Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties

A central feature of drugs of abuse is to induce gene expression in discrete brain structures that are critically involved in behavioral responses related to addictive processes. Although extracellular signal-regulated kinase (ERK) has been implicated in several neurobiological processes, including neuronal plasticity, its role in drug addiction remains poorly understood. This study was designed to analyze the activation of ERK by cocaine, its involvement in cocaine-induced early and long-term behavioral effects, as well as in gene expression. We show, by immunocytochemistry, that acute cocaine administration activates ERK throughout the striatum, rapidly but transiently. This activation was blocked when SCH 23390 [a specific dopamine (DA)-D1 antagonist] but not raclopride (a DA-D2 antagonist) was injected before cocaine. Glutamate receptors of NMDA subtypes also participated in ERK activation, as shown after injection of the NMDA receptor antagonist MK 801. The systemic injection of SL327, a selective inhibitor of the ERK kinase MEK, before cocaine, abolished the cocaine-induced ERK activation and decreased cocaine-induced hyperlocomotion, indicating a role of this pathway in events underlying early behavioral responses. Moreover, the rewarding effects of cocaine were abolished by SL327 in the place-conditioning paradigm. Because SL327 antagonized cocaine-induced c-fos expression and Elk-1 hyperphosphorylation, we suggest that the ERK intracellular signaling cascade is also involved in the prime burst of gene expression underlying long-term behavioral changes induced by cocaine. Altogether, these results reveal a new mechanism to explain behavioral responses of cocaine related to its addictive properties.

Angiotensin II antagonists DuP 753 and TCV 116.

BACKGROUND: Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve haemodynamics in some patients with congestive heart failure. It is now possible to chronically antagonize angiotensin II at its receptor using non-peptide angiotensin II inhibitors such as losartan (DuP 753/MK-954) or TCV 116. EFFECT OF NON-PEPTIDE ANGIOTENSIN II ANTAGONISTS: When administered by mouth, DuP 753 and TCV 116 induce dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the corresponding active metabolites E3174 and CV11974. Preliminary studies performed in hypertensive patients suggest that losartan lowers blood pressure to an equivalent extent to an angiotensin converting enzyme (ACE) inhibitor. CONCLUSIONS: Further investigation is required to show whether these new angiotensin II antagonists compounds compare favourably with ACE inhibitors.

Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype.

PURPOSE: To investigate the prognostic value of various cytogenetic components of a complex karyotype in acute myeloid leukemia (AML). PATIENTS AND METHODS: Cytogenetics and overall survival (OS) were analyzed in 1,975 AML patients age 15 to 60 years. RESULTS: Besides AML with normal cytogenetics (CN) and core binding factor (CBF) abnormalities, we distinguished 733 patients with cytogenetic abnormalities. Among the latter subgroup, loss of a single chromosome (n = 109) conferred negative prognostic impact (4-year OS, 12%; poor outcome). Loss of chromosome 7 was most common, but outcome of AML patients with single monosomy -7 (n = 63; 4-year OS, 13%) and other single autosomal monosomies (n = 46; 4-year OS, 12%) did not differ. Structural chromosomal abnormalities influenced prognosis only in association with a single autosomal monosomy (4-year OS, 4% for very poor v 24% for poor). We derived a monosomal karyotype (MK) as a predictor for very poor prognosis of AML that refers to two or more distinct autosomal chromosome monosomies (n = 116; 4-year OS, 3%) or one single autosomal monosomy in the presence of structural abnormalities (n = 68; 4-year OS, 4%). In direct comparisons, MK provides significantly better prognostic prediction than the traditionally defined complex karyotype, which considers any three or more or five or more clonal cytogenetic abnormalities, and also than various individual specific cytogenetic abnormalities (eg, del[5q], inv[3]/t[3;3]) associated with very poor outcome. CONCLUSION: MK enables (in addition to CN and CBF) the prognostic classification of two new aggregates of cytogenetically abnormal AML, the unfavorable risk MK-negative category (4-year OS, 26% +/- 2%) and the highly unfavorable risk MK-positive category (4-year OS, 4% +/- 1%).

Nucleation in supersaturated solutions 3He in 4He at negative pressure.

Depending on the 3He concentration, thermal nucleation in 3-4He supersaturated liquid mixtures at negative pressures may be originated either by bubble or by 3rich drop formation. We have investigated this phenomenon within a density-functional approach, determining the regions in the pressure¿3He-concentration plane where bubbles or drops likely drive the nucleation process. As an illustrative example, we also give the homogeneous nucleation pressure corresponding to 50 and 100 mK temperature.

Quadratic tranverse anisotropy term due to dislocations in Mn12 acetate crystals directly observed by EPR spectroscopy

High-sensitivity electron paramagnetic resonance experiments have been carried out in fresh and stressed Mn12 acetate single crystals for frequencies ranging from 40 GHz up to 110 GHz. The high number of crystal dislocations formed in the stressing process introduces a E(Sx2-Sy2) transverse anisotropy term in the spin Hamiltonian. From the behavior of the resonant absorptions on the applied transverse magnetic field we have obtained an average value for E=22 mK, corresponding to a concentration of dislocations per unit cell of c=10-3.

Odorant Receptor (Or) genes: polymorphism and divergence in the D. melanogaster and D. pseudoobscura Lineages

Background: In insects, like in most invertebrates, olfaction is the principal sensory modality, which provides animals with essential information for survival and reproduction. Odorant receptors are involved in this response, mediating interactions between an individual and its environment, as well as between individuals of the same or different species. The adaptive importance of odorant receptors renders them good candidates for having their variation shaped by natural selection. Methodology/Principal Findings: We analyzed nucleotide variation in a subset of eight Or genes located on the 3L chromosomal arm of Drosophila melanogaster in a derived population of this species and also in a population of Drosophila pseudoobscura. Some heterogeneity in the silent polymorphism to divergence ratio was detected in the D. melanogaster/D. simulans comparison, with a single gene (Or67b) contributing ~37% to the test statistic. However, no other signals of a very recent selective event were detected at this gene. In contrast, at the speciation timescale, the MK test uncovered the footprint of positive selection driving the evolution of two of the encoded proteins in both D. melanogaster ¿OR65c and OR67a ¿and D. pseudoobscura ¿OR65b1 and OR67c. Conclusions: The powerful polymorphism/divergence approach provided evidence for adaptive evolution at a rather high proportion of the Or genes studied after relatively recent speciation events. It did not provide, however, clear evidence for very recent selective events in either D. melanogaster or D. pseudoobscura.

Task 6: Material Thermal Input for Iowa Materials, May 2008

The present research project was designed to determine thermal properties, such as coefficient of thermal expansion (CTE) and thermal conductivity, of Iowa concrete pavement materials. These properties are required as input values by the Mechanistic-Empirical Pavement Design Guide (MEPDG). In this project, a literature review was conducted to determine the factors that affect thermal properties of concrete and the existing prediction equations for CTE and thermal conductivity of concrete. CTE tests were performed on various lab and field samples of portland cement concrete (PCC) at the Iowa Department of Transportation and Iowa State University. The variations due to the test procedure, the equipment used, and the consistency of field batch materials were evaluated. The test results showed that the CTE variations due to test procedure and batch consistency were less than 5%, and the variation due to the different equipment was less than 15%. Concrete CTE values were significantly affected by different types of coarse aggregate. The CTE values of Iowa concrete made with limestone+graval, quartzite, dolomite, limestone+dolomite, and limestone were 7.27, 6.86, 6.68, 5.83, and 5.69 microstrain/oF (13.08, 12.35, 12.03, 10.50, and 10.25 microstrain/oC), respectively, which were all higher than the default value of 5.50 microstrain/oF in the MEPDG program. The thermal conductivity of a typical Iowa PCC mix and an asphalt cement concrete (ACC) mix (both with limestone as coarse aggregate) were tested at Concrete Technology Laboratory in Skokie, Illinois. The thermal conductivity was 0.77 Btu/hr•ft•oF (1.33 W/m•K) for PCC and 1.21 Btu/hr•ft•oF (2.09 W/m•K) for ACC, which are different from the default values (1.25 Btu/hr•ft•oF or 2.16 W/m•K for PCC and 0.67 Btu/hr•ft•oF or 1.16 W/m•K for ACC) in the MEPDG program. The investigations onto the CTE of ACC and the effects of concrete materials (such as cementitious material and aggregate types) and mix proportions on concrete thermal conductivity are recommended to be considered in future studies.

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

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Référence bibliographique : Weigert, 51a

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

Lack of the alanine-serine-cysteine transporter 1 causes tremors, seizures, and early postnatal death in mice.

The Na(+)-independent alanine-serine-cysteine transporter 1 (Asc-1) is exclusively expressed in neuronal structures throughout the central nervous system (CNS). Asc-1 transports small neutral amino acids with high affinity especially for D-serine and glycine (K(i): 8-12 microM), two endogenous glutamate co-agonists that activate N-methyl-D-aspartate (NMDA) receptors through interacting with the strychnine-insensitive glycine binding-site. By regulating D-serine (and possibly glycine) levels in the synaptic cleft, Asc-1 may play an important role in controlling neuronal excitability. We generated asc-1 gene knockout (asc-1(-/-)) mice to test this hypothesis. Behavioral phenotyping combined with electroencephalogram (EEG) recordings revealed that asc-1(-/-) mice developed tremors, ataxia, and seizures that resulted in early postnatal death. Both tremors and seizures were reduced by the NMDA receptor antagonist MK-801. Extracellular recordings from asc-1(-/-) brain slices indicated that the spontaneous seizure activity did not originate in the hippocampus, although, in this region, a relative increase in evoked synaptic responses was observed under nominal Mg(2+)-free conditions. Taken together with the known neurochemistry and neuronal distribution of the Asc-1 transporter, these results indicate that the mechanism underlying the behavioral hyperexcitability in mutant mice is likely due to overactivation of NMDA receptors, presumably resulting from elevated extracellular D-serine. Our study provides the first evidence to support the notion that Asc-1 transporter plays a critical role in regulating neuronal excitability, and indicate that the transporter is vital for normal CNS function and essential to postnatal survival of mice.

Angiotensin II antagonists.

Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve hemodynamics in some patients with congestive heart failure. It is now possible to antagonize chronically angiotensin II at its receptor using the non-peptide angiotensin II inhibitor losartan (DuP 753, MK 954). When administered by mouth, this compound induces a dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the active metabolite E3174. Preliminary studies performed in hypertensive patients suggest that losartan has a blood pressure lowering action equivalent to that of an ACE inhibitor. Whether this compound will compare favorably with ACE inhibitors requires however further investigation.

Evaluation of Metakaolin for HPC Deck Overlays, MLR-11-01, 2011

The use of High Performance Concrete (HPC) in Iowa has consisted of achieving slightly higher compressive strengths with an emphasis on reduced permeability. Concrete with reduced permeability has increased durability by slowing moisture and chloride ingress. Achieving reduced permeability has typically been accomplished with combinations of slag and Class C fly ash, or the use of blended cements such as locally available Type IS(20), IS(25) and Type IP(25) in conjunction with Class C fly ash. Fly ash has been used in the majority of concrete placed in Iowa since 1984 and slag has been available in Iowa since 1995. During the economic downturn in 2008, one of the cement plants that produced a Type IS(25) cement was forced to shut down, which reduced the availability of blended cements, typically used on HPC deck overlays. Recently, a source of high reactivity metakaolin has been made available. Metakaolin is produced by heating a pure kaolinite clay to 650 to 700 °C in a rotary kiln (calcining). Metakaolin is a white pozzolan that is used to produce concrete with increased strengths, reduced permeability, reduced efflorescence, and resistance to alkali silica reactivity. The W.R. Grace MK-100 metakaolin will likely be available in dissolvable bags between 25 and 50 pounds. Thus, the mix designs were based on the anticipated bag size range for field use. This research evaluated metakaolin mixes with and without Class C fly ash. Results indicated a seven percent replacement with metakaolin produced concrete with increased strengths and low permeability. When used with Class C fly ash, permeability is reduced to very low rating. Metakaolin may be used to enhance hardened concrete properties for use in high performance concrete (HPC).

ORC-voimalan soveltuvuus hyödyntämään dieselvoimalan hukkalämpöä, Tekes DrNo 1549/401/98. Loppuraportti

Tässä loppuraportissa esitetään projektin "Kannattavuusanalyysi ORC-voimalan soveltamisesta hyödyntämään dieselvoimalan hukkalämpöä, Tekes DrNo 1549/401/98" tulokset. ORC-prosessilla (Organic Rankine Cycle) tarkoitetaan Rankine-prosessia, jossakiertoaineena veden asemesta on sopiva orgaaninen neste, esimerkiksi tolueeni. ORC-prosessi soveltuu hyvin nimenomaan matalalla lämpötilatasolla vapautuvan hukkalämmön hyödyntämiseen. Tutkimus liittyy vuonna 1981 aloitettuun suurnopeustekniikan tutkimushankkeeseen. Tutkimuksen lähtökohtana oli tropiikin olosuhteissa peruskuormaa ajava raskasöljykäyttöinen Wärtsilä NSD 18V46 voimalaitosmoottori, jonka hukkalämmöistä tuli kyetä tuottamaan sähköä mahdollisimman alhaisilla investointikustannuksilla. Kaukolämmöntuotanto rajattiin tämän selvityksen ulkopuolelle. Edullisimmaksi perustapaukseksi valittiin seitsemän turbogeneraattorin ORC-laitos, joka hyödyntää ainoastaan moottorin pakokaasulämpöä. Kyseisen ORC-laitoksen nettosähköteho on 1142 kW, joten se lisäisi dieselmoottorin tehoa 6,8 %. ORC-laitoksen myyntihinta olisi noin 7,67 Mmk, mikäli lauhdutin voidaan rakentaa ruostumattomasta teräksestä ja noin 9,01 Mmk, mikäli olisi käytettävä titaanilauhdutinta. ORC-laitoksen ominaisinvestointikustannus olisi siten noin 6700 mk/kW - 7900 mk/kW materiaalivalinnoista riippuen. Mainittu hinta sisältää sekä komponenttien valmistajien että systeemi-integraattorin katteet. Koska höyrystimen hinta vaikuttaa olennaisesti ORC-laitoksen hintaan, voidaan puhtailla maakaasupolton savukaasuilla arvioida ominaisinvestoinnin olevan noin 1000 mk/kW alhaisempi. Olettaen 6000 h/a huipun käyttöaika saadaan ORC:llä tuotetun sähkön hinnaksi noin 0,11 mk/kWh. Suomeen rakennettavalle ORC-laitokselle on todennäköisesti lisäksi saatavissa 30 % investointituki ja sähköveron palautus. - Teoriassa voidaan osoittaa, että dieselmoottorin tehoa voidaan ORC:llä lisätä jopa 18 %, mutta ominaisinvestointi on tällöin merkittävästi korkeampi. ORC-laitoksen turbiinin 1D suunnittelua tarkennettiin sekä laitoksen turbiini mallinnettiin CFD-laskennan (numeerisen virtauslaskennan) avulla osana tätä tutkimusta. Näin kyettiin nostamaan turbiinin hyötysuhdetta, ja CFD-laskennan perusteella voidaan nyt aikaisempaa varmemmin ennustaa turbiinin todellinen hyötysuhde. ORC-laitoksen dynaaminen simulointiohjelma saatiin niin ikään valmiiksi tämän projektin puitteissa. Simulointiohjelman avulla voitiin asettaa laitoksen säädinparametrit sekä simuloida voimalan käynnistys-, ajo- sekä häiriötilanteita. Tehtyjen simulointien perusteella tehtiin johtopäätökset laitoksen säätöjärjestelmän toimivuudesta ja tuorehöyryn tilaarvojen valinnasta.

Metsäteollisuuden lietteiden bioterminen kuivaus

Työssä tarkastellaan kompostointiin perustuvaa biotermistä kuivausprosessia, prosessiin vaikuttavia tekijöitä sekä sen soveltuvuutta metsäteollisuuden mekaanisesti kuivatun jätevesilietteen lisäkuivaukseen polttoa varten. Tutkimukseen kuuluvien paperitehtaiden lietteillä suoritettavien biotermisten kuivauskokeiden avulla tutkitaan tehtaiden lietteiden sopivuutta biotermiseen kuivaukseen. Lisäksi tehtaille suunnitellaan kuivauskokeiden ja paperitehtailla tehtävien selvitysten perusteella bioterminen kuivauslaitos. Suomen metsäteollisuus tuottaa nykyisin noin 400 000 – 500 000 kuiva-ainetonnia jätevedenpuhdistamolietteitä vuosittain. Tutkimukseen kuuluvan kahden tehdasintegraatin biologisilla puhdistamoilla syntyvien jätevesilietteiden määrät ovat keskimäärin 33 000 ja 15 000 kuiva-ainetonnia vuodessa. Ongelmana metsäteollisuudessa on jätevesilietteen alhainen kuiva-ainepitoisuus lietteen mekaanisen kuivauksen jälkeen. Tämä vaikeuttaa lietteen polttamista voimalaitoskattilassa ja lietteen poltosta talteen saatavan energian määrä jää vähäiseksi. Mekaanisesti kuivatun sekalietteen käsittely biotermisesti kuivaamalla mahdollistaa lietteen kuiva-ainepitoisuuden nostamisen yli 55 %:in kuiva-ainepitoisuuteen. Tämä helpottaa lietteen polton ongelmia ja kasvattaa lietteen poltosta talteen saatavan energian määrää. Bioterminen kuivaus soveltuu hyvin tutkimukseen kuuluvien tehtaiden sekalietteen kuivaukseen. Suositeltava sekalietteen lähtökuiva-ainepitoisuuden arvo on välillä 30 – 35 % ja tukiaineeksi lisättävän kuoren määrä noin 0,5 m3 yhtä lietekuutiota kohden. Kuivausprosessin kesto on tällöin 10 – 14 vuorokautta, kun haluttu lietepolttoaineen kuiva-ainepitoisuus on vähintään 55 %. Tehtaille suunnitelluissa laitoksissa käsiteltävä lietemäärä on noin 40 000 märkätonnia vuodessa. Tutkimukseen kuuluvalle paperitehtaalle yhdistetyn lietteenkuivausprosessin kustannukset ovat edullisimmat kun liete kuivataan ennen biotermistä kuivausta mekaanisesti 35 %:in kuiva-ainepitoisuuteen. Tällöin lietteenkäsittelyn hinnaksi tulee noin 150 mk/t.