979 resultados para Let me in


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The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.

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Values and value processes are said to be needed in every organization nowadays, as the world is changing and companies have to have something to "keep it together". Organizational values, which are approvedand used by the personnel, could be the key. Every organization has values. But what is the real value of values? The greatest and most crucial challenge is the feasibility of the value process. The main point in this thesis is tostudy how organizational members at different hierarchical levels perceive values and value processes in their organizations. This includes themes such as how values are disseminated, the targets of value processing, factors that affect the process, problems that occur during the value implementation and improvements that could be made when organizational values are implemented. These subjects are studied from the perspective of organizational members (both managers and employees); individuals in the organizations. The aim is to get the insider-perspective on value processing, from multiple hierarchical levels. In this research I study three different organizations (forest industry, bank and retail cooperative) and their value processes. The data is gathered from companies interviewing personnel in the head office and at the local level. The individuals areseen as members of organizations, and the cultural aspect is topical throughout the whole study. Values and cultures are seen as the 'actuality of reality' of organizations, interpreted by organizational members. The three case companies were chosen because they represented different lines of business and they all implemented value processing differently. Sincethe emphasis in this study is at the local level, the similar size of the local units was also an important factor. Values are in 'fashion' -but what does the fashion tell us about the real corporate practices? In annual reports companies emphasize the importance and power of official values. But what is the real 'point' of values? Values are publicly respected and advertised, but still it seems that the words do not meet the deeds. There is a clear conflict between theoretical, official and substantive organizational values: in the value processing from words to real action. This contradiction in value processing is studied through individual perceptions in this study. I study the kinds of perceptions organizationalmembers have when values are processed from the head office to the local level: the official value process is studied from the individual's perspective. Value management has been studied more during the 1990's. The emphasis has usually been on managers: how they consider the values in organizations and what effects it has on the management. Recent literature has emphasized values as tools for improving company performance. The value implementation as a process has been studied through 'good' and 'bad' examples, as if one successful value process could be copied to all organizations. Each company is different with different cultures and personnel, so no all-powerful way of processing values exists. In this study, the organizational members' perceptions at different hierarchical levels are emphasized. Still, managers are also interviewed; this is done since managerial roles in value dissemination are crucial. Organizational values cannot be well disseminated without management; this has been proved in several earlier studies (e.g. Kunda 1992, Martin 1992, Parker 2000). Recent literature has not sufficiently emphasized the individual's (organizational member's) role in value processing. Organizations consist of differentindividuals with personal values, at all hierarchical levels. The aim in this study is to let the individual take the floor. Very often the value process is described starting from the value definition and ending at dissemination, and the real results are left without attention. I wish to contribute to this area. Values are published officially in annual reports etc. as a 'goal' just like profits. Still, the results/implementationof value processing is rarely followed, at least in official reports. This is a very interesting point: why do companies espouse values, if there is no real control or feedback after the processing? In this study, the personnel in three different companies is asked to give an answer. In the empirical findings, there are several results which bring new aspects to the research area of organizational values. The targets of value processing, factors effecting value processing, the management's roles and the problems in value implementation are presented through the individual's perspective. The individual's perceptions in value processing are a recurring theme throughout the whole study. A comparison between the three companies with diverse value processes makes the research complete

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Les tumeurs de la famille du sarcome d'Ewing (ESFTs) sont les deuxièmes plus fréquentes formes de cancer de l'os chez l'enfant et l'adolescent. Le gène de fusion EWS-FLI1 est associé à 85-90% des ESFTs. Ce cancer a probablement pour origine des cellules souches mésenchymateuses (MSCs). Il a en effet été démontré que les MSCs pédiatriques (hpMSCs) sont particulièrement permissives pour le gène de fusion EWS-FLI1 et que celui-ci induit des gènes de cellules souches embryonnaires. Ceci génère une sous-population de cellules présentant des caractéristiques de cellules souches cancéreuses de sarcome d'Ewing (ESFT CSCs) in vitro. Ces cellules reprogrammées n'ont pas de potentiel tumorigénique et un certain nombre de microARN ne sont pas réprimés ou exprimés comme dans un sarcome d'Ewing primaire et sa sous-population de CSCs. Parmi ces microARN on trouve en particulier les membres de la famille let-7 qui jouent un rôle clé dans le contrôle de l'état de différenciation des cellules et régulent de nombreux oncogènes. De plus, leur répression serait capable de favoriser la tumorigénèse. Tous les membres de la famille des microARNs let-7 ont un régulateur commun, la protéine lin-28, qui exerce notamment son action en bloquant la maturation de ces microARNs. Dans ce travail, il s'agira d'évaluer si la co-expression de EWS-FLI1 et de lin-28 dans des hpMSCs permet de créer une sous-population de cellules présentant les caractéristiques de ESFT CSCs. Nous évaluerons l'effet de lin-28 sur les membres de la famille des let7 dans les hpMSCs et apprécierons le potentiel tumorigénique in vivo des hpMSCs exprimant EWS-FLI1 et lin-28. L'outil « Targetscan » est un logiciel qui permet de prédire les cibles des microARN en analysant leur séquence et en la comparant à l'ARN messager 3' non transcrit. Pour les microARN de la famille des let-7, cet outil identifie des gènes cibles potentiels qui jouent un rôle important dans le sarcome d'Ewing. Nous évaluerons si ces protéines sont en effet régulées de façon let-7 dépendante et les conséquences sur la pathogénèse des ESFTs.

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From recent calls for positioning forensic scientists within the criminal justice system, but also policing and intelligence missions, this paper emphasizes the need for the development of educational and training programs in the area of forensic intelligence, It is argued that an imbalance exists between perceived and actual understanding of forensic intelligence by police and forensic science managers, and that this imbalance can only be overcome through education. The challenge for forensic intelligence education and training is therefore to devise programs that increase forensic intelligence awareness, firstly for managers to help prevent poor decisions on how to develop information processing. Two recent European courses are presented as examples of education offerings, along with lessons learned and suggested paths forward. It is concluded that the new focus on forensic intelligence could restore a pro-active approach to forensic science, better quantify its efficiency and let it get more involved in investigative and managerial decisions. A new educational challenge is opened to forensic science university programs around the world: to refocus criminal trace analysis on a more holistic security problem solving approach.

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AbstractObjective:In the present study, the authors investigated the in vitrobehavior of radio-resistant breast adenocarcinoma (MDA-MB-231) cells line and radiosensitive peripheral blood mononuclear cells (PBMC), as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy.Materials and Methods:The cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min–1 and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed.Results:Radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB- 231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48–72 hours post-radiation.Conclusion:Low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer.

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Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain tumor in adults. Accumulating evidence suggests that tumors comprise a hierarchical organization that is, at least partially, not genetically driven. Cells that reside at the apex of this hierarchy are commonly referred to as cancer stem cells (CSCs) and are believed to largely contribute to recurrence and therapeutic failure. Although the complexity of epigenetic regulation of the genome precludes prediction as to which epigenetic changes dominate CSC specification in different cancer types, the ability of microRNAs (miRNAs) to fine-tune expression of entire gene networks places them among prime candidates for establishing CSC properties. In this study we characterized the miRNA expression profile of primary GBM grown either under conditions that enrich for GSCs or their differentiated non-tumorigenic progeny (DGCs). Although, we identified a subset of miRNAs that was strongly differentially expressed between GSCs and DGCs, we observed that in GSCs both let-7 and, paradoxically, their target genes are highly expressed, suggesting protection against let-7 action. Using PAR-CLIP we show that insulin-like growth factor-2 mRNA-binding protein 2 (IMP2) provides a mechanism for let-7 target gene protection that represents an alternative to LIN28A/B, which abrogates let-7 biogenesis in normal embryonic and certain malignant stem cells. By direct binding to miRNA recognition elements, IMP2 protects its targets from let-7 mediated decay. Importantly, depletion of IMP2 in GSCs strongly impairs their self- renewal properties and tumorigenicity in vivo, a phenotype that can be rescued by expression of LIN28B, suggesting that IMP2 mainly contributes to GSC maintenance by protecting let-7 target genes from silencing. Using mouse models, we show that depletion of IMP2 in neural stem cells (NSCs) induces let-7 target gene down-regulation, impairs their clonogenic capacity, and affects differentiation. Taken together, our observations describe a novel regulatory function of IMP2 in the let-7 axis whereby it supports GSC and NSC specification. Résumé (Français) Le glioblastome (GBM) est la tumeur primaire maligne du cerveau la plus fréquente. De nombreuses études ont démontré l'existence d'une organisation hiérarchique des cellules cancéreuses liée à des mécanismes épigénétiques. Les cellules qui se trouvent au sommet de cette hiérarchie sont appelées cellules souches cancéreuses (CSC), et contribuent à l'échec thérapeutique. Bien que la complexité des régulateurs épigénétiques permette difficilement de prédire quel mécanisme contribue le plus aux propriétés des CSC, la capacité des microRNAs (miRNAs) de réguler des réseaux entiers de gènes, les placent comme des candidats de premiers choix. Ici, nous avons caractérisé le profil d'expression des miRNAs dans des tumeurs primaires de GBM cultivées dans des conditions qui enrichissent soit pour les CSC, soit pour leur contrepartie de cellules cancéreuses différences (CCD). De manière surprenante et paradoxale la famille de miRNA let-7 et leurs gènes cibles étaient hautement exprimés dans les CSC, suggérant un mécanisme de protection contre l'action des let-7. Avec l'aide de la technologie PAR-CLIP, nous démontrons que la protéine IMP2, protège les mRNAs de l'action des let-7 et représente une alternative à Lin28A/B, qui d'ordinaire réprime fortement la maturation des let-7 dans les cellules souches embryonnaires et divers cancers. En se liant à la région ciblée par les let-7, IMP2 protège ses transcrits de l'action de cette classe de microRNA qui est tumoro-supressive. La déplétion d'IMP2 dans des CSC de GBM réduit fortement leur clonogénicité in vitro et leur tumorigénicité in vivo. Ceci peut être reversé en introduisant Lin28B dans des CSC de GBM, suggérant qu'IMP2 exerce ses fonctions pro-tumorigéniques en modulant l'axe let-7. Avec l'aide de modèles murins, nous observons que la déplétion de IMP2 dans les cellules souches neurales (CSN) induit une baisse de leur clonogénicité et des cibles des miRNAs let-7, suggérant une conservation de ce mécanisme entre les CSC de GBM et les CSN. En résumé, nos observations définissent une nouvelle fonction de IMP2 dans l'axe let-7 par lequel il contribue au maintien des propriétés des CSC et des CSN.

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Ei vapaa, vapautuu 2027?. Kosti Vehanen (1887-1957), André Tellier (1902?-??).

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This article discusses the current requirement for scientific research to be published in the English language and the problems arising from this requirement not only for authors whose first language is not English but also for society and for the world's scientific community. The assistance which is and should be available to authors is considered as well as a future looking towards multilingual publication.

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The objective of this study was to optimize and validate the solid-liquid extraction (ESL) technique for determination of picloram residues in soil samples. At the optimization stage, the optimal conditions for extraction of soil samples were determined using univariate analysis. Ratio soil/solution extraction, type and time of agitation, ionic strength and pH of extraction solution were evaluated. Based on the optimized parameters, the following method of extraction and analysis of picloram was developed: weigh 2.00 g of soil dried and sieved through a sieve mesh of 2.0 mm pore, add 20.0 mL of KCl concentration of 0.5 mol L-1, shake the bottle in the vortex for 10 seconds to form suspension and adjust to pH 7.00, with alkaline KOH 0.1 mol L-1. Homogenate the system in a shaker system for 60 minutes and then let it stand for 10 minutes. The bottles are centrifuged for 10 minutes at 3,500 rpm. After the settlement of the soil particles and cleaning of the supernatant extract, an aliquot is withdrawn and analyzed by high performance liquid chromatography. The optimized method was validated by determining the selectivity, linearity, detection and quantification limits, precision and accuracy. The ESL methodology was efficient for analysis of residues of the pesticides studied, with percentages of recovery above 90%. The limits of detection and quantification were 20.0 and 66.0 mg kg-1 soil for the PVA, and 40.0 and 132.0 mg kg-1 soil for the VLA. The coefficients of variation (CV) were equal to 2.32 and 2.69 for PVA and TH soils, respectively. The methodology resulted in low organic solvent consumption and cleaner extracts, as well as no purification steps for chromatographic analysis were required. The parameters evaluated in the validation process indicated that the ESL methodology is efficient for the extraction of picloram residues in soils, with low limits of detection and quantification.

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Life on earth is based on sunlight, which is captured in chemical form by photosynthetic reactions. In the chloroplasts of plants, light reactions of photosynthesis take place at thylakoid membranes, whereas carbon assimilation reactions occur in the soluble stroma. The products of linear electron transfer (LET), highly-energetic ATP molecules, and reducing power in the form of NADPH molecules, are further used in the fixation of inorganic CO2 molecules into organic sugars. Ferredoxin-NADP+ oxidoreductase (FNR) catalyzes the last of the light reactions by transferring electrons from ferredoxin (FD) to NADP+. In addition to LET, FNR has been suggested to play a role in cyclic electron transfer (CET), which produces ATP without the accumulation of reducing equivalents. CET is proposed to occur via two putative routes, the PGR5- route and the NDH-route. In this thesis, the leaf-type FNR (LFNR) isoforms LFNR1 and LFNR2 of a model organism, Arabidopsis thaliana, were characterized. The physiological roles of LFNRs were investigated using single and double mutant plants. The viability of the single mutants indicates functionality of both isoforms, with neither appearing to play a specific role in CET. The more severe phenotype of low-temperature adapted fnr2 plants compared to both wild-type (WT) and fnr1 plants suggests a specific role for LFNR2 under unfavorable growth conditions. The more severe phenotype of the fnr1 x fnr2 (F1 generation) plants compared to single mutants reflects down-regulated photosynthetic capacity, whereas slightly higher excitation pressure indicates mild over-excitation of electron transfer chain (ETC). However, induction of CET and various photoprotective mechanisms enable adaptation of fnr1 x fnr2 plants to scarcity of LFNR. The fnr1 fnr2 plants (F2 generation), without detectable levels of LFNR, were viable only under heterotrophic conditions. Moreover, drought stress induced acceleration of the rate of P700 + re-reduction in darkness was accompanied by a concomitant up-regulation of the PGR5-route specific components, PGR5 and PGRL1, demonstrating the induction of CET via the PGR5-route. The up-regulation of relative transcriptional expression of the FD1 gene indicates that the FD1 isoform may have a specific function in CET, while no such role could be defined for either of the LFNR isoforms. Both the membrane-bound and soluble LFNR1 and LFNR2 each appear as two distinct spots after 2D-PAGE with different isoelectric points (pIs), indicating the existence of post-translational modifications (PTMs) which do not determine the membrane attachment of LFNR. The possibility of phosphorylation and glycosylation PTMs were excluded, but all four LFNR forms were shown to contain acetylated lysine residues as well as alternative N-termini. N-terminal acetylation was shown to shift the pI of both LFNRs to be more acidic. In addition, all four LFNR forms were demonstrated to interact both with FD1 and FD2 in vitro

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Presentation at Open Repositories 2014, Helsinki, Finland, June 9-13, 2014

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This study examines the aftermath of mass violence in local communities. Two rampage school shootings that occurred in Finland are analyzed and compared to examine the ways in which communities experience, make sense of, and recover from sudden acts of mass violence. The studied cases took place at Jokela High School, in southern Finland, and at a polytechnic university in Kauhajoki, in western Finland, in 2007 and 2008 respectively. Including the perpetrators, 20 people lost their lives in these shootings. These incidents are part of the global school shooting phenomenon with increasing numbers of incidents occurring in the last two decades, mostly in North America and Europe. The dynamic of solidarity and conflict is one of the main themes of this study. It builds upon previous research on mass violence and disasters which suggests that solidarity increases after a crisis, and that this increase is often followed by conflict in the affected communities. This dissertation also draws from theoretical discussions on remembering, narrating, and commemorating traumatic incidents, as well as the idea of a cultural trauma process in which the origins and consequences of traumas are negotiated alongside collective identities. Memorialization practices and narratives about what happened are vital parts of the social memory of crises and disasters, and their inclusive and exclusive characteristics are discussed in this study. The data include two types of qualitative interviews; focused interviews with 11 crisis workers, and focused, narrative interviews with 21 residents of Jokela and 22 residents of Kauhajoki. A quantitative mail survey of the Jokela population (N=330) provided data used in one of the research articles. The results indicate that both communities experienced a process of simultaneous solidarity and conflict after the shootings. In Jokela, the community was constructed as a victim, and public expressions of solidarity and memorialization were promoted as part of the recovery process. In Kauhajoki, the community was portrayed as an incidental site of mass violence, and public expressions of solidarity by distant witnesses were labeled as unnecessary and often criticized. However, after the shooting, the community was somewhat united in its desire to avoid victimization and a prolonged liminal period. This can be understood as a more modest and invisible process of “silent solidarity”. The processes of enforced solidarity were partly made possible by exclusion. In some accounts, the family of the perpetrator in Jokela was excluded from the community. In Kauhajoki, the whole incident was externalized. In both communities, this exclusion included associating the shooting events, certain places, and certain individuals with the concept of evil, which helped to understand and explain the inconceivable incidents. Differences concerning appropriate emotional orientations, memorialization practices and the pace of the recovery created conflict in both communities. In Jokela, attitudes towards the perpetrator and his family were also a source of friction. Traditional gender roles regarding the expression of emotions remained fairly stable after the school shootings, but in an exceptional situation, conflicting interpretations arose concerning how men and women should express emotion. The results from the Jokela community also suggest that while increased solidarity was seen as important part of the recovery process, some negative effects such as collective guilt, group divisions, and stigmatization also emerged. Based on the results, two simultaneous strategies that took place after mass violence were identified; one was a process of fast-paced normalization, and the other was that of memorialization. Both strategies are ways to restore the feeling of security shattered by violent incidents. The Jokela community emphasized remembering while the Kauhajoki community turned more to the normalization strategy. Both strategies have positive and negative consequences. It is important to note that the tendency to memorialize is not the only way of expressing solidarity, as fast normalization includes its own kind of solidarity and helps prevent the negative consequences of intense solidarity.

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The motives for this study originated from the notion that surprisingly little academic literature is found on actually managing and putting corporate social responsibility (CSR) into practice, in comparison with the definitions and frameworks of the concept itself. Regardless of the author, CSR has been considered consisting of three dimensions: economic, social and environmental. The question behind the three dimensions has always been whether socially and environmentally responsible behavior can lead to increased economic performance and improve the competitiveness of a company. Most of the current CSR development has related to the quantification of environmental and social performance in order to review these along with the established financial key ratios, which are based on the law and the reporting obligation of the companies. However, the previous research has mainly focused on US companies whereas studies with a European viewpoint, let alone Nordic, have been mostly lacking. Furthermore, it has been discovered recently that the integration of corporate responsibility into business is identified as the greatest challenge in CSR management in Finnish large companies. Therefore the integration of CSR into business in Finnish consumer goods companies provided an interesting, topical and somewhat obscure purpose for this study. This was further divided into three research questions concerning the reasons for CSR engagement, the role of the stakeholders and the practice of corporate responsibility. This study did not aim to build a new theory; instead an explorative viewpoint was regarded more appropriate. Accordingly, qualitative research approach and case study design were adopted in the study. Semi-structured theme interviews were used as a primary data collection method and complemented with secondary data such as websites, responsibility reports and another recent CSR study. There were four Finnish managers as interviewees of whom three presented companies and one non-profit organization. The results were somewhat convergent but differences arose as a result of the companies being at different stages as regards corporate responsibility. However, this provided only more insight into the implementation of CSR. The voluntary CSR initiatives, responsibility reporting, stakeholders and CSR management were identified as the most important viewpoints on the practical side of CSR, besides a key requirement for the integration of CSR into business to be credible was found to be a favorable management attitude. Based on the findings of this study it was admitted that giving concrete advice on CSR management is really a challenge and there is no one generally accepted and right manner to integrate corporate responsibility successfully into business.

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MicroRNAs (miRNAs) may be important mediators of the profound molecular and cellular changes that occur after traumatic brain injury (TBI). However, the changes and possible roles of miRNAs induced by voluntary exercise prior to TBI are still not known. In this report, the microarray method was used to demonstrate alterations in miRNA expression levels in the cerebral cortex of TBI mice that were pretrained on a running wheel (RW). Voluntary RW exercise prior to TBI: i) significantly decreased the mortality rate and improved the recovery of the righting reflex in TBI mice, and ii) differentially changed the levels of several miRNAs, upregulating some and downregulating others. Furthermore, we revealed global upregulation of miR-21, miR-92a, and miR-874 and downregulation of miR-138, let-7c, and miR-124 expression among the sham-non-runner, TBI-non-runner, and TBI-runner groups. Quantitative reverse transcription polymerase chain reaction data (RT-qPCR) indicated good consistency with the microarray results. Our microarray-based analysis of miRNA expression in mice cerebral cortex after TBI revealed that some miRNAs such as miR-21, miR-92a, miR-874, miR-138, let-7c, and miR-124 could be involved in the prevention and protection afforded by voluntary exercise in a TBI model.