The human Ia-associated invariant chain is synthesized in Ia-negative B cell variants and is not expressed on the cell surface of both Ia-negative and Ia-positive parental cells.

The expression of Ia-associated human Invariant (In) chain glycoproteins was studied in the Raji B cells as well as in their RJ 2.2.5 Ia-negative derived variant cells by using a specific rabbit anti-human In chain antiserum. Two-dimensional gel electrophoresis of immunoprecipitates from either biosynthetically labeled or surface labeled cells were analyzed. In addition, flow microfluorometric analysis of stained cells was performed. The results indicate that the In chain is constitutively produced in the Ia-negative B cell variant. Moreover, it appears that several forms of In chain-related molecules, with different charges and distinct m.w. are equally expressed in Ia-positive and Ia-negative B cells. Finally, no evidence could be obtained that the In molecular family was expressed on the cell surface of Ia-positive Raji and Ia-negative RJ 2.2.5 cells.

Efficiency of recombinant human TNF in human cancer therapy.

Recombinant human tumour necrosis factor (TNF) has a selective effect on angiogenic vessels in tumours. Given that it induces vasoplegia, its clinical use has been limited to administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs. When combined with the alkylating agent melphalan, a single ILP produces a very high objective response rate. In melanoma, the complete response (CR) rate is around 80% and the overall objective response rate greater than 90%. In soft tissue sarcomas that are inextirpable, ILP is a neoadjuvant treatment resulting in limb salvage in 80% of the cases. The CR rate averages 20% and the objective response rate is around 80%. The mode of action of TNF-based ILP involves two distinct and successive effects on the tumour-associated vasculature: first, an increase in endothelium permeability leading to improved chemotherapy penetration within the tumour tissue, and second, a selective killing of angiogenic endothelial cells resulting in tumour vessel destruction. The mechanism whereby these events occur involves rapid (of the order of minutes) perturbation of cell-cell adhesive junctions and inhibition of alphavbeta3 integrin signalling in tumour-associated vessels, followed by massive death of endothelial cells and tumour vascular collapse 24 hours later. New, promising approaches for the systemic use of TNF in cancer therapy include TNF targeting by means of single chain antibodies or endothelial cell ligands, or combined administration with drugs perturbing integrin-dependent signalling and sensitizing angiogenic endothelial cells to TNF-induced death.

Bistability of mitochondrial respiration underlies paradoxical reactive oxygen species generation induced by anoxia

Increased production of reactive oxygen species (ROS) in mitochondria underlies major systemic diseases, and this clinical problem stimulates a great scientific interest in the mechanism of ROS generation. However, the mechanism of hypoxia-induced change in ROS production is not fully understood. To mathematically analyze this mechanism in details, taking into consideration all the possible redox states formed in the process of electron transport, even for respiratory complex III, a system of hundreds of differential equations must be constructed. Aimed to facilitate such tasks, we developed a new methodology of modeling, which resides in the automated construction of large sets of differential equations. The detailed modeling of electron transport in mitochondria allowed for the identification of two steady state modes of operation (bistability) of respiratory complex III at the same microenvironmental conditions. Various perturbations could induce the transition of respiratory chain from one steady state to another. While normally complex III is in a low ROS producing mode, temporal anoxia could switch it to a high ROS producing state, which persists after the return to normal oxygen supply. This prediction, which we qualitatively validated experimentally, explains the mechanism of anoxia-induced cell damage. Recognition of bistability of complex III operation may enable novel therapeutic strategies for oxidative stress and our method of modeling could be widely used in systems biology studies.

Towards a global criteria based framework for the sustainability assessment of bioethanol supply chains: application to the Swiss dilemma : is local produced bioethanol more sustainable than bioethanol imported from Brazil?

Biofuels are considered as a promising substitute for fossil fuels when considering the possible reduction of greenhouse gases emissions. However limiting their impacts on potential benefits for reducing climate change is shortsighted. Global sustainability assessments are necessary to determine the sustainability of supply chains. We propose a new global criterion based framework enabling a comprehensive international comparison of bioethanol supply chains. The interest of this framework is that the selection of the sustainability indicators is qualified on three criterions: relevance, reliability and adaptability to the local context. Sustainability issues have been handled along environmental, social and economical issues. This new framework has been applied for a specific issue: from a Swiss perspective, is locally produced bioethanol in Switzerland more sustainable than imported from Brazil? Thanks to this framework integrating local context in its indicator definition, Brazilian production of bioethanol is shown as energy efficient and economically interesting for Brazil. From a strictly economic point of view, bioethanol production within Switzerland is not justified for Swiss consumption and questionable for the environmental issue. The social dimension is delicate to assess due to the lack of reliable data and is strongly linked to the agricultural policy in both countries. There is a need of establishing minimum sustainability criteria for imported bioethanol to avoid unwanted negative or leakage effects.

Immunogenicity and safety of an intradermal boosting strategy for vaccination against influenza in lung transplant recipients.

The immunogenicity of influenza vaccine is suboptimal in lung transplant recipients. Use of a booster dose and vaccine delivery by the intradermal rather than intramuscular route may improve response. We prospectively evaluated the immunogenicity and safety of a 2-dose boosting strategy of influenza vaccine. Sixty lung transplant recipients received a standard intramuscular injection of the 2006-2007 inactivated influenza vaccine, followed 4 weeks later by an intradermal booster of the same vaccine. Immunogenicity was assessed by measurement of geometric mean titer of antibodies after both the intramuscular injection and the intradermal booster. Vaccine response was defined as 4-fold or higher increase of antibody titers to at least one vaccine antigen. Thirty-eight out of 60 patients (63%) had a response after intramuscular vaccination. Geometric mean titers increased for all three vaccine antigens following the first dose (p < 0.001). However, no significant increases in titer were observed after the booster dose for all three antigens. Among nonresponders, 3/22 (13.6%) additional patients responded after the intradermal booster (p = 0.14). The use of basiliximab was associated with a positive response (p = 0.024). After a single standard dose of influenza vaccine, a booster dose given by intradermal injection did not significantly improve vaccine immunogenicity in lung transplant recipients.

Long-Life Concrete: How Long Will My Concrete Last? A Synthesis of Knowledge of Potential Durability of Concrete, TPF-5(159), 2013

There is an ongoing discussion about moving toward performance-based specifications for concrete pavements. This document seeks to move the discussion forward by outlining the needs and the challenges, and proposing some immediate actions. However, this approach may increase risk for all parties until performance requirements are agreed upon and, more importantly, how the requirements can be measured. A fundamental issue behind pavement construction activities is that the owner/designer needs to be assured that the concrete in place will survive for the intended period (assuming there are no changes in the environment or loading) and, therefore, that full payment should be made. At the same time, each party along the supply chain needs to be assured that the material being supplied to them is able to meet the required performance, as is the product/system they are delivering. The focus of this document is a discussion of the issues behind this need, and the technologies that are available, or still needed, to meet this need, particularly from the point of view of potential durability

Aplicación de la metodología “policy deployment” planificación estratégica a un departamento de suministro de materiales para aerogeneradores para reducir inventarios

Debido a la necesidad de diferenciarse y hacer frente a la competencia, las empresas han apostado por desarrollar operaciones que den valor al cliente, por eso muchas de ellas han visto en las herramientas lean la oportunidad para mejorar sus operaciones. Esta mejora implica la reducción de dinero, personas, equipos grandes, inventario y espacio, con dos objetivos: eliminar despilfarro y reducir la variabilidad. Para conseguir los objetivos estratégicos de la empresa es imprescindible qué éstos estén alineados con los planes de la gerencia a nivel medio y a su vez con el trabajo realizado por los empleados para asegurar que cada persona está alineada en la misma dirección y al mismo tiempo. Ésta es la filosofía de la planificación estratégica. Por ello uno de los objetivos de este proyecto será el desarrollar una herramienta que facilite la exposición de los objetivos de la empresa y la comunicación de los mismos a todos los niveles de la organización para a partir de ellos y tomando como referencia la necesidad de reducir inventarios en la cadena de suministro se realizará un estudio de la producción de un componente de control del aerogenerador para conseguir nivelarla y reducir su inventario de producto terminado. Los objetivos particulares en este apartado serán reducir el inventario en un 28%, nivelar la producción reduciendo la variabilidad del 31% al 24%, mantener un stock máximo de 24 unidades garantizando el suministro ante una demanda variable, incrementar la rotación del inventario en un 10% y establecer un plan de acción para reducir el lead time entre un 40-50%. Todo ello será posible gracias a la realización del mapa de valor presente y futuro para eliminar desperdicios y crear un flujo continuo y el cálculo de un supermercado que mantenga el stock en un nivel óptimo.

Evaluación y optimización de los servicios de un taller de mantenimiento mediante el software de simulación ARENA

Debido a la necesidad de diferenciarse y hacer frente a la competencia, las empresas han apostado por desarrollar operaciones que den valor al cliente, por eso muchas de ellas han visto en las herramientas lean la oportunidad para mejorar sus operaciones. Esta mejora implica la reducción de dinero, personas, equipos grandes, inventario y espacio, con dos objetivos: eliminar despilfarro y reducir la variabilidad. Para conseguir los objetivos estratégicos de la empresa es imprescindible qué éstos estén alineados con los planes de la gerencia a nivel medio y a su vez con el trabajo realizado por los empleados para asegurar que cada persona está alineada en la misma dirección y al mismo tiempo. Ésta es la filosofía de la planificación estratégica. Por ello uno de los objetivos de este proyecto será el desarrollar una herramienta que facilite la exposición de los objetivos de la empresa y la comunicación de los mismos a todos los niveles de la organización para a partir de ellos y tomando como referencia la necesidad de reducir inventarios en la cadena de suministro se realizará un estudio de la producción de un componente de control del aerogenerador para conseguir nivelarla y reducir su inventario de producto terminado. Los objetivos particulares en este apartado serán reducir el inventario en un 28%, nivelar la producción reduciendo la variabilidad del 31% al 24%, mantener un stock máximo de 24 unidades garantizando el suministro ante una demanda variable, incrementar la rotación del inventario en un 10% y establecer un plan de acción para reducir el lead time entre un 40-50%. Todo ello será posible gracias a la realización del mapa de valor presente y futuro para eliminar desperdicios y crear un flujo continuo y el cálculo de un supermercado que mantenga el stock en un nivel óptimo.

Vendor Managed Inventory: the Critical Success Factors from the Manufacturer Point of View

Yritykset ovat pakotettuja erilaisiin yhteistyömuotoihin pärjätäkseen kiristyvässä kilpailussa. Yhteistyösuhteet kulkevat eri nimillä riippuen teollisuuden alasta ja siitä, missä kohtaa toimitusketjua ne toteutuvat, mutta periaatteessa kaikki pohjautuvat samaan ideaan kuin Vendor Managed Inventory (VMI); varastoon jakysyntään liittyvä tieto jaetaan toimitusketjun eri osapuolien kesken, jotta tuotanto, jakelu ja varastonhallinta olisi mahdollista optimoida. Vendor Managed Inventory on ideana yksinkertainen, mutta vaatii onnistuakseen paljon. Perusolettamus on, että toimittajan on kyettävä hallinnoimaan asiakkaan varastoa paremmin kuin asiakas itse. Tämä ei kuitenkaan ole mahdollista ilman riittävää yhteistyötä, oikeanlaista informaatiota tai sopivia tuoteominaisuuksia. Tämän työn tarkoitus on esitellä kriittiset menestystekijät valmistajan kannalta, kun näkyvyys todelliseen kysyntään on heikko ja kyseessäolevat tuotteet ovat ominaisuuksiltaan toimintamalliin huonosti soveltuvia. VMItoimintamallin soveltuvuus matkapuhelimia valmistavan yrityksen liiketoimintaan, sekä sen vaikutus asiakasyhteistyöhön, kannattavuuteen ja toiminnan tehostamiseen on myös tutkittu.

The Role of Third-Party Service Provider in B2B Integration

Sähköisen kaupankäynnin kasvun myötä, itsenäisten yritysten tietojärjestelmien integraation tarve on moninkertaistunut viime vuosien aikana. Yritykset ovat huomanneet, että tilaus-toimitusketjun automatisointiin tähtäävällä kokonaisvaltaisella integraatio-ratkaisulla on mahdollista päästä kattaviin kustannussäästöihin sekä tulojen kasvuun. Pääsääntöisesti yritykset kuitenkin etenevät hitaammin, integroimalla aluksi pienempiä liiketoiminnan tietojärjestelmien toimintoja. Positiivisten kokemusten perusteella yritykset ovat valmiitalaajentamaan sähköisen kaupankäynnin automatisointia myös muissa toiminnoissa. Tässä työssä keskitytään tarkastelemaan eri lähestymistapojayritystenvälisen integraation toteuttamiseen, sekä analysoimaan eri keinojen liiketoiminnallisia ja teknisiä vaikutuksia. Työ on tehty yhteistyössä UPM-KymmeneWood Oy:n kanssa, jonka tavoitteena oli saada perusteelliset tiedot yrityksenvälisestä integraatiosta ja syventää tietoja sekä integraatio-palveluita tarjoavien kolmansien osapuolten toimintatavoista että heidän tarjoamista palveluista ja niiden käyttökelpoisuudesta puutuoteteollisuudessa toimivassa yrityksessä. Käytännön osuudessa on tarkemmin esitelty integraatio-palveluita tarjoavien operaattoreiden kanssa käytyjen palaverien sekä heidän toimittamien materiaalien perusteella tehdyn tutkimustyön tuloksia, sisältäen yksityiskohtaiset kuvaukset yritystenvälisen integraation mahdollistavista palveluista.

Performance measurement oforder-delivery chain in SMEs: Case study

Tutkimus pyrkii selvittämään, kuinka tehokas suorituskykymittaristo voidaan parhaiten suunnitella pk-yrityksessä. Tutkimuksen tavoitteena on luoda suorituskykymittaristo pienen kohdeyrityksen johtajien tarpeisiin. Päähuomion kohteena on yrityksen tilaus-toimitusketju ja arvoverkko. Työ on luonteeltaan kvalitatiivinen toimintatutkimus, joka noudattaa toiminta-analyyttista tutkimusotetta. Työn teoriaosassa selvitetään, kuinka suorituskyvyn mittaaminen sekä materiaali-, tieto- ja rahavirtojen hallinta on kehittynyt viime vuosina pk-yrityksen näkökulmasta. Mittariston suunnittelu aloitetaan kohdeyrityksen perusteellisella analyysilla. Tämän pohjalta määritellään yrityksen kriittiset menestystekijät, joista lopulta johdetaan suorituskykymittarit. Tutkimuksen perusteella voidaan todeta, että yleinen asenne mittaamista kohtaan, strategian huomioinnin puute sekä tietojärjestelmien rajoitteet ovat päähaasteita pk-yrityksen suorituskyvyn mittaamisessa. Mittareiden tuleekin olla melko yksinkertaisia ja helppoja käyttää, jotta mittaamisen ei koettaisi kuluttavan rajallisia resursseja liikaa. Mittariston tulee kuitenkin antaa kokonaisvaltainen kuva yrityksen suorituskyvystä, johon vaikuttavat kaikki arvoverkon osapuolet ja heidän yhteistyö toistensa kanssa.

PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells.

Insulin secretion from pancreatic beta cells is stimulated by glucose metabolism. However, the relative importance of metabolizing glucose via mitochondrial oxidative phosphorylation versus glycolysis for insulin secretion remains unclear. von Hippel-Lindau (VHL) tumor suppressor protein, pVHL, negatively regulates hypoxia-inducible factor HIF1alpha, a transcription factor implicated in promoting a glycolytic form of metabolism. Here we report a central role for the pVHL-HIF1alpha pathway in the control of beta-cell glucose utilization, insulin secretion, and glucose homeostasis. Conditional inactivation of Vhlh in beta cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhlh-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminate in impaired systemic glucose tolerance. Importantly, combined deletion of Vhlh and Hif1alpha rescued these phenotypes, implying that they are the result of HIF1alpha activation. Together, these results identify pVHL and HIF1alpha as key regulators of insulin secretion from pancreatic beta cells. They further suggest that changes in the metabolic strategy of glucose metabolism in beta cells have profound effects on whole-body glucose homeostasis.

Onnistuneen uuden tuotteen kehittäminen ja hallinta - Tapaustutkimus: Tekstiilialan yritys

Tuotesuunnittelu on yrityksen selviämisen kannalta erittäin tärkeä toiminto. Menestynyt tuotesuunnittelu vaatii selkeän tuotestrategian, laadukkaasti suoritetun tuotesuunnitteluprosessin ja tarvittavienresurssien yhdistämistä sekä uuden tuotteen tuottojen hallintaa myynnin seurannalla. Kohdeyrityksessä uusien tuotteiden suunnittelun ja hallinnan tärkeys on huomattu ja niiden kehittämiseksi yritys on lisäämässä panostustaan. Tämä tutkimuspyrkii tuomaan kohdeyrityksen tietoon tuotesuunnitteluun ja uuden tuotteen hallintaan vaikuttavat menestystekijät sekä tuomaan esille näitä toimintoja tukevia kehittämismahdollisuuksia. Tutkimus on normatiivinen tapaustutkimus, jossa teoria on koottu tieteellisistä, lähinnä empiirisistä tutkimuksista koostuvista artikkeleista. Yrityksen tuotesuunnitteluun liittyvät prosessit ja toiminnot on selvitetty puolistrukturoiduilla haastatteluilla sekä havainnoimalla. Tutkimuksessa havaittiin selkeitä eroja uuden tuotteen hallinnan menestystekijöiden ja yrityksen toimintojen välillä. Tuotesuunnitteluprosessin uudelleen organisointi, toimitusketjun hallinta ja tuotekohtainen kustannuslaskenta ovat asioita, joita kehittämällä yritys voi mahdollisesti parantaa uusien tuotteiden elinkaaren aikaista hallintaa ja taloudellista onnistumista sekä lisätä yrityksen kannattavuutta.

Exploration of the social dimension of corporate responsibility in a welfare state

This study focuses on corporate social responsibility (or CSR)as the latest dimension to emerge in the corporate responsibility and sustainability agenda, which in the recent past has rapidly risen to the top of the list of concerns for civil societies worldwide. Despite the continuing debates and discussions about the scope, benefits, and impacts of CSR to business and community in various sectors, levels, and types of society, many companies have moved forward to confront the opportunities and challenges of CSR. Thus, this study is about those proactive companies with a focus on the importance of CSR and its management inside and outside the company. It is an exploration and learning from the experience of Finnish companies, as well as other actors interested or involved in shaping the course of CSR, locally and globally. It also looks closely at how national culture affects the views, thinking, and management of CSR in a welfare state. This dissertation primarily draws on the analyses of information collected from a series of qualitative interviews and the existing literature in the area. This is complemented by an analysis of written and published documents on CSR from various sources. The results of the study give insightful information and detailed descriptions of a roadmap useful in learning and understanding CSR in Finnish companies. Despite the varying conceptual connotations, essential roadmap indicators point to the importance of framing CSR within the corporate responsibility concept, Finnish development and the welfare state system, globalization, stakeholders, and the pursuit of sustainable development as the main drivers of CSR, the remarkable progress of CSR in companies, and identification of key management areas and practices relevant to CSR. Similarly,the study reveals the importance of culture as essential in understanding and learning CSR. Finnish culture has a positive influence on the views, thinking, and management practices of CSR issues. Such a positive influence of culture, therefore, makes it easy for business people to discuss and understand CSR, because those CSR issues are already considered common and taken-for-granted by Finns and are implicit in the welfare state provisions. The experience of Finnish companies in implementing CSR policies in the supply chain is a concrete proactive step in advancing the message of CSR, that is, to bring companies and suppliers together to work on improving and strengthening relationships towards socially responsible practices worldwide. Such a forward step to deal with CSR issues in the supply chain reflects the companies' commitments and belief that CSR can be managed with the suppliers and gain positive benefits. Despite the problems and complexities, particularly in the global supply chain, managing CSR for Finnish companies presents new opportunities and challenges that are expected to intensify in the near future. The focus on CSR policy implementation inthe supply chain points to the importance of companies taking initiatives and forging cooperation with suppliers with the aim of addressing and improving CSR questions in the supply chains. The proactive stance of Finnish companies toward CSR is complemented by the active supporting role of important societalactors such as the government and NGOs. These actors carry out various promotional efforts and campaigns, thus bringing CSR into the mainstream of Finnish companies and strengthening the synergistic learning about CSR within the Finnish business and civil circles. The efforts of the government and NGOs to promote CSR are indicative of the importance of multipartite involvement and the emergence of better civil regulations. Likewise, their drive to learn from each other, exchange experiences, and contribute in CSR debates facilitated the evolution of CSRnetworks in the country. The results of this study add to the mounting evidence that CSR, in general, has created a new dimension in managing corporate sustainability. This study provides compelling empirical evidence and some direct quotations about CSR in the Finnish context. This information can be used to learn and gain new useful insights, approaches, and concepts for managing CSR.