Blood-Borne Circadian Signal Stimulates Daily Oscillations in Actin Dynamics and SRF Activity.

In peripheral tissues circadian gene expression can be driven either by local oscillators or by cyclic systemic cues controlled by the master clock in the brain's suprachiasmatic nucleus. In the latter case, systemic signals can activate immediate early transcription factors (IETFs) and thereby control rhythmic transcription. In order to identify IETFs induced by diurnal blood-borne signals, we developed an unbiased experimental strategy, dubbed Synthetic TAndem Repeat PROMoter (STAR-PROM) screening. This technique relies on the observation that most transcription factor binding sites exist at a relatively high frequency in random DNA sequences. Using STAR-PROM we identified serum response factor (SRF) as an IETF responding to oscillating signaling proteins present in human and rodent sera. Our data suggest that in mouse liver SRF is regulated via dramatic diurnal changes of actin dynamics, leading to the rhythmic translocation of the SRF coactivator Myocardin-related transcription factor-B (MRTF-B) into the nucleus.

Prosessimaisen toimintatavan soveltuvuus konepajan liiketoimintaprosessien johtamiseen

Kiristyvä kilpailu ja nopeat ympäristömuutokset aiheuttavat haasteita organisaatioiden johtamiseen. Yritykseltä edellytetään samaan aikaan reagointikykyä, joustavuutta, asiakasläheisyyttä sekä kustannustehokkuutta. Näihin haasteisiin voidaanvastata prosessimaisella toimintatavalla. Tämän työn tavoitteena on arvioida prosessimaisen toimintatavan soveltuvuutta konepajan toimintojenjohtamiseen ja arvioida millaisia hyötyjä prosessimaisella toimintatavalla voidaan saavuttaa. Työn teoriaosuudessa on perehdytty prosessiajattelun terminologiaan, prosessimaisen toiminnan kehittämiseen, avainprosessien tunnistamiseen ja prosessien kuvaamiseen sekä prosessien suorituskyvyn mittaamiseen. Työn käytännön osuudessa on perehdytty yrityksen toimintojen johtamiseen ja niissä ilmenneisiin ongelmiin, joihin prosessimaisella toiminnalla voitaisiin vaikuttaa. Lisäksi on huomioitu mitä ongelmia prosessimaisen toiminnan implementoinnissa saattaa esiintyä. Työssä on esitelty malli, jonka mukaisesti prosessimaista toimintaa voidaan yrityksessä kehittää. Työn tuloksena yrityksen avainprosessit on tunnistettu ja niistä on muodostettu prosessikartta sekä yrityksen tarjous- ja myyntiprosessi on kuvattu prosessinkuvausmenetelmällä.

Propionibacterium acnes Promotes Th17 and Th17/Th1 Responses in Acne Patients.

Propionibacterium acnes is a Gram-positive commensal bacterium thought to be involved in the pathogenesis of acne vulgaris. Although the ability of P. acnes in the initiation of pro-inflammatory responses is well documented, little is known about adaptive immune responses to this bacterium. The observation that infiltrating immune cells consist mainly of CD4(+) T cells in the perifollicular space of early acne lesions suggests that helper T cells may be involved in immune responses caused by the intra-follicular colonization of P. acnes. A recent report showing that P. acnes can induce IL-17 production by T cells suggests that acne might be a T helper type 17 (Th17)-mediated disease. In line with this, we show in this work that, in addition to IL-17A, both Th1 and Th17 effector cytokines, transcription factors, and chemokine receptors are strongly upregulated in acne lesions. Furthermore, we found that, in addition to Th17, P. acnes can promote mixed Th17/Th1 responses by inducing the concomitant secretion of IL-17A and IFN-γ from specific CD4(+) T cells in vitro. Finally, we show that both P. acnes-specific Th17 and Th17/Th1 cells can be found in the peripheral blood of patients suffering from acne and, at lower frequencies, in healthy individuals. We therefore identified P. acnes-responding Th17/Th1 cells as, to our knowledge, a previously unreported CD4(+) subpopulation involved in inflammatory acne.

Efficacy of a dilemma-focused intervention for unipolar depression: study protocol for a multicenter randomized controlled trial

Background Depression is one of the more severe and serious health problems because of its morbidity, disabling effects and for its societal and economic burden. Despite the variety of existing pharmacological and psychological treatments, most of the cases evolve with only partial remission, relapse and recurrence. Cognitive models have contributed significantly to the understanding of unipolar depression and its psychological treatment. However, success is only partial and many authors affirm the need to improve those models and also the treatment programs derived from them. One of the issues that requires further elaboration is the difficulty these patients experience in responding to treatment and in maintaining therapeutic gains across time without relapse or recurrence. Our research group has been working on the notion of cognitive conflict viewed as personal dilemmas according to personal construct theory. We use a novel method for identifying those conflicts using the repertory grid technique (RGT). Preliminary results with depressive patients show that about 90% of them have one or more of those conflicts. This fact might explain the blockage and the difficult progress of these patients, especially the more severe and/or chronic. These results justify the need for specific interventions focused on the resolution of these internal conflicts. This study aims to empirically test the hypothesis that an intervention focused on the dilemma(s) specifically detected for each patient will enhance the efficacy of cognitive behavioral therapy (CBT) for depression. Design A therapy manual for a dilemma-focused intervention will be tested using a randomized clinical trial by comparing the outcome of two treatment conditions: combined group CBT (eight, 2-hour weekly sessions) plus individual dilemma-focused therapy (eight, 1-hour weekly sessions) and CBT alone (eight, 2-hour group weekly sessions plus eight, 1-hour individual weekly sessions). Method Participants are patients aged over 18 years meeting diagnostic criteria for major depressive disorder or dysthymic disorder, with a score of 19 or above on the Beck depression inventory, second edition (BDI-II) and presenting at least one cognitive conflict (implicative dilemma or dilemmatic construct) as assessed using the RGT. The BDI-II is the primary outcome measure, collected at baseline, at the end of therapy, and at 3- and 12-month follow-up; other secondary measures are also used. Discussion We expect that adding a dilemma-focused intervention to CBT will increase the efficacy of one of the more prestigious therapies for depression, thus resulting in a significant contribution to the psychological treatment of depression. Trial registration ISRCTN92443999; ClinicalTrials.gov Identifier: NCT01542957.

An Analysis of Eye Scanpath Entropy in a Progressively Forming Virtual Environment

A sign of presence in virtual environments is that people respond to situations and events as if they were real, where response may be considered at many different levels, ranging from unconscious physiological responses through to overt behavior,emotions, and thoughts. In this paper we consider two responses that gave different indications of the onset of presence in a gradually forming environment. Two aspects of the response of people to an immersive virtual environment were recorded: their eye scanpath, and their skin conductance response (SCR). The scenario was formed over a period of 2 min, by introducing an increasing number of its polygons in random order in a head-tracked head-mounted display. For one group of experimental participants (n 8) the environment formed into one in which they found themselves standing on top of a 3 m high column. For a second group of participants (n 6) the environment was otherwise the same except that the column was only 1 cm high, so that they would be standing at normal ground level. For a third group of participants (n 14) the polygons never formed into a meaningful environment. The participants who stood on top of the tall column exhibited a significant decrease in entropy of the eye scanpath and an increase in the number of SCR by 99 s into the scenario, at a time when only 65% of the polygons had been displayed. The ground level participants exhibited a similar decrease in scanpath entropy, but not the increase in SCR. The random scenario grouping did not exhibit this decrease in eye scanpath entropy. A drop in scanpath entropy indicates that the environment had cohered into a meaningful perception. An increase in the rate of SCR indicates the perception of an aversive stimulus. These results suggest that on these two dimensions (scanpath entropy and rate of SCR) participants were responding realistically to the scenario shown in the virtual environment. In addition, the response occurred well before the entire scenario had been displayed, suggesting that once a set of minimal cues exists within a scenario,it is enough to form a meaningful perception. Moreover, at the level of the sympathetic nervous system, the participants who were standing on top of the column exhibited arousal as if their experience might be real. This is an important practical aspect of the concept of presence.

Uses of cancer registries for public health and clinical research in Europe : results of the European Network of Cancer Registries survey among 161 population-based cancer registries during 2010-2012

AIM: To provide insight into cancer registration coverage, data access and use in Europe. This contributes to data and infrastructure harmonisation and will foster a more prominent role of cancer registries (CRs) within public health, clinical policy and cancer research, whether within or outside the European Research Area. METHODS: During 2010-12 an extensive survey of cancer registration practices and data use was conducted among 161 population-based CRs across Europe. Responding registries (66%) operated in 33 countries, including 23 with national coverage. RESULTS: Population-based oncological surveillance started during the 1940-50s in the northwest of Europe and from the 1970s to 1990s in other regions. The European Union (EU) protection regulations affected data access, especially in Germany and France, but less in the Netherlands or Belgium. Regular reports were produced by CRs on incidence rates (95%), survival (60%) and stage for selected tumours (80%). Evaluation of cancer control and quality of care remained modest except in a few dedicated CRs. Variables evaluated were support of clinical audits, monitoring adherence to clinical guidelines, improvement of cancer care and evaluation of mass cancer screening. Evaluation of diagnostic imaging tools was only occasional. CONCLUSION: Most population-based CRs are well equipped for strengthening cancer surveillance across Europe. Data quality and intensity of use depend on the role the cancer registry plays in the politico, oncomedical and public health setting within the country. Standard registration methodology could therefore not be translated to equivalent advances in cancer prevention and mass screening, quality of care, translational research of prognosis and survivorship across Europe. Further European collaboration remains essential to ensure access to data and comparability of the results.

Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

Sildenafil as a therapeutic option for digital ischemic ulceration: case report.

We report the case of a 37-year-old woman who developed critical upper limb ischemia caused by a cervical rib. Because the malformation was initially undiagnosed, a vascular bypass was performed, and failure occurred. Following a 6-month therapy with sildenafil, revascularization of the arm was successful and amputation was avoided. A 6-year follow-up shows a rich collateral network at the compression site and normal values of digital plethysmography. Because hand surgeons often see patients with digital ulcerations and other manifestations of peripheral vascular pathology, therapy of ischemia with sildenafil could be an effective treatment option in patients not responding to classic drugs.

Transfer pricing tool development process based on valve package production costs

Tämän diplomityön päätavoitteena oli parantaa kehitetyn kustannusperusteisen siirtohinnoittelutyökalun ominaisuuksia osastokohtaisen kustannusarviointiprosessin käyttöön. Työ on vaikeutunut lähimenneisyyden heikosta hintakyselyiden vastauskyvystä. Työn pääongelmana oli kerätä luotettavaa tuotannonohjausjärjestelmän kustannusaineistoa osittain vanhentuneista vakioventtiilien koneistus- ja materiaalitiedosta. Tutkimuksessa käytetyt tärkeimmät tutkimusmenetelmät voidaan jakaa siirtohinnoittelu- ja kustannusarvioprosessien kirjallisuustutkimukseen, kenttäanalyysiin ja nykyisen Microsoft Excel –siirtohinnoittelutyökalun kehittämiseen eri osastojen rajapinnassa. Siirtohinnoittelumenetelmät ovat yleisesti jaettu kustannus-, markkina- ja neuvotteluperusteisiin malleihin, jotka harvoin sellaisenaan kohtaavat siirtohinnoittelulle asetetut tavoitteet. Tämä ratkaisutapa voi johtaa tilanteisiin, jossa kaksi erillistä menetelmää sulautuvat yhteen. Lisäksi varsinaiseen siirtohinnoittelujärjestelmään yleensä vaikuttavat useat sisäiset ja ulkoiset tekijät. Lopullinen siirtohinnoittelumenetelmä tulisi ehdottomasti tukea myös yrityksen visiota ja muita liiketoiminnalle asetettuja strategioita. Työn tuloksena saatiin laajennettu Microsoft Excel –sovellus, joka vaatii sekä vuosittaista että kuukausittaista erikoisventtiilimateriaalien hinta- ja toimitusaikatietojen päivittämistä. Tämä ratkaisutapa ehdottomasti parantaa kustannusarviointiprosessia, koska myös alihankkijatietoja joudutaan tutkimaan systemaattisesti. Tämän jälkeen koko siirtohinnoitteluprosessia voidaan kehittää muuntamalla kokoonpano- ja testaustyövaiheiden kustannusrakennetta toimintoperustaisen kustannuslaskentamallin mukaiseksi.

Potential of local bio-geoengineering to mitigate dangerous temperature increases in a global warming scenario

Crops and forests are already responding to rising atmospheric carbon dioxide and air temperatures. Increasing atmospheric CO2 concentrations are expected to enhance plant photosynthesis. Nevertheless, after long-term exposure, plants acclimate and show a reduction in photosynthetic activity (i.e. down-regulation). If in the future the Earth"s temperature is allowed to rise further, plant ecosystems and food security will both face significant threats. The scientific community has recognized that an increase in global temperatures should remain below 2°C in order to combat climate change. All this evidence suggests that, in parallel with reductions in CO2 emissions, a more direct approach to mitigate global warming should be considered. We propose here that global warming could be partially mitigated directly through local bio-geoengineering approaches. For example, this could be done through the management of solar radiation at surface level, i.e. by increasing global albedo. Such an effect has been documented in the south-eastern part of Spain, where a significant surface air temperature trend of -0.3°C per decade has been observed due to a dramatic expansion of greenhouse horticulture.

Reseptilääkkeiden lanseerausprosessi. Case: Ormox & Origlucon

Lääketeollisuuden tuotelanseerausten riskit ovat huomattavan suuria. Lääkkeiden tuotekehitysprojektien pitkä kesto ja valtaisat kustannukset ajavat yrityksen vaikeaan tilanteeseen. Lääkkeiden markkinoille tuonnin eli lanseerauksen on onnistuttava, jotta tuotekehityksen kustannukset voidaan kattaa. Tämän takia lääkkeiden lanseerauksen kehittäminen on yrityksille erittäin tärkeää. Lanseerauksen kehittäminen on samalla tutkimuksen pääongelma. Tutkielma keskittyy erityisesti suomalaisten reseptilääkkeiden lanseerausprosessin läpikäymiseen. Tutkielma jakautuu kahteen osaan: ensimmäinen osa käsittelee lanseerausta käsitteenä, lääkemarkkinoinnin erityispiirteitä sekä lanseerausprosessin teoriaa lääkeyhtiöiden näkökulmasta. Tutkielman toinen eli empiirinen osio, käsittelee Orion Pharman läpikäymää Ormox & Origlucon lanseerausta ja sen toteutusta. Erityisesti pyrittiin tunnistamaan, mitkä olivat keskeisimmät menestystekijät kyseisessä lanseerauksessa ja kuinka sitä voitaisiin kehittää. Ensimmäisenä menestystekijänä kyseisessä tutkimuksessa voidaan pitää hyvää markkinatuntemusta, jonka organisaatio oli koonnut toimiessaan aiempien lääkkeiden parissa. Toinen merkittävä menestystekijä on voimakas panostus, aina johdon tasolta asti, kyseiseen projektiin. Kolmantena tärkeänä menestystekijänä voidaan pitää tarvelähtöisyyttä, jonka avulla voitiin muotoilla asiakkaiden hyväksymä ja ymmärtämä markkinointiviesti. Keskeisimmiksi kehittämisen kohteiksi osoittautuivat sisäinen markkinointi, myyntitoiminnan organisointi sekä työn suunnittelun jatkuvuus.

Characterization of an antennal carboxylesterase from the pest moth Spodoptera littoralis degrading a host plant odorant.

Background: Carboxyl/cholinesterases (CCEs) are highly diversified in insects. These enzymes have a broad range of proposed functions, in neuro/developmental processes, dietary detoxification, insecticide resistance or hormone/pheromone degradation. As few functional data are available on purified or recombinant CCEs, the physiological role of most of these enzymes is unknown. Concerning their role in olfaction, only two CCEs able to metabolize sex pheromones have been functionally characterized in insects. These enzymes are only expressed in the male antennae, and secreted into the lumen of the pheromone-sensitive sensilla. CCEs able to hydrolyze other odorants than sex pheromones, such as plant volatiles, have not been identified. Methodology: In Spodoptera littoralis, a major crop pest, a diversity of antennal CCEs has been previously identified. We have employed here a combination of molecular biology, biochemistry and electrophysiology approaches to functionally characterize an intracellular CCE, SlCXE10, whose predominant expression in the olfactory sensilla suggested a role in olfaction. A recombinant protein was produced using the baculovirus system and we tested its catabolic properties towards a plant volatile and the sex pheromone components. Conclusion: We showed that SlCXE10 could efficiently hydrolyze a green leaf volatile and to a lesser extent the sex pheromone components. The transcript level in male antennae was also strongly induced by exposure to this plant odorant. In antennae, SlCXE10 expression was associated with sensilla responding to the sex pheromones and to plant odours. These results suggest that a CCE-based intracellular metabolism of odorants could occur in insect antennae, in addition to the extracellular metabolism occurring within the sensillar lumen. This is the first functional characterization of an Odorant- Degrading Enzyme active towards a host plant volatile.

How we experience immersive virtual environments: the concept of presence and its measurement

This paper reviews the concept of presence in immersive virtual environments, the sense of being there signalled by people acting and responding realistically to virtual situations and events. We argue that presence is a unique phenomenon that must be distinguished from the degree of engagement, involvement in the portrayed environment. We argue that there are three necessary conditions for presence: the (a) consistent low latency sensorimotor loop between sensory data and proprioception; (b) statistical plausibility: images must be statistically plausible in relation to the probability distribution of images over natural scenes. A constraint on this plausibility is the level of immersion;(c) behaviour-response correlations: Presence may be enhanced and maintained over time by appropriate correlations between the state and behaviour of participants and responses within the environment, correlations that show appropriate responses to the activity of the participants. We conclude with a discussion of methods for assessing whether presence occurs, and in particular recommend the approach of comparison with ground truth and give some examples of this.

Assessing the Paradox Between Transmitted and Acquired HIV Type 1 Drug Resistance Mutations in the Swiss HIV Cohort Study From 1998 to 2012.

BACKGROUND: Transmitted human immunodeficiency virus type 1 (HIV) drug resistance (TDR) mutations are transmitted from nonresponding patients (defined as patients with no initial response to treatment and those with an initial response for whom treatment later failed) or from patients who are naive to treatment. Although the prevalence of drug resistance in patients who are not responding to treatment has declined in developed countries, the prevalence of TDR mutations has not. Mechanisms causing this paradox are poorly explored. METHODS: We included recently infected, treatment-naive patients with genotypic resistance tests performed ≤1 year after infection and before 2013. Potential risk factors for TDR mutations were analyzed using logistic regression. The association between the prevalence of TDR mutations and population viral load (PVL) among treated patients during 1997-2011 was estimated with Poisson regression for all TDR mutations and individually for the most frequent resistance mutations against each drug class (ie, M184V/L90M/K103N). RESULTS: We included 2421 recently infected, treatment-naive patients and 5399 patients with no response to treatment. The prevalence of TDR mutations fluctuated considerably over time. Two opposing developments could explain these fluctuations: generally continuous increases in the prevalence of TDR mutations (odds ratio, 1.13; P = .010), punctuated by sharp decreases in the prevalence when new drug classes were introduced. Overall, the prevalence of TDR mutations increased with decreasing PVL (rate ratio [RR], 0.91 per 1000 decrease in PVL; P = .033). Additionally, we observed that the transmitted high-fitness-cost mutation M184V was positively associated with the PVL of nonresponding patients carrying M184V (RR, 1.50 per 100 increase in PVL; P < .001). Such association was absent for K103N (RR, 1.00 per 100 increase in PVL; P = .99) and negative for L90M (RR, 0.75 per 100 increase in PVL; P = .022). CONCLUSIONS: Transmission of antiretroviral drug resistance is temporarily reduced by the introduction of new drug classes and driven by nonresponding and treatment-naive patients. These findings suggest a continuous need for new drugs, early detection/treatment of HIV-1 infection.

State of Logistics and Operations Management in Finnish and Swedish Companies – Survey Research Findings

In this research we are examining what is the status of logistics and operations management in Finnish and Swedish companies. Empirical data is based on the web based questionnaire, which was completed in the end of 2007 and early 2008. Our examination consists of roughly 30 answers from largest manufacturing (highest representation in our sample), trade and logistics/distribution companies. Generally it could be argued that these companies operate in complex environment, where number of products, raw materials/components and suppliers is high. However, usually companies rely on small amount of suppliers per raw material/component (highest frequency is 2), and this was especially the case among Swedish companies, and among those companies, which favoured overseas sourcing. Sample consisted of companies which mostly are operating in an international environment, and are quite often multinationals. Our survey findings reveal that companies in general have taken logistics and information technology as part of their strategy process; utilization of performance measures as well as system implementations have followed the strategy decisions. In the transportation mode side we identify that road transports dominate all transport flow classes (inbound, internal and outbound), followed by sea and air. Surprisingly small amount of companies use railways, but in general we could argue that Swedish companies prefer this mode over Finnish counterparts. With respect of operations outsourcing, we found that more traditional areas of logistics outsourcing are driving factors in company's performance measurement priority. In contrary to previous research, our results indicate that the scope of outsourcing is not that wide in logistics/operations management area, and companies are not planning to outsource more in the near future. Some support is found for more international operations and increased outsourcing activity. From the increased time pressure of companies, we find evidence that local as well as overseas customers expect deliveries within days or weeks, but suppliers usually supply within weeks or months. So, basically this leads into considerable inventory holding. Interestingly local and overseas sourcing strategy does not have that great influence on lead time performance of these particular sourcing areas - local strategy is anyway considerably better in responding on market changes due to shorter supply lead times. In the end of our research work we have completed correlation analysis concerning items asked with Likert scale. Our analysis shows that seeing logistics more like a process rather than function, applying time based management, favouring partnerships and measuring logistics within different performance dimensions results on preferred features and performance found in logistics literature.