Role of neutrophils in the early shaping of the Leishmania major specific immune response in experimental murine cutaneous Leishmaniasis

The development of a protective immune response to microorganisms involves complex interactions between the host and the pathogen. The murine model of infection with Leishmania major (L. major) allows the study of the factors leading to the development of a protective immune response. Following infection with the protozoan parasite L. major, most strains of mice heal their lesions, while a few fail to control infection, both processes linked to the development of specific T helper subsets. The early events occurring during the first days following parasite inoculation are thought to be critical in the development of the Leishmania-specific immune response. Neutrophils are the first cells arriving massively to the site of infection, and recent evidence points to their role as organizers of the immune response, yet their specific role in this process remains elusive. Through interactions with cells present at the parasite inoculation site, and possibly within the draining lymph nodes, neutrophils could have an impact not only on the recruitment of inflammatory cells but also on the activation of local as well as newly migrated cells that will be crucial in shaping the Leishmania-specific immune response.

Functional plasticity of the LACK-reactive Vbeta4-Valpha8 CD4(+) T cells normally producing the early IL-4 instructing Th2 cell development and susceptibility to Leishmania major in BALB / c mice.

Early production of IL-4 by LACK-reactive Vbeta4-Valpha8 CD4(+) T cells instructs aberrant Th2 cell development and susceptibility to Leishmania major in BALB / c mice. This was demonstrated using Vbeta4(+)-deficient BALB / c mice as a result of chronic infection with MMTV (SIM), a mouse mammary tumor virus expressing a Vbeta4-specific superantigen. The early IL-4 response was absent in these mice which develop a Th1 response to L. major. Here, we studied the functional plasticity of LACK-reactive Vbeta4-Valpha8 CD4(+) T cells using BALB/ c mice inoculated with L. major shortly after infection with MMTV (SIM), i. e. before deletion of Vbeta4(+) cells. These mice fail to produce the early IL-4 response to L. major and instead exhibit an IFN-gamma response that occurs within LACK-reactive Vbeta4-Valpha8 CD4(+) T cells. Neutralization of IFN-gamma restores the production of IL-4 by these cells. These data suggest that the functional properties of LACK-reactive Vbeta4-Valpha8 CD4(+) T cells are not irreversibly fixed.

New pool of cortical interneuron precursors in the early postnatal dorsal white matter.

The migration of cortical γ-aminobutyric acidergic interneurons has been extensively studied in rodent embryos, whereas few studies have documented their postnatal migration. Combining in vivo analysis together with time-lapse imaging on cortical slices, we explored the origin and migration of cortical interneurons during the first weeks of postnatal life. Strikingly, we observed that a large pool of GAD65-GFP-positive cells accumulate in the dorsal white matter region during the first postnatal week. Part of these cells divides and expresses the transcription factor paired box 6 indicating the presence of local transient amplifying precursors. The vast majority of these cells are immature interneurons expressing the neuronal marker doublecortin and partly the calcium-binding protein calretinin. Time-lapse imaging reveals that GAD65-GFP-positive neurons migrate from the white matter pool into the overlying anterior cingulate cortex (aCC). Some interneurons in the postnatal aCC express the same immature neuronal markers suggesting ongoing migration of calretinin-positive interneurons. Finally, bromodeoxyuridine incorporation experiments confirm that a small fraction of interneurons located in the aCC are generated during the early postnatal period. These results altogether reveal that at postnatal ages, the dorsal white matter contains a pool of interneuron precursors that divide and migrate into the aCC.

Russian transition in the early 21st century

Tässä tutkimuksessa käsitellään Venäjän talouden kehitystä uudella vuosituhannella. Kylmän sodan aikaan Neuvostoliitto oli suurvalta, jonka asema perustui sotilasmahtiin. Sotateollisuuden konversio palvelemaan nykytarpeita ei ole ollut helppo tehtävä. Vuoden 1998 talouskriisin jälkeen elintaso on toipunut verraten nopeasti, mikä on nähtävissä tarkastellessa kotitalouksien kulutusrakenteita, joita käsitellään tarkemmin luvussa 2. Siirtymätalouksissa vaihtotaseen vajeet ovat yleisiä, mutta luonnonrikkauksiensa ansiosta Venäjän vaihtotaseet ovat olleet huomattavan ylijäämäisiä, mitä pohditaan luvussa 3. Vaihtotaseen ylijäämien heijatusvaikutus on ollut Venäjän rooli pääomien nettoviejänä. Venäjän investointikertymä onedelleen erittäin vaatimaton suhteutettuna maan kehitysvaiheeseen. Jokaisessa menestyksekkäässä taloudessa investoinnit ovat pitkän aikavälintaloudellisen menestyksen avaintekijä. Venäjän erityispiirteitä tähän liittyen on kuvattu luvussa 4. Raportti päättyy talouden nykytilanteen analyysiin (luvut 5 ja 6).

Supporting knowledge creation and sharing in the early phases of the strategic innovation process

The driving forces of technology and globalization continuously transform the business landscape in a way which undermines the existing strategies and innovations of organizations. The challenge for organizations is to establish such conditions where they are able to create new knowledge for innovative business ideas in interaction between other organizations and individuals. Innovation processes continuously need new external stimulations and seek new ideas, new information and knowledge locating more and more outside traditional organizational boundaries. In several studies, the early phases of the innovation process have been considered as the most critical ones. During these phases, the innovation process can emerge or conclude. External knowledge acquirement and utilization are noticed to be important at this stage of the innovation process giving information about the development of future markets and needs for new innovative businessideas. To make it possible, new methods and approaches to manage proactive knowledge creation and sharing activities are needed. In this study, knowledge creation and sharing in the early phases of the innovation process has been studied, and the understanding of knowledge management in the innovation process in an open and collaborative context advanced. Furthermore, the innovation management methods in this study are combined in a novel way to establish an open innovation process and tested in real-life cases. For these purposes two complementary and sequentially applied group work methods - the heuristic scenario method and the idea generation process - are examined by focusing the research on the support of the open knowledge creation and sharing process. The research objective of this thesis concerns two doctrines: the innovation management including the knowledge management, and the futures research concerning the scenario paradigm. This thesis also applies the group decision support system (GDSS) in the idea generation process to utilize the converged knowledge during the scenario process.

Welding time models for cost calculations in the early stages of the design process

It is generally accepted that between 70 and 80% of manufacturing costs can be attributed to design. Nevertheless, it is difficult for the designer to estimate manufacturing costs accurately, especially when alternative constructions are compared at the conceptual design phase, because of the lack of cost information and appropriate tools. In general, previous reports concerning optimisation of a welded structure have used the mass of the product as the basis for the cost comparison. However, it can easily be shown using a simple example that the use of product mass as the sole manufacturing cost estimator is unsatisfactory. This study describes a method of formulating welding time models for cost calculation, and presents the results of the models for particular sections, based on typical costs in Finland. This was achieved by collecting information concerning welded products from different companies. The data included 71 different welded assemblies taken from the mechanical engineering and construction industries. The welded assemblies contained in total 1 589 welded parts, 4 257 separate welds, and a total welded length of 3 188 metres. The data were modelled for statistical calculations, and models of welding time were derived by using linear regression analysis. Themodels were tested by using appropriate statistical methods, and were found to be accurate. General welding time models have been developed, valid for welding in Finland, as well as specific, more accurate models for particular companies. The models are presented in such a form that they can be used easily by a designer, enabling the cost calculation to be automated.

Saccharomyces cerevisiae Grx6 and Grx7 are monothiol glutaredoxins associated with the early secretory pathway

Saccharomyces cerevisiae Grx6 and Grx7 are two monothiol glutaredoxins whose active-site sequences (CSYS and CPYS, respectively) are reminiscent of the CPYC active-site sequence of classical dithiol glutaredoxins. Both proteins contain an N-terminal transmembrane domain which is responsible for their association to membranes of the early secretory pathway vesicles, facing the luminal side. Thus, Grx6 localizes at the endoplasmic reticulum and Golgi compartments, while Grx7 is mostly at the Golgi. Expression of GRX6 is modestly upregulated by several stresses (calcium, sodium, and peroxides) in a manner dependent on the Crz1-calcineurin pathway. Some of these stresses also upregulate GRX7 expression under the control of the Msn2/4 transcription factor. The N glycosylation inhibitor tunicamycin induces the expression of both genes along with protein accumulation. Mutants lacking both glutaredoxins display reduced sensitivity to tunicamycin, although the drug is still able to manifest its inhibitory effect on a reporter glycoprotein. Grx6 and Grx7 have measurable oxidoreductase activity in vivo, which is increased in the presence of tunicamycin. Both glutaredoxins could be responsible for the regulation of the sulfhydryl oxidative state at the oxidant conditions of the early secretory pathway vesicles. However, the differences in location and expression responses against stresses suggest that their functions are not totally overlapping.

Lipid phosphate phosphatase 3 participates in transport carrier formation and protein trafficking in the early secretory pathway

The inhibition of phosphatidic acid phosphatase (PAP) activity by propanolol indicates that diacylglycerol (DAG) is required for the formation of transport carriers at the Golgi and for retrograde trafficking to the ER. Here we report that the PAP2 family member lipid phosphate phosphatase 3 (LPP3, also known as PAP2b) localizes in compartments of the secretory pathway from ER export sites to the Golgi complex. The depletion of human LPP3: (i) reduces the number of tubules generated from the ER-Golgi intermediate compartment and the Golgi, with those formed from the Golgi being longer in LPP3-silenced cells than in control cells; (ii) impairs the Rab6-dependent retrograde transport of Shiga toxin subunit B from the Golgi to the ER, but not the anterograde transport of VSV-G or ssDsRed; and (iii) induces a high accumulation of Golgi-associated membrane buds. LPP3 depletion also reduces levels of de novo synthesized DAG and the Golgi-associated DAG contents. Remarkably, overexpression of a catalytically inactive form of LPP3 mimics the effects of LPP3 knockdown on Rab6-dependent retrograde transport. We conclude that LPP3 participates in the formation of retrograde transport carriers at the ER-Golgi interface, where it transitorily cycles, and during its route to the plasma membrane.

External assessment of the Early Mortality Risk Score in patients with adenocarcinoma undergoing pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomies (PD) still have a substantial mortality rate. Recently, different scores have been published to predict the mortality risk pre-operatively after PD. This retrospective study was designed to perform an external assessment of an Early Mortality Risk Score (EMRS). METHODS: From 2000 to 2012, all PD cases performed at our institution were documented. Only patients treated for pancreatic head adenocarcinomas were included. Survival time and EMRS (based on age, tumour size, tumour differentiation and comorbidities) were calculated for every patient. Relative risks (RR) of early death 9 and 12 months after PD were then calculated. RESULTS: Of 270 PD for various aetiologies, 120 PD for adenocarcinomas were included. The median follow-up was 37 months, and the overall median survival was 19 months. EMRS of 4 showed a mortality RR of 5.1 at 9 months (P = 0.048) and of 4.5 at 12 months (P = 0.020). CONCLUSIONS: EMRS of 4 is a predictor of tumour-related mortality at 9 and 12 months after PD for adenocarcinoma. The EMRS was externally assessed in our patient cohort and can be implemented in clinical practice. Clinical implications of this score still need to be studied.

The Early Phases of Innovation Process - Case: New Wireless E-Business Opportunities in Forest Industry

Tutkimuksen tavoitteena oli soveltaa innovaatioprosessiteorioita käytäntöön konteksti huomioonottaen, koska langattoman sähköisen liiketoiminnan nopeat muutokset, metsäteollisuuden erityispiirteet ja ei-kaupallisuus asettavat erityistarpeita innovoinnille. Painopiste on prosessin aikaisissa vaiheissa, koska ne ovat kriittisiä koko innovaatioprosessin menestymisen kannalta. Tähtäimenä oli löytää yrityssektorille uusia langattomia sähköisen liiketoiminnan mahdollisuuksia, jotka hyödyttävät tutkimuksessa mukanaolevaa yritystä. Tutkimuksessa käytettiin konstruktiivista tutkimusotetta ja metodeina sähköistä aivomyrskyä, tarkistuslistaa sekä GDSS- ja postikyselyä.Tutkimuksen tuloksena on esitetty innovaatioprosessin aikaiset vaiheet kirjallisuudesta, metsäteollisuuden erityispiirteet ja innovaatioprosessisovellus. Lisäksi tämä tutkimus tuotti uusia sähköisen liiketoiminnan ideoita, suoritti niille seulonnan ja kävi läpi alustavan tutkimuksen.