RasGAP Shields Akt from Deactivating Phosphatases in Fibroblast Growth Factor Signaling but Loses This Ability Once Cleaved by Caspase-3.

Fibroblast growth factor receptors (FGFRs) are involved in proliferative and differentiation physiological responses. Deregulation of FGFR-mediated signaling involving the Ras/PI3K/Akt and the Ras/Raf/ERK MAPK pathways is causally involved in the development of several cancers. The caspase-3/p120 RasGAP module is a stress sensor switch. Under mild stress conditions, RasGAP is cleaved by caspase-3 at position 455. The resulting N-terminal fragment, called fragment N, stimulates anti-death signaling. When caspase-3 activity further increases, fragment N is cleaved at position 157. This generates a fragment, called N2, that no longer protects cells. Here, we investigated in Xenopus oocytes the impact of RasGAP and its fragments on FGF1-mediated signaling during G2/M cell cycle transition. RasGAP used its N-terminal Src homology 2 domain to bind FGFR once stimulated by FGF1, and this was necessary for the recruitment of Akt to the FGFR complex. Fragment N, which did not associate with the FGFR complex, favored FGF1-induced ERK stimulation, leading to accelerated G2/M transition. In contrast, fragment N2 bound the FGFR, and this inhibited mTORC2-dependent Akt Ser-473 phosphorylation and ERK2 phosphorylation but not phosphorylation of Akt on Thr-308. This also blocked cell cycle progression. Inhibition of Akt Ser-473 phosphorylation and entry into G2/M was relieved by PHLPP phosphatase inhibition. Hence, full-length RasGAP favors Akt activity by shielding it from deactivating phosphatases. This shielding was abrogated by fragment N2. These results highlight the role played by RasGAP in FGFR signaling and how graded stress intensities, by generating different RasGAP fragments, can positively or negatively impact this signaling.

ADUBAÇÃO N-K NO ABACAXIZEIRO ‘BRS IMPERIAL’ - I - EFEITO NO DESENVOLVIMENTO E NA FLORAÇÃO DA PLANTA

RESUMO O abacaxizeiro ‘BRS Imperial’ é cultivar resistente à fusariose, com folhas sem espinhos, e que carece de informações técnicas específicas para o seu manejo. Este trabalho teve como objetivo avaliar o efeito de doses de N e K2O no desenvolvimento vegetativo, na floração e nos atributos de desenvolvimento da folha ‘D’ do ‘BRS Imperial’, buscando estabelecer parâmetros da planta para a indução artificial do florescimento. Em delineamento em blocos ao acaso e cinco repetições, testaram-se quatro doses de N (0; 160; 320; 550 kg ha-1) e quatro doses de K2O (0; 240; 480 e 600 kg ha-1), em esquema fatorial completo 4 x 4. A adubação potássica influenciou de forma positiva na massa fresca e no comprimento da planta, bem como no número de mudas por planta após a colheita dos frutos, enquanto a aplicação de N influenciou na emissão de folhas e na massa fresca de mudas. A adubação nitrogenada diminuiu o percentual de florescimento induzido artificialmente, enquanto a potássica aumentou esse parâmetro. A massa máxima estimada da folha ‘D’ foi de 56 g na dose de 364 kg ha-1 de N e na maior dose de K2O (600 kg ha-1). A massa da folha ‘D’ apresentou a melhor correlação com a massa do fruto, sendo estimada a massa mínima de 44 g para obtenção de frutos de 900 g, massa mínima exigida pelo mercado para comercialização.

ADUBAÇÃO N-K NO ABACAXIZEIRO ‘BRS IMPERIAL’ – II EFEITO NO SOLO, NA NUTRIÇÃO DA PLANTA E NA PRODUÇÃO

RESUMO O abacaxizeiro ‘BRS Imperial’ é uma cultivar resistente à fusariose, apresenta frutos saborosos, mas ainda é pouco conhecido dos fruticultores. Este trabalho teve como objetivo avaliar o efeito de diferentes doses de N e K nas características químicas do solo, nos teores foliares de nutrientes e nas variáveis de produção de um cultivo de ‘BRS Imperial’. O experimento foi instalado no espaçamento 0,90 x 0,40 x 0,40 m, com quatro doses de N (0; 160; 320 e 550 kg ha-1) e quatro de K2O (0; 240; 480 e 600 kg ha-1), em blocos ao acaso, com cinco repetições, em fatorial completo 4 x 4. Foram realizadas análises químicas das folhas e do solo, e mensuradas as variáveis de produção. O cultivo do abacaxizeiro sem N e K ou apenas com adubação nitrogenada resultaram em menores índices de pH, K+, Ca e 2+Mg2+ no solo, no final do ciclo de cultivo, em relação aos teores iniciais. Mesmo na maior dose de K aplicada, o teor deste nutriente no solo ficou baixo. Os teores foliares de N e K estimados, nas doses máximas testadas, foram 12,8 e 31,8 g kg-1, respectivamente. As variáveis de colheita mostraram significância para as doses de N em todas as avaliações, enquanto as doses de K2O influenciaram apenas na relação comprimento/diâmetro do fruto. Pela análise de regressão, as doses de N mostraram efeito quadrático na massa dos frutos com coroa, a qual se apresentou com 1.086 g na dose máxima física de 365 kg ha-1 e produtividade estimada de 42 t ha-1.

Yrityksen sisäisen kilpailun ja yhteistyön innovaatiovaikutus ja johtaminen t&k-toiminnassa

Tiedon luomiseen ja hyödyntämiseen perustuvassa liiketoiminnassa yrityksen kyky luoda tietoa ja käyttää hallussaan olevaa tietoa muodostaa perustan kilpailukyvylle ja kilpailueduille. Tutkielmassa rakennetaan konstruktiivista tutkimusotetta käyttäen innovaatioiden synnyn johtamiseen soveltuva toimintamalli Teecen tietoprosesseihin, Nonakan tiedonkonversioprosesseihin ja Ståhlen tietoympäristöihin perustuen. Tietoa syntyy esimerkiksi innovaatioissa. Innovaatioiden voidaan katsoa syntyvän vastakkaisten voimien jatkuvassa vuorovaikutuksessa. Tämä innovaatioita tuottava mekanismi rakentuu tietoa lisäävistä ja tietoa järjestävistä prosesseista, joita voidaan kuvata sekä seci-prosessin että kolmitasoisen tietoympäristön avulla. Sisäinen kilpailu ja yhteistyö vaikuttavat tämän mekanismin toimintaan. Yhteistyö lisää tiedon jakamista ja mahdollistaa radikaalien innovaatioiden ja tuoteinnovaatioiden synnyn. Kilpailun lisääminen vähentää keskinäistä tiedon jakamista ja siirtää innovaatioita fokuksen mukaisiin prosessi-innovaatioihin. Kilpailun ja yhteistyön määrään ja keskinäiseen suhteeseen voidaan vaikuttaa kolmitasoisesta tietoympäristömallista johdettujen kolmen erillisen, joskin toisiinsa vaikuttavan, johtamistavoitteen avulla. Mahdollistava johtaminen rakentaa luottamuksen ja yrityksen toiminnan perustaa. Valtuuttava johtaminen houkuttaa yhteistyöhön mahdollistaen tiedon lisääntymisen. Ohjaavan johtamisen prosessit vievät yritystä strategian mukaiseen suuntaan hyödyntäen sisäistä kilpailua.

Luomutuotteiden ostamiseen vaikuttavat tekijät: Case Lappeenrannan K-citymarket

Tutkimuksen tavoite oli selvittää sitä ristiriitaa, joka vallitsee kuluttajien ilmoittaman ja todellisen luomutuotteiden ostokäyttäytymisen välillä. Tätä ristiriitaa tutkittiin selvittämällä ostoprosessin eri osia ja niihin vaikuttavia tekijöitä, kuten sitoutumisastetta, arvoja ja asenteita. Tutkimusmenetelmänä käytettiin kyselytutkimusta, jonka aineisto kerättiin kontrolloidulla kyselyllä yhden viikon aikana Lappeenrannan K-citymarketissa.Tulokset osoittivat, että kuluttajat ostavat luomutuotteita, jos ne koetaan omaa itseä hyödyttäviksi, eli tärkeimmät ostamisen syyt olivat hyvä maku, lisäaineettomuus ja terveellisyys. Sen sijaan kollektiivinen etu, kuten ympäristöystävällisyys, ei ollut kovinkaan tärkeä luomunostoperuste. Näyttäisi myös siltä, että ne, jotka arvo- ja ajatusmaailmansa puolesta olisivat potentiaalisia luomutuotteiden kuluttajia, ostavat muita tuotteita tottumuksen perusteella.

Alterations of Na, K and Rb concentrations in Mycenaean pottery and a proposed explanation using X-ray diffraction

One of the most important reference groups for Mycenaean pottery is the Mycenae/Berbati (MB). In several studies, a second group has been identified (MBKR). The chemical compositions were similar to MB, but with important differences in the Na, K and Rb contents. The present study suggests that these differences are due to selective alteration and contamination processes that are indirectly determined by the original firing temperature. Therefore, groups MB and MBKR should be considered as a single reference group.

Interplay of vitamin D, erythropoiesis, and the renin-angiotensin system.

For many years deficiency of vitamin D was merely identified and assimilated to the presence of bone rickets. It is now clear that suboptimal vitamin D status may be correlated with several disorders and that the expression of 1-α-hydroxylase in tissues other than the kidney is widespread and of clinical relevance. Recently, evidence has been collected to suggest that, beyond the traditional involvement in mineral metabolism, vitamin D may interact with other kidney hormones such as renin and erythropoietin. This interaction would be responsible for some of the systemic and renal effects evoked for the therapy with vitamin D. The administration of analogues of vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Moreover, vitamin D deficiency could contribute to an inappropriately activated or unsuppressed RAS, as a mechanism for progression of CKD and/or cardiovascular disease. Experimental data on the anti-RAS and anti-inflammatory effects treatment with active vitamin D analogues suggest a therapeutic option particularly in proteinuric CKD patients. This option should be considered for those subjects that are intolerant to anti-RAS agents or, as add-on therapy, in those already treated with anti-RAS but not reaching the safe threshold level of proteinuria.

STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer.

BACKGROUND: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials. METHODS/DESIGN: STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies. DISCUSSION: The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013. TRIAL REGISTRATION: STRATEGIC-1 is registered at Clinicaltrials.gov: NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.

Theoretical modeling of photon and electron-stimulated Na and K desorption from SiO2

The mechanism of generation of atomic Na and K from SiO2 samples has been studied using explicitly correlated wave function and density functional theory cluster calculations. Possible pathways for the photon and electron stimulated desorption of Na and K atoms from silicates are proposed, thus providing new insight on the generation of the tenuous Na and K atmosphere of the Moon.

Increased voltage-dependent K+ channel Kv1.3 and Kv1.5 expression correlates with leiomyosarcoma aggressiveness

Voltage-dependent K+ channels (Kv) are involved in the proliferation and differentiation of mammalian cells, since Kv antagonists impair cell cycle progression. Although myofibers are terminally differentiated, some myoblasts may re-enter the cell cycle and proliferate. Since Kv1.3 and Kv1.5 expression is remodeled during tumorigenesis and is involved in smooth muscle proliferation, the purpose of this study was to analyze the expression of Kv1.3 and Kv1.5 in smooth muscle neoplasms. In the present study, we examined human samples of smooth muscle tumors together with healthy speci­mens. Thus, leiomyoma (LM) and leiomyosarcoma (LMS) tumors were analyzed. Results showed that Kv1.3 was poorly expressed in the healthy muscle and indolent LM specimens, whereas aggressive LMS showed high levels of Kv1.3 expression. Kv1.5 staining was correlated with malignancy. The findings show a remodeling of Kv1.3 and Kv1.5 in human smooth muscle sarcoma. A correlation of Kv1.3 and Kv1.5 expression with tumor aggressiveness was observed. Thus, our results indicate Kv1.5 and Kv1.3 as potential tumorigenic targets for aggressive human LMS.

Descripció geoambiental i paisatgística del sistema platja-duna de cala Borró (cap Ras, Alt Empordà- Costa Brava, Girona)

The geoambiental and landscape description of the beach-dune system of Cala Borró, (Cap Ras), placed in the town of Colera (Alt Empordà), is carried out. The dunar system, developed with orientation and N-S, links three beach pockets following the topographic slopes of the torrential basins. We find coalescence of dunes in the upper zones, which were possibly an object of reafforestation in the 19thC. to avoid erosion

Fem Sånger af K. C.

Soitinnus: lauluääni, piano.

Updates in the perioperative and emergency management of non-vitamin K antagonist oral anticoagulants.

Perioperative management of patients treated with the non-vitamin K antagonist oral anticoagulants is an ongoing challenge. Due to the lack of good clinical studies involving adequate monitoring and reversal therapies, management requires knowledge and understanding of pharmacokinetics, renal function, drug interactions, and evaluation of the surgical bleeding risk. Consideration of the benefit of reversal of anticoagulation is important and, for some low risk bleeding procedures, it may be in the patient's interest to continue anticoagulation. In case of major intra-operative bleeding in patients likely to have therapeutic or supra-therapeutic levels of anticoagulation, specific reversal agents/antidotes would be of value but are currently lacking. As a consequence, a multimodal approach should be taken which includes the administration of 25 to 50 U/kg 4-factor prothrombin complex concentrates or 30 to 50 U/kg activated prothrombin complex concentrate (FEIBA®) in some life-threatening situations. Finally, further studies are needed to clarify the ideal therapeutic intervention.