Highly efficient, multigram and enantiopure synthesis of (S)-2-(2,4′-bithiazol-2-yl)pyrrolidine

(S)-2-(4-Bromo-2,4"-bithiazole)-1-(tert-butoxycarbonyl)pyrrolidine ((S)-1) was obtained as a single enantiomer and in high yield by means of a two-step modified Hantzsch thiazole synthesis reaction when bromoketone 3 and thioamide (S)-4 were used. Further conversion of (S)-1 into trimethyltin derivative (S)-2 broadens the scope for further cross-coupling reactions.

Electronic Data Interchange in Logistics Processes

Tämän diplomityön tarkoituksena oli tehdä selvitys EDI:in liittyvistä vaikutuksista, tarpeista ja eduista sekä valmistella Oracle Applications- toiminnanohjausjärjestelmän EDI Gateway- modulin ottamista tuotantokäyttöön. Tietoa tarvekartoitukseen saatiin keskustelujen avulla. Uusia kaupallisista lähtökohdista johdettuja, yritysten väliseen kaupankäyntiin ja internet-teknologian hyödyntämiseen kehitettyjä aloitteita käsiteltiin EDI-näkökulmasta tulevaisuutta varten. Ajankohtaisinta tietoa tätä diplomityötä varten löydettiin myös internetistä. Tämän jälkeen oli mahdollista toteuttaa sopivan laaja mutta rajattu EDI pilottiprojekti EDI-konseptin luomista varten. EDI:n vaikutuksiin ostossa keskityttiin tässä diplomityössä enemmän ja EDI:ä päätettiin soveltaa aluksi ostotilauksissa. EDI:n hyötyjä on vaikea mitata numeerisesti. Suurta määrää rahaa tai tuoteyksiköitä on käsiteltävä EDI-partnerin kanssa riittävän usein. EDI:n käyttöönottovaiheessa pääongelmat ovat sovelluksiin liittyviä tietotekniikkaongelmia. Selvityksistä ja EDI-projektista saatu tieto on mahdollista hyödyntää jatkokehityksessä. Lisätoimenpiteitä tarvitaan kokonaan toimivan järjestelmän luomiseksi.

Prosessihyötysuhteen parantamiskohteiden kartoitus painevesireaktorityyppisessä ydinvoimalaitoksessa

Työn tavoitteena on kartoittaa painevesireaktorityyppisen ydinvoimalaitoksen prosessihyötysuhteen parantamiskohteita. Aluksi kirjallisuudesta etsitään hyötysuhteen parantamiskeinoja ideaalisessa höyryvoimalaitosprosessissa. Näistä valitaan sopivimmat tarkastelun kohteeksi todellisessa voimalaitoksessa: syöttöveden esilämmityksen tehostaminen väliottohöyryvirtausta kasvattamalla ja syöttöveden esilämmittimen lämmönsiirtopintaa lisäämällä. Tarkastelussa pyritään löytämään paras mahdollinen hyötysuhde väliottohöyrylinjojen putkikokoa sekä esilämmittimien putkien lukumäärää muuttamalla. Diskreetin optimoinnin iteraatioaskel määritetään hyötysuhteen osittaisderivaattojen avulla. Tehtäviä muutoksia simuloidaan APROS-simulointiohjelmalla, jossa käytetään Loviisan voimalaitoksesta tehtyä mallia VVER-440. Työssä havaittiin, että pelkkiä väliottohöyrylinjojen putkikokoja – ja massavirtaa – kasvattamalla Loviisan voimalaitoksen hyötysuhdetta voidaan parantaa parhaimmillaan 32,75%:sta 32,85%:iin. Syöttöveden esilämmittimien lämmönsiirtopintaa lisäämällä saadaan suurempi parannus hyötysuhteeseen: 32,75%:sta 32,99%:iin. Näissä tapauksissa muutettiin kaikkia väliottohöyrylinjoja tai syöttöveden esilämmittimien lämpöpintoja. Työssä tarkasteltiin myös joitakin pienempiä muutoskohteita, joista paras hyötysuhteen kasvu saatiin korkeapaine-esilämmittimien lämmönsiirtopintaa kasvattamalla sekä toisen väliottohöyrylinjan (RD12) ja sitä vastaavan syöttöveden esilämmittimen muutosten yhteisvaikutuksena.

Kytkettyjen johdannaisten tunnistaminen, tilinpäätöskäsittely ja esiintyminen – IAS 39

Tutkielman tavoitteena oli tutkia IAS 39 -standardissa käsiteltyjen kytkettyjen johdannaisten tunnistamista, tilinpäätöskäsittelyä ja esiintymistä sekä verrata eroja IAS- ja US GAAP –standardien välillä tarkasteltaessa erotetaanko kytketty johdannainen pääsopimuksesta. Lisäksi tutkittiin kytkettyjen johdannaisten esiintymistä neljässä eri toimialan suomalaisessa pörssiyrityksessä. Tutkielmassa päädyttiin johtopäätökseen, että sopimuksen tavanomaiset taloudelliset piirteet ja riskit tulee ymmärtää, jotta pystytään tunnistamaan siihen liittyvä mahdollinen johdannainen. Merkittäviä periaatteellisia eroja IAS- ja US GAAP-standardien välillä ei ollut tarkasteltaessa erotetaanko kytketty johdannainen pääsopimuksesta. Kytketyt johdannaiset ovat vaikea osa-alue yrityksille sekä niiden käsittelymenetelmät ovat ainakin joissain määrin vielä avoimia. Käytännössä monet sopimukset sisältävät näitä johdannaisen kaltaisia ehtoja, vaikka niitä ei vielä olisikaan tunnistettu ja juuri tunnistamisen haastavuuden vuoksi kytketyt johdannaiset ovat luultua yleisempiä. Neljässä suomalaisessa pörssiyrityksessä tehtyjen haastattelujen perusteella kytkettyjä johdannaisia esiintynee erityisesti ulkomaankaupan osto- ja myyntisopimuksissa.

Self-expandable metal stents in the treatment of acute esophageal variceal bleeding.

Acute variceal bleeding (AVB) is a life-threatening complication in patients with cirrhosis. Hemostatic therapy of AVB includes early administration of vasoactive drugs that should be combined with endoscopic therapy, preferably banding ligation. However, failure to control bleeding or early rebleed within 5 days still occurs in 15-20% of patients with AVB. In these cases, a second endoscopic therapy may be attempted (mild bleeding in a hemodynamically stable patient) or we can use a balloon tamponade as a bridge to definitive derivative treatment (i.e., a transjugular intrahepatic portosystemic shunt). Esophageal balloon tamponade provides initial control in up to 80% of AVB, but it carries a high risk of major complications, especially in cases of long duration of tamponade (>24 h) and when tubes are inserted by inexperienced staff. Preliminary reports suggest that self-expandable covered esophageal metallic stents effectively control refractory AVB (i.e., ongoing bleeding despite pharmacological and endoscopic therapy or massive bleeding precluding endoscopic therapy) with a low incidence of complications. Thus, covered self-expanding metal stents may represent an alternative to the Sengstaken-Blakemore balloon for the temporary control of bleeding in treatment failures. Further studies are required to determine the role of this new device in AVB.

Short stature and primary ovarian insufficiency possibly due to chromosomal position effect in a balanced X;1 translocation.

BACKGROUND: Primary ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea), a decrease in the initial primordial follicle number, high follicle-stimulating hormone (FSH) levels and hypoestrogenism. Although the etiology of a majority of POI cases is not yet identified, several data suggest that POI has a strong genetic component. Conventional cytogenetic and molecular analyses have identified regions of the X chromosome that are associated with ovarian function, as well as POI candidate genes, such as FMR1 and DIAPH2. Here we describe a 10.5-year-old girl presenting with high FSH and luteinizing hormone (LH) levels, pathologic GH stimulation arginine and clonidine tests, short stature, pterygium, ovarian dysgenesis, hirsutism and POI. RESULTS: Cytogenetic analysis demonstrated a balanced reciprocal translocation between the q arms of chromosomes X and 1, with breakpoints falling in Xq21 and 1q41 bands. Molecular studies did not unravel any chromosome microdeletion/microduplication, and no XIST-mediated inactivation was found on the derivative chromosome 1. Interestingly, through immunofluorescence assays, we found that part of the Xq21q22 trait, translocated to chromosome 1q41, was late replicating and therefore possibly inactivated in 30 % metaphases both in lymphocytes and skin fibroblasts, in addition to a skewed 100 % inactivation of the normal X chromosome. These findings suggest that a dysregulation of gene expression might occur in this region. Two genes mapping to the Xq translocated region, namely DIAPH2 and FMR1, were found overexpressed if compared with controls. CONCLUSIONS: We report a case in which gonadal dysgenesis and POI are associated with over-expression of DIAPH2 gene and of FMR1 gene in wild type form. We hypothesize that this over-expression is possibly due to a phenomenon known as "chromosomal position effect", which accounts for gene expression variations depending on their localization within the nucleus. For the same effect a double mosaic inactivation of genes mapping to the Xq21-q22 region, demonstrated by immunofluorescence assays, may be the cause of a functional Xq partial monosomy leading to most Turner traits of the proband's phenotype.

Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.

In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.

Investigation and data adaptive analysis of CARS spectra

In this diploma work advantages of coherent anti-Stokes Raman scattering spectrometry (CARS) and various methods of the quantitative analysis of substance structure with its help are considered. The basic methods and concepts of the adaptive analysis are adduced. On the basis of these methods the algorithm of automatic measurement of a scattering strip size of a target component in CARS spectrum is developed. The algorithm uses known full spectrum of target substance and compares it with a CARS spectrum. The form of a differential spectrum is used as a feedback to control the accuracy of matching. To exclude the influence of a background in CARS spectra the differential spectrum is analysed by means of its second derivative. The algorithm is checked up on the simulated simple spectra and on the spectra of organic compounds received experimentally.

Very high-resolution digital elevation models: are multi-scale-derived variables ecologically relevant?

1. Digital elevation models (DEMs) are often used in landscape ecology to retrieve elevation or first derivative terrain attributes such as slope or aspect in the context of species distribution modelling. However, DEM-derived variables are scale-dependent and, given the increasing availability of very high-resolution (VHR) DEMs, their ecological relevancemust be assessed for different spatial resolutions. 2. In a study area located in the Swiss Western Alps, we computed VHR DEMs-derived variables related to morphometry, hydrology and solar radiation. Based on an original spatial resolution of 0.5 m, we generated DEM-derived variables at 1, 2 and 4 mspatial resolutions, applying a Gaussian Pyramid. Their associations with local climatic factors, measured by sensors (direct and ambient air temperature, air humidity and soil moisture) as well as ecological indicators derived fromspecies composition, were assessed with multivariate generalized linearmodels (GLM) andmixed models (GLMM). 3. Specific VHR DEM-derived variables showed significant associations with climatic factors. In addition to slope, aspect and curvature, the underused wetness and ruggedness indices modelledmeasured ambient humidity and soilmoisture, respectively. Remarkably, spatial resolution of VHR DEM-derived variables had a significant influence on models' strength, with coefficients of determination decreasing with coarser resolutions or showing a local optimumwith a 2 mresolution, depending on the variable considered. 4. These results support the relevance of using multi-scale DEM variables to provide surrogates for important climatic variables such as humidity, moisture and temperature, offering suitable alternatives to direct measurements for evolutionary ecology studies at a local scale.

MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study.

Diffuse large B-cell lymphoma (DLBCL) with MYC rearrangement (MYC-R) carries an unfavorable outcome. We explored the prognostic value of the MYC translocation partner gene in a series of MYC-R de novo DLBCL patients enrolled in first-line prospective clinical trials (Groupe d'Etudes des Lymphomes de l'Adulte/Lymphoma Study Association) and treated with rituximab-anthracycline-based chemotherapy. A total of 774 DLBCL cases characterized for cell of origin by the Hans classifier were analyzed using fluorescence in situ hybridization with BCL2, BCL6, MYC, immunoglobulin (IG)K, and IGL break-apart and IGH/MYC, IGK/MYC, and IGL/MYC fusion probes. MYC-R was observed in 51/574 (8.9%) evaluable DLBCL cases. MYC-R cases were predominantly of the germinal center B-cell-like subtype 37/51 (74%) with no distinctive morphologic and phenotypic features. Nineteen cases were MYC single-hit and 32 cases were MYC double-hit (MYC plus BCL2 and/or BCL6) DLBCL. MYC translocation partner was an IG gene in 24 cases (MYC-IG) and a non-IG gene (MYC-non-IG) in 26 of 50 evaluable cases. Noteworthy, MYC-IG patients had shorter overall survival (OS) (P = .0002) compared with MYC-negative patients, whereas no survival difference was observed between MYC-non-IG and MYC-negative patients. In multivariate analyses, MYC-IG predicted poor progression-free survival (P = .0051) and OS (P = .0006) independently from the International Prognostic Index and the Hans classifier. In conclusion, we show in this prospective randomized trial that the adverse prognostic impact of MYC-R is correlated to the MYC-IG translocation partner gene in DLBCL patients treated with immunochemotherapy. These results may have an important impact on the clinical management of DLBCL patients with MYC-R who should be routinely characterized according to MYC partner gene. These trials are individually registered at www.clinicaltrials.gov as #NCT00144807, #NCT01087424, #NCT00169143, #NCT00144755, #NCT00140660, #NCT00140595, and #NCT00135499.

Flexible Multibody Simulation Approach in the Dynamic Analysis of Bone Strains Activity

The objective of this study is to show that bone strains due to dynamic mechanical loading during physical activity can be analysed using the flexible multibody simulation approach. Strains within the bone tissue play a major role in bone (re)modeling. Based on previous studies, it has been shown that dynamic loading seems to be more important for bone (re)modeling than static loading. The finite element method has been used previously to assess bone strains. However, the finite element method may be limited to static analysis of bone strains due to the expensive computation required for dynamic analysis, especially for a biomechanical system consisting of several bodies. Further, in vivo implementation of strain gauges on the surfaces of bone has been used previously in order to quantify the mechanical loading environment of the skeleton. However, in vivo strain measurement requires invasive methodology, which is challenging and limited to certain regions of superficial bones only, such as the anterior surface of the tibia. In this study, an alternative numerical approach to analyzing in vivo strains, based on the flexible multibody simulation approach, is proposed. In order to investigate the reliability of the proposed approach, three 3-dimensional musculoskeletal models where the right tibia is assumed to be flexible, are used as demonstration examples. The models are employed in a forward dynamics simulation in order to predict the tibial strains during walking on a level exercise. The flexible tibial model is developed using the actual geometry of the subject’s tibia, which is obtained from 3 dimensional reconstruction of Magnetic Resonance Images. Inverse dynamics simulation based on motion capture data obtained from walking at a constant velocity is used to calculate the desired contraction trajectory for each muscle. In the forward dynamics simulation, a proportional derivative servo controller is used to calculate each muscle force required to reproduce the motion, based on the desired muscle contraction trajectory obtained from the inverse dynamics simulation. Experimental measurements are used to verify the models and check the accuracy of the models in replicating the realistic mechanical loading environment measured from the walking test. The predicted strain results by the models show consistency with literature-based in vivo strain measurements. In conclusion, the non-invasive flexible multibody simulation approach may be used as a surrogate for experimental bone strain measurement, and thus be of use in detailed strain estimation of bones in different applications. Consequently, the information obtained from the present approach might be useful in clinical applications, including optimizing implant design and devising exercises to prevent bone fragility, accelerate fracture healing and reduce osteoporotic bone loss.

Drug-induced mitochondrial dysfunction and cardiotoxicity.

Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs [anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar)], antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics [e.g., rosiglitazone (Avandia)]. Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities.

Total synthesis of entecavir

Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron-aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl-catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction.

Peptide-decorated chitosan derivatives enhance fibroblast adhesion and proliferation in wound healing.

RGD peptide sequences are known to regulate cellular activities by interacting with α5β1, αvβ5 and αvβ3 integrin, which contributes to the wound healing process. In this study, RGDC peptide was immobilized onto chitosan derivative 1,6-diaminohexane-O-carboxymethyl-N,N,N-trimethyl chitosan (DAH-CMTMC) to display RGDC-promoting adhesion for enhanced wound healing. The efficiency of N-methylation, O-carboxymethylation and spacer grafting was quantitatively and qualitatively analyzed by (1)H NMR and FTIR, yielding 0.38 degree of substitution for N-methylation and >0.85 for O-carboxymethylation. The glass transition temperatures for chitosan derivatives were also studied. Peptide immobilization was achieved through sulfhydryl groups using sulfosuccinimidyl (4-iodoacetyl)amino-benzoate (sulfo-SIAB method). RGDC immobilized peptide onto DAH-CMTMC was found to be about 15.3μg/mg of chitosan derivative by amino acid analysis (AAA). The significant increase of human dermal fibroblast (HDF) viability in vitro over 7 days suggests that RGDC-functionalized chitosan may lead to enhanced wound healing (viability >140%). Moreover, bio-adhesion and proliferation assays confirmed that coatings of RGDC-functionalized chitosan derivatives exhibit in vitro wound healing properties by enhancing fibroblast proliferation and adhesion. These results showed that RGDC peptide-functionalized chitosan provides an optimal environment for fibroblast adhesion and proliferation.

Determination of Rod and Cone Influence to the Early and Late Dynamic of the Pupillary Light Response.

PURPOSE: This study aims to identify which aspects of the pupil light reflex are most influenced by rods and cones independently by analyzing pupil recordings from different mouse models of photoreceptor deficiency. METHODS: One-month-old wild type (WT), rodless (Rho-/-), coneless (Cnga3-/-), or photoreceptor less (Cnga3-/-; Rho-/- or Gnat1-/-) mice were subjected to brief red and blue light stimuli of increasing intensity. To describe the initial dynamic response to light, the maximal pupillary constriction amplitudes and the derivative curve of the first 3 seconds were determined. To estimate the postillumination phase, the constriction amplitude at 9.5 seconds after light termination was related to the maximal constriction amplitude. RESULTS: Rho-/- mice showed decreased constriction amplitude but more prolonged pupilloconstriction to all blue and red light stimuli compared to wild type mice. Cnga3-/- mice had constriction amplitudes similar to WT however following maximal constriction, the early and rapid dilation to low intensity blue light was decreased. To high intensity blue light, the Cnga3-/- mice demonstrated marked prolongation of the pupillary constriction. Cnga3-/-; Rho-/- mice had no pupil response to red light of low and medium intensity. CONCLUSIONS: From specific gene defective mouse models which selectively voided the rod or cone function, we determined that mouse rod photoreceptors are highly contributing to the pupil response to blue light stimuli but also to low and medium red stimuli. We also observed that cone cells mainly drive the partial rapid dilation of the initial response to low blue light stimuli. Thus photoreceptor dysfunction can be derived from chromatic pupillometry in mouse models.