Structural Insight into the Mode of Action of a Direct Inhibitor of Coregulator Binding to the Thyroid Hormone Receptor.

The development of nuclear hormone receptor antagonists that directly inhibit the association of the receptor with its essential coactivators would allow useful manipulation of nuclear hormone receptor signaling. We previously identified 3-(dibutylamino)-1-(4-hexylphenyl)-propan-1-one (DHPPA), an aromatic β-amino ketone that inhibits coactivator recruitment to thyroid hormone receptor β (TRβ), in a high-throughput screen. Initial evidence suggested that the aromatic β-enone 1-(4-hexylphenyl)-prop-2-en-1-one (HPPE), which alkylates a specific cysteine residue on the TRβ surface, is liberated from DHPPA. Nevertheless, aspects of the mechanism and specificity of action of DHPPA remained unclear. Here, we report an x-ray structure of TRβ with the inhibitor HPPE at 2.3-Å resolution. Unreacted HPPE is located at the interface that normally mediates binding between TRβ and its coactivator. Several lines of evidence, including experiments with TRβ mutants and mass spectroscopic analysis, showed that HPPE specifically alkylates cysteine residue 298 of TRβ, which is located near the activation function-2 pocket. We propose that this covalent adduct formation proceeds through a two-step mechanism: 1) β-elimination to form HPPE; and 2) a covalent bond slowly forms between HPPE and TRβ. DHPPA represents a novel class of potent TRβ antagonist, and its crystal structure suggests new ways to design antagonists that target the assembly of nuclear hormone receptor gene-regulatory complexes and block transcription.

A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

Dynamic range extension of SiPM detectors with the time-gated operation

The silicon photomultiplier (SiPM) is a novel detector technology that has undergone a fast development in the last few years, owing to its single-photon resolution and ultra-fast response time. However, the typical high dark count rates of the sensor may prevent the detection of low intensity radiation fluxes. In this article, the time-gated operation with short active periods in the nanosecond range is proposed as a solution to reduce the number of cells fired due to noise and thus increase the dynamic range. The technique is aimed at application fields that function under a trigger command, such as gated fluorescence lifetime imaging microscopy.

Catalogue-tarif à prix forts et nets des journaux, revues et publications périodiques parus à Paris ... : contenant les titres complets par ordre alphabétique, les noms des rédacteurs, le format, la tomaison, la date d'origine, le mode de publication... : suivi d'une table systématique et du tarif postal pour la France et l'étranger / publié par Henri Le Soudier

1897 (A18).

Catalogue-tarif à prix forts et nets des journaux, revues et publications périodiques parus à Paris ... : contenant les titres complets par ordre alphabétique, les noms des rédacteurs, le format, la tomaison, la date d'origine, le mode de publication... : suivi d'une table systématique et du tarif postal pour la France et l'étranger / publié par Henri Le Soudier

Variante(s) de titre : Annuaire-tarif des journaux, revues et publications périodiques parus à Paris

Business Process Reengineering - Liiketoimintaprosessin uudistaminen Helsingin ja Uudenmaan sairaanhoitopiirin laboratorioliikelaitoksessa

Tutkimuksen tavoitteena on selvittää laboratoriotutkimuksien liiketoimintaprosessin uudistamisen hyödyt ja haitat Helsingin ja Uudenmaan sairaanhoitopiirin laboratorioliikelaitokselle. Tutkimuksessa selvitetään myös, kannattaako HUSLAB:n uudistaa nykyistä laboratoriotutkimuksien liiketoimintaprosessiaan sekä mitkä ovat liiketoimintaprosessin uudistamisen vaikutukset HUSLAB:lle. Tutkimuksessa mallinnetaan laboratoriotutkimuksien nykyinen liiketoimintaprosessi, jonka pohjalta muodostetaan kuvaus uudistettavasta prosessista. Prosessien välisiä eroja tutkitaan tarkemmin HUSLAB:n yhdessä toimipisteessä. Tutkimuksessa selvitetään, kuinka toimipisteen kustannusrakenne ja toimintamalli muuttuisivat prosessin uudistamisen myötä. Tutkimuksen empiiristen tulosten mukaan HUSLAB:n ei kannata uudistaa laboratoriotutkimuksien liiketoimintaprosessiaan tutkimuksessa kuvatulla tavalla. Liiketoimintaprosessin uudistaminen osoittautui kannattamattomaksi, koska uudistamisen haitat muodostuivat hyötyjä suuremmiksi. Vaikka BPR:ää ei kannatta toteuttaa tutkimuksessa esitetyllä tavalla, voi BPR kuitenkin olla tulevaisuudessa varteenotettava vaihtoehto HUSLAB:n toimintaa muutettaessa.

Entry Mode Choice in a Hard Service Company

Pro gradun tavoitteena oli löytää tärkeimmät seikat, jotka vaikuttavat kansainvälisen operaatiomuodon valintaan. Tutkimuskohteena olivat suomalaiset pienet tai keskisuuret tuotteistetut ohjelmistopalveluyritykset. Tutkimusmenetelmänä käytettiin kvalitatiivista tutkimusta sekä case-tutkimusta. Tutkimus koostui kahdesta osasta: teoreettinen osa sekä empiirinen kahden case yrityksen analyysi. Operaatiomuodon valintaan vaikuttavat tekijät jaettiin sisäisiin (yritys, tuote ja päätöksentekijä), ulkoisiin (ala ja maa) ja operaatiomuodon (kontrolli, riski, resurssit, joustavuus, tuotot ja kulut) tekijöihin. Teoreettisesti operaatiomuodon valinta on erittäin monimutkainen päätös ja sitä on tutkittu monelta kannalta. Tämä empiirinen tutkimus osoittaa, että yrityksen resurssit olivat tärkein vaikuttava tekijä molemmissa yrityksissä.

Means and challenges in international operations for a Finnish mobile application provider

Master’s Thesis concentrates to means and challenges in international operations for a Finnish mobile application provider Small Planet Oy during its various company stages from founding till maturing and during macro economical phases between year 1998 and 2008. Small Planet has just celebrated its 10 year anniversary and is therefore quite an extraordinary company which has survived all the highs and lows during past ten years and which has operated in the market as long as the whole mobile application industry has existed. Master’s Thesis describes possibilities for a company’s internationalization with different entry modes like exporting, licensing, investment entry and co-operative operations which are suitable for a mobile application provider. Unsuitable entry modes like franchising or contract manufacturing are not explained. The goal has been to analyze Small Planet’s international operations and to make conclusions from the practical experiences. Analysis and conclusions shall help Small Planet in its international operations in the future and should give insight to other mobile application companies and their managers who are in the situation of planning their own international operations. Results show that the best ways for Small Planet to internationalize its operations has been the co-operation with a big domestic client and the co-operation with Finnish operator infrastructure providers which have complementary products with Small Planet. Through these co-operations Small Planet has got lot of new international clients. Same time financial risks and investment need for international operations have been low. Co-operative international sales can be the most efficient international entry mode for a mobile application provider.

Toiminnan kehittäminen ohutlevykonepajassa

Yritysmaailma elää jatkuvassa muutoksessa. Yrityksen kehittäminen on yrityksen menestymisen kannalta välttämätöntä. Mikäli yritystä ei aktiivisesti kehitetä, kilpailijat valtaavat yrityksen elintilan ja yritys taantuu ja lopulta yrityksen toiminta lakkaa. Tämän työn tarkoituksena oli kehittää Compusteel Oy:n toimintaa ja edistää yhtiön kilpailukykyä lähitulevaisuudessa. Compusteel Oy on luonteeltaan alihankkija / komponenttitoimittaja. Tällaisen yrityksen tärkein kilpailutekijä on tehokas tuotanto. Tässä työssä keskityttiin tutkimaan erityisesti keinoja, millä tuotantoa voidaan tehostaa. Useissa työn lähteenä käytetyissä tutkimuksissa on havaittu tiedon välittämisen merkitys nykyaikaisen yrityksen kilpailutekijänä. Tyypillisimmillään toiminnan virheet johtuvat tiedon puutteellisesta välittämisestä sekä tiedon käytettävyyden heikosta tasosta tarvetilanteessa. Tutkimus toteutettiin kirjallisuuden ja muun lähdeaineiston kuten koulutusten avulla. Tutkimuksessa paneuduttiin erityisesti erilaisten tuotannonohjausmenetelmien kartoittamiseen sekä niiden hyödyntämiseen yrityksen toiminnassa. Työn tuloksena syntyi Compusteel Oy:öön uusi toimintamalli tiettyihin yrityksen ydin prosesseihin. Erityisen tärkeänä nähtiin uuden ajattelumallin omaksuminen tuotannonohjaushenkilöstössä. Uutta ajattelumallia voidaan tulevaisuudessa soveltaa useissa yrityksen kehittämishankkeissa. Lisäksi työn tuloksena käyttöönotettiin uusi toiminnanohjausjärjestelmä, joka tukee uutta toimintamallia.

Epigenetic regulatory elements: Recent advances in understanding their mode of action and use for recombinant protein production in mammalian cells.

Successful generation of high producing cell lines requires the generation of cell clones expressing the recombinant protein at high levels and the characterization of the clones' ability to maintain stable expression levels. The use of cis-acting epigenetic regulatory elements that improve this otherwise long and uncertain process has revolutionized recombinant protein production. Here we review and discuss new insights into the molecular mode of action of the matrix attachment regions (MARs) and ubiquitously-acting chromatin opening elements (UCOEs), i.e. cis-acting elements, and how these elements are being used to improve recombinant protein production. These elements can help maintain the chromatin environment of the transgene genomic integration locus in a transcriptionally favorable state, which increases the numbers of positive clones and the transgene expression levels. Moreover, the high producing clones tend to be more stable in long-term cultures even in the absence of selection pressure. Therefore, by increasing the probability of isolating a high producing clone, as well as by increasing transcription efficiency and stability, these elements can significantly reduce the time and cost required for producing large quantities of recombinant proteins.

A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

Targeted cell elimination reveals an auxin-guided biphasic mode of lateral root initiation.

To sustain a lifelong ability to initiate organs, plants retain pools of undifferentiated cells with a preserved proliferation capacity. The root pericycle represents a unique tissue with conditional meristematic activity, and its tight control determines initiation of lateral organs. Here we show that the meristematic activity of the pericycle is constrained by the interaction with the adjacent endodermis. Release of these restraints by elimination of endodermal cells by single-cell ablation triggers the pericycle to re-enter the cell cycle. We found that endodermis removal substitutes for the phytohormone auxin-dependent initiation of the pericycle meristematic activity. However, auxin is indispensable to steer the cell division plane orientation of new organ-defining divisions. We propose a dual, spatiotemporally distinct role for auxin during lateral root initiation. In the endodermis, auxin releases constraints arising from cell-to-cell interactions that compromise the pericycle meristematic activity, whereas, in the pericycle, auxin defines the orientation of the cell division plane to initiate lateral roots.

Governance mode vs. governance fit: Performance implications of make-or-ally choices for product innovation in the worldwide aircraft industry, 1942-2000

We examine the impact of governance mode and governance fit on performance in make-or-ally decisions. We argue that while horizontal collaboration and autonomous governance have direct and countervailing performance implications, the alignment of make-or-ally choices with the focal firm's resource endowment and the activity's resource requirements leads to better performance. Data on the aircraft industry show that relative to aircraft developed autonomously, collaborative aircraft exhibit greater sales but require longer time-to-market. However, governance fit increases unit sales and reduces time-to-market. We contribute to the alliance and economic organization literatures. (Copyright © 2013 John Wiley & Sons, Ltd.)