types of stakeholders in construction projects. Based on these challenges, the main areas of PCC are structured, solving the depicted production challenges, enabling a wasteless and cost-efficient production phase to avoid unnecessary delays and problems. Parallel implementation of PCC and design processes of the building naturally also improve the result of the design itself. With PCC, contractors can recognize the need for improvement in their processes but, more importantly, can directly contribute to the design of the building. Described PCC process solves major challenges emerging from the case company interviews. Earlier literature on capability creation is scarce, and for the construction industry it is even more narrow. The PCC process presented in this research enables significant improvement in efficiency and effectiveness, and the elimination of waste in the construction industry

Maintenance capability creation for buildings:concurrent process with design and construction

Abstract Purpose: This study describes how maintenance capability should be created during the design and construction phases of construction projects. Purpose of the abstract to define the elements for creating the maintenance capability and the process to be used in construction life cycle projects for buildings. Design/Methodology/Approach: An inductive and qualitative research method was used to construct the proposed process based on the literature and 18 interviews in two large construction companies. Findings: The results indicate that the maintenance phase is usually overlooked during the design and construction phases, and capabilities are not systematically built. In particular, processes are lacking in data management, causing severe problems in maintenance. Originality/value: This study presents a process including key requirements and activities for creating maintenance capability in conjunction with the design and construction phases, which is novel to the literature. The validated process can be adapted based on the needs of the construction company