Acid-base Balance and Oxidative Metabolism in Calcified Tissues

The calcified tissues, comprising bone and cartilage, are metabolically active tissues that bind and release calcium, bicarbonate and other substances according to systemic needs. Understanding the regulation of cellular metabolism in bone and cartilage is an important issue, since a link between the metabolism and diseases of these tissues is clear. An essential element in the function of bone-resorbing osteoclasts, namely regulation of bicarbonate transport, has not yet been thoroughly studied. Another example of an important but at the same time fairly unexplored subject of interest in this field is cartilage degeneration, an important determinant for development of osteoarthritis. The link between this and oxidative metabolism has rarely been studied. In this study, we have investigated the significance of bicarbonate transport in osteoclasts. We found that osteoclasts possess several potential proteins for bicarbonate transport, including carbonic anhydrase IV and XIV, and an electroneutral bicarbonate co-transporter NBCn1. We have also shown that inhibiting the function of these proteins has a significant impact on bone resorption and osteoclast morphology. Furthermore, we have explored oxidative metabolism in chondrocytes and found that carbonic anhydrase III (CA III), a protein linked to the prevention of protein oxidation in muscle cells, is also present in mouse chondrocytes, where its expression correlates with the presence of reactive oxygen species. Thus, our study provides novel information on the regulation of cellular metabolism in calcified tissues.

Osingonjakopäätökset pienissä osakeyhtiöissä. Empiirinen tutkimus osakeyhtiölain varojenjakosäännösten toteutumisesta

Tässä väitöstutkimuksessa tarkastellaan Suomen osakeyhtiölain pakottavien varojenjakosäännösten vaikutusta osingonjakopaatoksiin. Lain vaikutuksen seuraamisen lisäksi pyritään muodostamaan kokonaiskuva tekijöistä, jotka vaikuttavat pienissä yhtiöissä tehtäviin osingonjakopäätöksiin. Väitöskirja koostuu kahdesta eri osasta. Ensimmäisessä osassa osoitetaan, kuinka toisen osan artikkelit muodostavat kokonaisuuden ja esitellään tutkimustulokset. Väitöskirjan toinen osa koostuu neljästä toisiaan täydentävästä artikkelista. Tutkimus etenee julkaisujen myötä ensin maksukykytestin määrittelystä maksukykytestiin liittyviin oikeudellisiin ongelmiin sekä tilinpaatoksen merkitykseen osingonjakopäätöksissä, siirtyen sitten omistaja johtajan tarpeisiin ja tavoitteisiin, päättyen lopuksi velkojan näkökulmaan. Tutkimuksen tavoitteeksi asetettiin kokonaiskuvan muodostaminen niistä tekijöistä, jotka vaikuttavat osingonjakopäätöksen tekemiseen pienissä osakeyhtiöissä. Tavoitteena oli myös selvittää kuinka osakeyhtiölain 13 luvun varojenjakosäännökset otetaan huomioon osingonjakopäätöstä tehtäessä. Tutkimusaineistona käytettiin sekä kyselytutkimusaineistoa että tilinpäätöstietoja. Aineistoa analysoitiin kvantitatiivisin menetelmin. Tutkimusaineistosta löydettiin kolme erilaista varallisuuden siirtämisen strategiaa. Ne nimettiin seuraavasti: tulojen maksimointi, verosuunnittelu, palkan jousto. Tutkimuksesta nousee esiin kolme keskeistä tulosta. Ensinnäkin, liiketaloustieteellinen maksukyvyn merkitys poikkeaa oikeustieteessä käsitetystä maksukyvystä. Toiseksi, osakeyhtiölain 13 luvun varojenjakosäännökset tulee ottaa huomioon sekä osingonjakopäätöstä tehtäessä että varojen tosiasiallisesti siirtyessä pois yhtiön vaikutuspiiristä. Kolmanneksi, pääomatuloverotuksen kiristyessä omistaja johtaja saattaa siirtää varallisuutta yhtiöstä yksityistalouteen osingon sijasta palkkana. Tämän seurauksena maksukykytestin merkitys vähenee erityisesti pienissä yhtiöissä. Tulosten perusteella tasetesti näyttää olevan pienissä yhtiöissä maksukykytestiä merkityksellisempi.

Keille yliopiston portit avautuvat? Tutkimus suomalaisiin yliopistoihin ja eri tieteenaloille valikoitumisesta 2000-luvun alussa

Tutkimuksessa tarkastellaan suomalaisiin yliopistoihin valikoitumista 2000-luvun alussa. Tarkastelu pohjautuu yliopistoon hakeneiden, opiskelemaan hyväksyttyjen ja opiskelupaikkaa ilman jääneiden taustojen vertailuun. Tutkimuksen tarkoituksena on selvittää, miten koulutuksellinen tasa-arvo toteutuu opiskelemaan pääsyssä. Erityistä huomiota kiinnitetään sukupuolten, eri-ikäisten, sosiaalisten ryhmien sekä eri alueella asuvien opiskelijavalinnoissa pärjäämiseen. Lisäksi pohditaan, millaiset taustatekijät ovat yhteydessä opiskelemaan pääsyyn ja miten suomalainen yliopistokenttä on lohkoutunut yliopistoittain ja aloittain hakijoiden ja sisään päässeiden taustojen perusteella. Tutkimuksen pääaineistona on henkilöpohjainen rekisteriaineisto, joka on laadittu valtakunnallisen hakijarekisterin (HAREK) ja Tilastokeskuksen yhteistyönä. Aineisto käsittää 40 %:n satunnaisotoksen vuonna 2003 suomalaisiin yliopistoihin hakeneista (N = 55 790). Aineiston muuttujat kuvaavat hakijoiden taustoja, elämäntilannetta, aiempaa koulutusta ja lapsuudenperheen asemaa. Tutkimuksessa hyödynnetään lisäksi kokonaisjoukosta muodostettua taulukkoaineistoa (N = 139 668). Yliopistoihin hakevat eivät ole yhtenäinen ryhmä. Vaikka suurin osa hakijoista oli nuoria, oli joukossa myös varttuneempia hakijoita, jotka olivat ehtineet hankkia koulutusta ja muuta elämänkokemusta. Päävalinnat toimivat siten myös aikuishakijoiden hakuväylänä; erillisvalintoja eivät hyödynnä läheskään kaikki, joilla siihen olisi mahdollisuus. Klusterianalyysin avulla hakijoista voitiin erottaa neljä ryhmää: 1) nuoret ylioppilaat, 2) toisen tutkinnon suorittajat, 3) koulutuspääoman kartuttajat sekä 4) aikuiset lisäkouluttautujat. Opiskelemaan pääsyyn vaikuttavia tekijöitä analysoitiin logistisen regressioanalyysin avulla. Analyysin mukaan hakijan iällä oli muista taustatekijöistä riippumaton vaikutus opiskelemaan pääsyyn niin, että todennäköisyys päästä yliopistoon vähenee hakijan iän kohotessa. Parhaiten opiskelemaan pääsivät kaikkein nuorimmat, alle 20-vuotiaat hakijat, jotka siis useimmiten ovat saman kevään ylioppilaita. Vanhemmille hakijoille oli usein kertynyt jo koulutusta, mutta aiemmat tutkinnot paransivat sisäänpääsyn mahdollisuuksia vain, mikäli ne olivat korkea-asteelta. Alemmilla ammatillisilla tutkinnoilla oli pikemminkin opiskelemaan pääsyä heikentävä vaikutus. Myös se, mitä hakija oli tehnyt ennen valintakokeita, vaikutti sisäänpääsyn mahdollisuuksiin. Parhaiten valinnoissa pärjäsivät päätoimiset opiskelijat, heikoiten työttömät hakijat. Vaikka miesten hyväksymisprosentit olivat keskimäärin korkeammat kuin naisten, sukupuoli ei osoittautunut itsenäiseksi opiskelemaan pääsyä selittäväksi tekijäksi. Naisten huonompi pärjääminen valinnoissa selittyykin pitkälti sukupuolten eriytyneillä alavalinnoilla. Naisten suosimat alat kun ovat pääsääntöisesti vaikeapääsyisempiä kuin miesten. Tutkimuksessa selvisi myös, että kaupunkilaisuus lisäsi todennäköisyyttä tulla hyväksytyksi. Toisaalta opiskelemaan pääsy erosi myös asuinmaakunnittain, mikä kertoo lähinnä siitä, että eri yliopistojen sisäänpääsyasteissa on varsin suuria eroja. Yliopistojen lohkoutuminen hakijoiden sosiaalisen taustan mukaan oli paljon selvempää kuin alojen. Kaikki pääkaupunkiseudun yliopistot – lukuun ottamatta Teatterikorkeakoulua – luokittuivat isän asemalla mitaten elitistisiksi. Matalimmista taustoista haettiin Lapin, Joensuun ja Vaasan yliopistoihin. Alojen paikka elitistisyyskansanomaisuus -ulottuvuudella vaihteli suuresti yliopistoittain. Teknillistieteellinen, matemaattis-luonnontieteellinen ja kauppatieteellinen ala sijoittuivat kuitenkin keskimääräistä ylemmäs, kun taas kasvatustiede ja farmasia olivat kansanomaisimpia hakukohteita. Opiskelijaksi valikoitumisen peruselementit toistuivat myös tässä tutkimuksessa: koulutetuimpien ja hyvässä asemassa olevien vanhempien jälkeläiset saivat opiskelupaikan useammin kuin muut. Yliopistolaitoksessa vuosikymmenten saatossa toteutetut rakenteelliset muutokset eivät siis ole muuttaneet valikoitumisen peruslinjaa, joskin uutena huomiona nousi maanviljelijöiden jälkeläisten hyvä valinnoissa pärjääminen. Maanviljelijäperheestä tulevien opiskelemaan pääsyn todennäköisyys oli kaikkein suurin.

Mistä on uudistumiskykyinen organisaatiokulttuuri tehty, case: Kouvolan kaupunki

Tutkimuksen tarkoituksena on selvittää organisaatiokulttuurin merkitystä organisaation uudistumiskykyyn. Lisäksi selvitetään, mitkä uudistumiskykyä tukevat tai estävät organisaatiokulttuurin piirteet toteutuvat Kouvolan kaupungin aikuissosiaalipalveluissa. Tutkimus toteutetaan laadullisena tapaustutkimuksena huomioiden organisaatiossa vuonna 2010 tehty organisaation uudistumiskyvyn kyselytutkimus. Aineistonkeruumenetelmänä käytetään puolistrukturoituja yksilöhaastatteluita, joissa haastateltavina ovat organisaation harkinnanvaraisesti valitsemat haastateltavat. Aineiston kerääminen ja analysointi toteutetaan teorialähtöisesti. Kohdeorganisaation vahvuudeksi voidaan nähdä hyvin tunnistettu strategia sekä siihen liittyvät päämäärät ja arvot, mikä antaa organisaatiolle mahdollisuuden toteuttaa strategian mahdollistamia organisaatiokulttuurin uudistumista edistäviä piirteitä. Vahvuutena voidaan pitää myös asiakaslähtöisyyden sisäistämistä toimintaa ohjaavana arvona sekä vahvaa sitoutumista omaan työhön. Organisaatiokulttuuria pidetään vielä hahmottumattomana, mikä vaatii sekä kulttuurin että identiteetin vahvistamista. Uudistumiskykyä tukeva organisaatiokulttuuri näkyy hyvänä ja avoimena yhteistyönä ja vuorovaikutuksena sekä organisaation sisällä että yhteistyökumppanien kanssa. Kehittämiskohteeksi Kouvolassa nouseekin yhteistyön parantaminen ja tehostaminen ylittämällä palvelualue- ja toimialarajoja sekä pyrkimällä poliittisen ja virkamiesjohdon entistä yhtenäisempään näkemykseen toimintaa tukevista innovatiivisista ratkaisuista. Kannustamisen ja palkitsemisen kohdistamisella uudistumista edistävään toimintaan voidaan saada aikaan uskallusta ja halua ideoida sekä innovoida.

Marcadores tumorais no câncer colorretal

Colorectal cancer is a clinical entity of a persistent relevance in clinical practice and its early diagnosis is a determinant factor to obtain better therapeutic results. Tumor markers are helpful means for a better approach to individuals with such neoplasm. In the present review, the authors analyze the phases in which surgical-clinical treatment markers must be used: diagnosis, determination of tumor stage, establishment of prognosis and detection of recurrence. Current and future markers and the consensus on their use are discussed. Causal factors for errors in diagnosis with markers and perspectives of use are also presented.

Fratura de pênis com trauma uretra

We reported a case of a twenty-nine-year-old male who presented a penile fracture associated with urethral injury caused by a sexual intercourse. An ideal anamnesis and a special physical examination were determinant to correct diagnostics. Ultrasonography and uretrocistography must be performed for confirmation. The treatment is based on the presence of associated urethral injury. The surgical repair of cavernous body and urethra can produce good results, with a favorable prognosis and minimal rate of complications.

"Cara inchada" of cattle, an infectious, apparently soil antibiotics-dependant periodontitis in Brazil

The objective of this review on the investigation of "cara inchada" in cattle (CI), pursued over the last 30 years, was to elucidate the pathogenicity of the disease and come to proper conclusions on its etiology. CI has been widely considered to be of nutritional origin, caused primarily by mineral deficiency or imbalance. However, the disease consists of a rapidly progressive periodontitis, affecting the periodontal tissues at the level of the premolars and molars during the period of tooth eruption generally starting in young calves. The disease led to great economic losses for farmers in central-western Brazil, after the occupation of new land for cattle raising in the 1960s and 1970s. The lateral enlargement of the maxillary bones of affected calves gave the disease the popular name of "cara inchada", i.e., swollen or enlarged face. The enlargement was found to be due to a chronic ossifying periostitis resulting from the purulent alveolitis of CI. Black-pigmented non-saccharolytic Bacteroides melaninogenicus, always together with Actinomyces (Corynebacterium) pyogenes, were isolated in large numbers from the periodontal lesions. B. melaninogenicus could be isolated in small numbers also from the marginal gingiva of a few healthy calves maintained on CI-free farms. "In vitro"-assays showed that streptomycin and actinomycin, as well as the supernatants of cultivates of actinomycetes from soils of CI-prone farms, applied in subinhibitory concentrations to the bacteria tested, enhanced significantly (up to 10 times) the adherence of the black-pigmented B.melaninogenicus to epithelial cells of the bovine gingiva. The antibiotics are apparently produced in large quantities by the increased number of soil actinomycetes, including the genus Streptomyces, that develop when soil microflora are modified by cultivating virgin forest or "Cerrado" (tree-savanna) for the first time for cattle grazing. The epidemiology of CI now provides strong evidence that the ingestion with the forage of such antibiotics could possibly be an important determinant factor for the onset and development of this infectious periodontitis. The antibiotic enhanced adherence of B.melaninogenicus to the sulcus-epithelium of the marginal gingiva, is thought to allow it to colonize, form a plaque and become pathogenic. There is experimental evidence that this determinant factor for the development of the periodontitis is present also in the milk of the mothers of CI-diseased calves. It has been shown that the bacteria isolated from the periodontal CI-lesions produce enzymes and endotoxins capable of destroying the periodontal tissues. The epidemiology of CI, with its decline in incidence and its disappearance after several years, could be explained by the fact that the former equilibrium of the microflora of the once undisturbed virgin soil has been reached again and that the number of antibiotic producing actinomycetes has been anew reduced. By this reasoning and all the data available, CI should be considered as a multifactorial infectious disease, caused primarily by the anaerobic black-pigmented non-saccharolytic Bacteroides melaninogenicus, always together with the micro-anaerobic Actinomyces pyogenes. Accordingly, the onset and development of the infectious periodontitis is apparently determined by ingestion with the forage of subinhibitory concentrations of antibiotics produced in recently cultivated virgin soils. This hypothesis is supported by the recent observation of renewed outbreaks of CI-periodontitis in former CI-prone areas, following fresh cultivation after many years. The infectious nature of CI is confirmed by trials in which virginiamycin was used efficiently for the oral treatment of CI-diseased cattle. Previously it has been shown, that spiramycin and virginiamycin, used as additives in mineral supplements, prevented CI-periodontitis.

JNK, a versatile regulator of kinesin-1 transport and cytoskeleton dynamics

C-Jun N-terminal kinase (JNK) is traditionally recognized as a crucial factor in stress response and inducer of apoptosis upon various stimulations. Three isoforms build the JNK subfamily of MAPK; generally expressed JNK1 and JNK2 and brain specific JNK3. Degenerative potency placed JNK in the spotlight as potential pharmacological option for intervention. Unfortunately, adverse effects of potential drugs and observation that expression of only JNK2 and JNK3 are induced upon stress, restrained initial enthusiasm. Notably, JNK1 demonstrated atypical high constitutive activity in neurons that is not responsive to cellular stresses and indicated existence of physiological activity. This thesis aimed at revealing the physiological functions of JNK1 in actin homeostasis through novel effector MARCKS-Like 1 (MARCKSL1) protein, neuronal trafficking mediated by major kinesin-1 motor protein and microtubule (MT) dynamics via STMN2/SCG10. The screen for novel physiological JNK substrates revealed specific phosphorylation of C-terminal end of MARCKSL1 at S120, T148 and T183 both ex vivo and in vitro. By utilizing site-specific mutagenesis, various actin dynamics and migrations assays we were able to demonstrate that JNK1 phosphorylation specifically facilitates F-actin bundling and thus filament stabilisation. Consecutively, this molecular mechanism was proved to enhance formation of filopodia; cell surface projections that allow cell sensing surrounding environment and migrate efficiently. Our results visualize JNK dependent and MARCKSL1 executed induction of filopodia in neurons and fibroblast indicating general mechanism. Subsequently, inactivation of JNK action on MARCKSL1 shifts cellular actin machinery into lamellipodial dynamic arrangement. Tuning of actin cytoskeleton inevitably melds with cell migration. We observed that both active JNK and JNK pseudo-phosphorylated form of MARCKSL1 reduce actin turnover in intact cells leading to overall diminished cell motility. We demonstrate that tumour transformed cells from breast, prostate, lung and muscle-derived cancers upregulate MARCKSL1. We showed on the example of prostate cancer PC-3 cell line that JNK phosphorylation negatively controls MARCKSL1 ability to induce migration, which precedes cancer cell metastasis. The second round of identification of JNK physiological substrates resulted in detection of predominant motor protein kinesin-1 (Kif5). Mass spectrometry detailed analysis showed evident endogenous phosphorylation of kinesin-1 on S176 within motor domain that interacts with MT. In vitro phosphorylation of bacterially expressed kinesin heavy chain by JNK isoforms displayed higher specificity of JNK1 when compared to JNK3. Since, JNK1 is constitutively active in neurons it signified physiological aspect of kinesin-1 regulation. Subsequent biochemical examination revealed that kinesin-1, when not phosphorylated on JNK site, exhibits much higher affinity toward MTs. Expression of the JNK non-phosphorable kinesin-1 mutant in intact cells as well as in vitro single molecule imaging using total internal reflection fluorescence microscopy indicated that the mutant loses normal speed and is not able to move processively into proper cellular compartments. We identify novel kinesin-1 cargo protein STMN2/SCG10, which along with known kinesin-1 cargo BDNF is showing impaired trafficking when JNK activity is inhibited. Our data postulates that constitutive JNK activity in neurons is crucial for unperturbed physiologically relevant transport of kinesin-1 dependant cargo. Additionally, my work helps to validate another novel physiological JNK1 effector STMN2/SCG10 as determinant of axodendritic neurites dynamics in the developing brain through regulation of MT turnover. We show successively that this increased MT dynamics is crucial during developmental radial migration when brain layering occurs. Successively, we are able to show that introduction of JNK phosphorylation mimicking STMN2/SCG10 S62/73D mutant rescues completely JNK1 genetic deletion migration phenotype. We prove that STMN2/SCG10 is predominant JNK effector responsible for MT depolymerising activity and neurite length during brain development. Summarizing, this work describes identification of three novel JNK substrates MARCKSL1, kinesin-1 and STMN2/SCG10 and investigation of their roles in cytoskeleton dynamics and cargo transport. This data is of high importance to understand physiological meaning of JNK activity, which might have an adverse effect during pharmaceutical intervention aiming at blocking pathological JNK action.

Effects of Socioeconomic Status and Sociodemographic Features on Cardiovascular Disease. Mortality and Morbidity in Finland

Despite declining trends in morbidity and mortality, cardiovascular diseases have a considerable impact on Finnish public health. A goal in Finnish health policy is to reduce inequalities in health and mortality among population groups. The aim of this study was to assess inequalities in cardiovascular diseases according to socioeconomic status (SES), language groups and other sociodemographic characteristics. The main data source was generated from events in 35-99 year-old men and women registered in the population-based FINMONICA and FINAMI myocardial infarction registers during the years ranging from 1988-2002. Information on population group characteristics was obtained from Statistics Finland. Additional data were derived from the FINMONICA and FINSTROKE stroke registers and the FINRISK Study. SES, measured by income level, was a major determinant of acute coronary syndrome (ACS) mortality. Among middle-aged men, the 28-day mortality rate of the lowest group of six income groups was 5.2 times and incidence 2.7 times as high when compared to the highest income group. Among women, the differences were even larger. Among the unmarried, the incidence of ACS was approximately 1.6 times as high and their prognosis was significantly worse than among married persons - both in men and women and independent of age. Higher age-standardized attack rates of ACS and stroke were found among Finnish-speaking compared to Swedish-speaking men in Turku and these differences could not be completely explained by SES. In these language groups, modest differences were found in traditional risk factor levels possibly explaining part of the found morbidity and mortality inequality. In conclusion, there are considerable differences in the morbidity and mortality of ACS and stroke between socioeconomic and sociodemographic groups, in Finland. Focusing measures to reduce the excess morbidity and mortality, in groups at high risk, could decrease the economic burden of cardiovascular diseases and thus be an important public health goal in Finland.

Cellular responses to stress and kinase signaling activation : apoptosis and differentiation

Stressignaler avkänns många gånger av membranbundna proteiner som översätter signalerna till kemisk modifiering av molekyler, ofta proteinkinaser Dessa kinaser överför de avkodade budskapen till specifika transkriptionsfaktorer genom en kaskad av sekventiella fosforyleringshändelser, transkriptionsfaktorerna aktiverar i sin tur de gener som behövs för att reagera på stressen. En av de mest kända måltavlorna för stressignaler är transkriptionsfaktor AP-1 familjemedlemen c-Jun. I denna studie har jag identifierat den nukleolära proteinet AATF som en ny regulator av c-Jun-medierad transkriptionsaktivitet. Jag visar att stresstimuli inducerar omlokalisering av AATF vilket i sin tur leder till aktivering av c-Jun. Den AATF-medierad ökningen av c-Jun-aktiviteten leder till en betydande ökning av programmerad celldöd. Parallellt har jag vidarekarakteriserat Cdk5/p35 signaleringskomplexet som tidigare har identifierats i vårt laboratorium som en viktig faktor för myoblastdifferentiering. Jag identifierade den atypiska PKCξ som en uppströms regulator av Cdk5/p35-komplexet och visar att klyvning och aktivering av Cdk5 regulatorn p35 är av fysiologisk betydelse för differentieringsprocessen och beroende av PKCξ aktivitet. Jag visar att vid induktion av differentiering fosforylerar PKCξ p35 vilket leder till calpain-medierad klyvning av p35 och därmed ökning av Cdk5-aktiviteten. Denna avhandling ökar förståelsen för de regulatoriska mekanismer som styr c-Jun-transkriptionsaktiviteten och c-Jun beroende apoptos genom att identifiera AATF som en viktig faktor. Dessutom ger detta arbete nya insikter om funktionen av Cdk5/p35-komplexet under myoblastdifferentiering och identifierar PKCξ som en uppströms regulator av Cdk5 aktivitet och myoblast differentiering.

Regulation of cell fate by c-FLIP phosphorylation

Programmed cell death is an important physiological cellular process that maintains homeostasis and protects multicellular organisms from diseases. Apoptosis is the principal mode of cell death, which eliminates unwanted cells and an enormous effort has been made to understand the molecular mechanisms of the signaling pathway and its regulatory systems. Irregular apoptosis often has life-threatening consequences to humans, including cancer, autoimmune diseases and degenerative diseases. In cancer for example, cell death is an attractive target to eradicate uncontrollably proliferating cells that have disregard pro-apoptotic signaling. Targeted therapeutic approaches are not as effective as once expected, since now we know that the cell death pathways are not sole entities in cells, but are highly associated with various cellular processes. Proteins that regulate apoptosis can also control non-apoptotic signaling pathways. For example, c-FLIP is a protein that can either inhibit or promote caspase-8 activation, which is required to induce apoptosis. Not only has c-FLIP opposing effects on initiating apoptosis, but it also regulates various pro-survival signaling pathways in the cell. It is well known that protein expression level is a determinant of how c-FLIP can regulate different signaling pathways, but other regulatory mechanisms potentially affecting the role of c-FLIP are less well understood. This work addresses novel insights into the mechanisms of c-FLIP post-translational modifications and their functional consequences. We have identified that phosphorylation is an important inception for subcellular localization of c-FLIP, thereby dictating which apoptotic and non-apoptotic signaling pathways c-FLIP could regulate to promote cell survival. Furthermore, we have constructed mathematical models to unite independent studies to establish more systematic c-FLIP signaling pathways to understand the dynamics of extrinsically-induced apoptosis.

Streamside management zone (SMZ) efficiency in herbicide retention from simulated surface flow

Plot-scale overland flow experiments were conducted to evaluate the efficiency of streamside management zones (SMZs) in retaining herbicides in runoff generated from silvicultural activities. Herbicide retention was evaluated for five different slopes (2, 5, 10, 15, and 20%), two cover conditions (undisturbed O horizon and raked surface), and two periods under contrasting soil moisture conditions (summer dry and winter wet season) and correlated to O horizon and site conditions. Picloram (highly soluble in water) and atrazine (moderately sorbed into soil particles) at concentrations in the range of 55 and 35 µg L-1 and kaolin clay (approximately 5 g L-1) were mixed with 13.000 liters of water and dispersed over the top of 5 x 10 m forested plots. Surface flow was collected 2, 4, 6, and 10 m below the disperser to evaluate the changes in concentration as it moved through the O horizon and surface soil horizon-mixing zone. Results showed that, on average, a 10 m long forested SMZ removed around 25% of the initial concentration of atrazine and was generally ineffective in reducing the more soluble picloram. Retention of picloram was only 6% of the applied quantity. Percentages of mass reduction by infiltration were 36% for atrazine and 20% for picloram. Stronger relationships existed between O horizon depth and atrazine retention than in any other measured variable, suggesting that better solid-solution contact associated with flow through deeper O horizons is more important than either velocity or soil moisture as a determinant of sorption.

Interleukin-15 as a potential regulator of the innate immune response

Interleukin-15 (IL-15) is a newly-discovered cytokine that is produced by activated monocytes early in the course of the innate immune response. IL-15 is able to bind to components of the interleukin-2 receptor (IL-2R) despite the fact that it has no sequence homology with IL-2. IL-15 stimulates human natural killer cell proliferation, cytotoxicity, and cytokine production and can substitute for IL-2 under most conditions. In vitro studies indicate that monocyte-derived IL-15 may be an important determinant of IFN-gamma production by NK cells. In addition, IL-15 is able to promote the survival of natural killer cells under serum-free conditions. The IL-15 receptor is a heterotrimeric complex which is composed of the IL-2Rß and g chains in combination with a unique alpha chain (IL-15a). The IL-15Ra chain has strong sequence homology to the IL-2Ra chain and confers high affinity binding to the IL-15R. In contrast to IL-2, transcript for IL-15 and IL-15a is expressed in a number of tissues and indicates that IL-15 may be an important ligand for cells that express components of the IL-2R

Role of Th1 and Th2 cells in autoimmune demyelinating disease

Evidence is accumulating that Th1 cells play an important role in the development of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), whereas Th2 cells contribute to recovery from disease. A major determinant in the development of Th1 and Th2 cells is the type of antigen-presenting cell (APC) involved and its functional characteristics, e.g., the production of interleukin-12. Therefore, modulation of APC might interfere with the development of Th1 type responses and as such be beneficial for MS and EAE. The potential of cytokines, in particular interleukin-10, and glucocorticoids to exert a selective effect on APC, and as a consequence to affect the Th1-Th2 balance in EAE, is discussed

Relationship of cytokines and cytokine signaling to immunodeficiency disorders in the mouse

The contributions of cytokines to the development and progression of disease in a mouse model of retrovirus-induced immunodeficiency (MAIDS) are controversial. Some studies have indicated an etiologic role for type 2 cytokines, while others have emphasized the importance of type 1 cytokines. We have used mice deficient in expression of IL-4, IL-10, IL-4 and IL-10, IFN-g, or ICSBP - a transcriptional protein involved in IFN signaling - to examine their contributions to this disorder. Our results demonstrate that expression of type 2 cytokines is an epiphenomenon of infection and that IFN-g is a driving force in disease progression. In addition, exogenously administered IL-12 prevents many manifestations of disease while blocking retrovirus expression. Interruption of the IFN signaling pathways in ICSBP-/- mice blocks induction of MAIDS. Predictably, ICSBP-deficient mice exhibit impaired responses to challenge with several other viruses. This immunodeficiency is associated with impaired production of IFN-g and IL-12. Unexpectedly, however, the ICSBP-/- mice also develop a syndrome with many similarities to chronic myelogenous leukemia in humans. The chronic phase of this disease is followed by a fatal blast crisis characterized by clonal expansions of undifferentiated cells. ICSBP is thus an important determinant of hematopoietic growth and differentiation as well as a prominent signaling molecule for IFNs