Carbon isotope fractionation for cotton genotype selection

The objective of this work was to evaluate the carbon isotope fractionation as a phenomic facility for cotton selection in contrasting environments and to assess its relationship with yield components. The experiments were carried out in a randomized block design, with four replicates, in the municipalities of Santa Helena de Goiás (SHGO) and Montividiu (MONT), in the state of Goiás, Brazil. The analysis of carbon isotope discrimination (Δ) was performed in 15 breeding lines and three cultivars. Subsequently, the root growth kinetic and root system architecture from the selected genotypes were determined. In both locations, Δ analyses were suitable to discriminate cotton genotypes. There was a positive correlation between Δ and seed-cotton yield in SHGO, where water deficit was more severe. In this site, the negative correlations found between Δ and fiber percentage indicate an integrative effect of gas exchange on Δ and its association with yield components. As for root robustness and growth kinetic, the GO 05 809 genotype performance contributes to sustain the highest values of Δ found in MONT, where edaphoclimatic conditions were more suitable for cotton. The use of Δ analysis as a phenomic facility can help to select cotton genotypes, in order to obtain plants with higher efficiency for gas exchange and water use.

Selection of the most informative morphoagronomic descriptors for cassava germplasm

The objective of this work was to select the most informative morphoagronomic descriptors for cassava (Manihot esculenta) germplasm and to evaluate the ability of different methods to select the descriptors. Ninety-five accessions were characterized using 51 morphoagronomic descriptors. Data were subjected to a multiple correspondence analysis (MCA), whose information was used in the following four methods of descriptor selection: reverse order of the descriptor for the pth factorial axis of the MCA (Jolliffe); sequential, multiple correspondence analysis (SMCA); mean of the contribution orders of the descriptor in the first three factorial axes (C3PA); and C3PA method weighted by the respective eigenvalues of the full analysis (C3PAWeig). The correlations between the dissimilarity matrix with all descriptors and the most informative descriptors were high and significant (0.75, 0.77, 0.83, and 0.84 for C3PAWeig, C3PA, SMCA, and Jolliffe, respectively). The less informative descriptors were discarded, considering those common among the selection methods and relevant for the breeding interests. Therefore, 32 morphoagronomic descriptors with correlation between the dissimilarity matrices (r=0.81) were selected, due to their high capacity to discriminate cassava germplasm and to their ability to maintain some preliminary agronomic traits, useful for the initial characterization of the germplasm.

egr-4, a target of EGFR signaling, is required for the formation of the brian primordial and head regeneration in planarians

During the regeneration of freshwater planarians, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/β-catenin and Hh signaling pathways in re-establishing anterior-posterior (AP) polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its AP identity are less well understood. Previous studies have described a role of Smed-egfr-3, a planarian epidermal growth factor receptor, in blastema growth and differentiation. Here, we identify Smed-egr-4, a zinc-finger transcription factor belonging to the early growth response gene family, as a putative downstream target of Smed-egfr-3. Smed-egr-4 is mainly expressed in the central nervous system and its silencing inhibits anterior regeneration without affecting the regeneration of posterior regions. Single and combinatorial RNA interference to target different elements of the Wnt/β-catenin pathway, together with expression analysis of brain- and anterior-specific markers, revealed that Smed-egr-4: (1) is expressed in two phases - an early Smed-egfr-3-independent phase and a late Smed-egfr-3-dependent phase; (2) is necessary for the differentiation of the brain primordia in the early stages of regeneration; and (3) that it appears to antagonize the activity of the Wnt/β-catenin pathway to allow head regeneration. These results suggest that a conserved EGFR/egr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the proper progression of head regeneration.

Competitiveness Survey of a Biofuel Power Plant

Työn tarkoituksena on tarkastella Euroopan siirtymätalousalueelta kotimaisen biopoltto-ainevoimalaitoksen kilpailukykyä potentiaalisimmiksi markkinakohteiksi arvioitujen nykyisten Eu-valtioiden osalta. Työ tehdään osana kokoluokaltaan 3,5 MWth/1,0 MWe pienvoimalaitoksen tuotekehityshanketta, joka on käynnistynyt Varkaudessa tämän vuoden maaliskuussa. Potentiaalisimpien siirtymätalousmaiden valintakriteereinä on käytetty aiempia tutkimuksia ja raportteja. Huomio keskitetään kiinteän biopolttoaineen resursseihin ja biopolttoaineisiin pohjautuvalle energiantuotannolle asetettuihin tavoitteisiin. Edellä mainittujen kriteerien pohjalta tarkasteltaviksi valittujen valtioiden osalta tehtiin tarkemmat kilpailukykyanalyysit, otettiin yhteyttä markkina-alueeltaalan ammattilaisiin ja kartoitettiin potentiaalisimmat markkinakohteet. Tavoitteena on arvioida varteenotettavin kilpailija kiinteisiin biopolttoaineisiin pohjautuvalle sähkön ja lämmön yhteistuotannolle, jonka perusteella laaditaan mallivoimalaitoksen kilpailukykyisen hinnan määrittämiseksi tiettyyn takaisinmaksuaikaan ja korkotekijään perustuen. Lopulta tehdään maakohtaisesti yhteenveto merkittävimmistä markkinapotentiaaliin vaikuttavista kilpailutekijöistä, arvioidaan potentiaalisin kohdemaa sekä esitetään mahdollinen investoinnin rahoitusvaihtoehto ja keinoja markkinoida tuotetta potentiaalisille asiakkaille.

Hes1 is a critical but context-dependent mediator of canonical Notch signaling in lymphocyte development and transformation.

Although canonical Notch signaling regulates multiple hematopoietic lineage decisions including T cell and marginal zone B cell fate specification, the downstream molecular mediators of Notch function are largely unknown. We showed here that conditional inactivation of Hes1, a well-characterized Notch target gene, in adult murine bone marrow (BM) cells severely impaired T cell development without affecting other Notch-dependent hematopoietic lineages such as marginal zone B cells. Competitive mixed BM chimeras, intrathymic transfer experiments, and in vitro culture of BM progenitors on Delta-like-expressing stromal cells further demonstrated that Hes1 is required for T cell lineage commitment, but dispensable for Notch-dependent thymocyte maturation through and beyond the beta selection checkpoint. Furthermore, our data strongly suggest that Hes1 is essential for the development and maintenance of Notch-induced T cell acute lymphoblastic leukemia. Collectively, our studies identify Hes1 as a critical but context-dependent mediator of canonical Notch signaling in the hematopoietic system.

Averting inflammation by targeting the cytokine environment.

Cytokines are key instigators and regulators of immune responses and therefore hold great potential as targets for new therapeutic strategies. However, the selection of which cytokines to target, and in particular the identification of which cytokines regulate the rate-limiting steps of disease pathways, is crucial to the success of such strategies. Moreover, balancing the need for ablating pathological inflammatory responses and simultaneously maintaining the ability to control infectious agents is a key consideration. Recent advances in our understanding of cytokine networks, as well as technical progress in blocking cytokines in vivo, are likely to be a source for new drugs that can control chronic inflammatory diseases.

The incidence and selection of multiple mating in plants.

Mating with more than one pollen donor, or polyandry, is common in land plants. In flowering plants, polyandry occurs when the pollen from different potential sires is distributed among the fruits of a single individual, or when pollen from more than one donor is deposited on the same stigma. Because polyandry typically leads to multiple paternity among or within fruits, it can be indirectly inferred on the basis of paternity analysis using molecular markers. A review of the literature indicates that polyandry is probably ubiquitous in plants except those that habitually self-fertilize, or that disperse their pollen in pollen packages, such as polyads or pollinia. Multiple mating may increase plants' female component by alleviating pollen limitation or by promoting competition among pollen grains from different potential sires. Accordingly, a number of traits have evolved that should promote polyandry at the flower level from the female's point of view, e.g. the prolongation of stigma receptivity or increases in stigma size. However, many floral traits, such as attractiveness, the physical manipulation of pollinators and pollen-dispensing mechanisms that lead to polyandrous pollination, have probably evolved in response to selection to promote male siring success in general, so that polyandry might often best be seen as a by-product of selection to enhance outcross siring success. In this sense, polyandry in plants is similar to geitonogamy (selfing caused by pollen transfer among flowers of the same plant), because both polyandry and geitonogamy probably result from selection to promote outcross siring success, although geitonogamy is almost always deleterious while polyandry in plants will seldom be so.

IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.

XIAP prevents apoptosis by binding to and inhibiting caspases, and this inhibition can be relieved by IAP antagonists, such as Smac/DIABLO. IAP antagonist compounds (IACs) have therefore been designed to inhibit XIAP to kill tumor cells. Because XIAP inhibits postmitochondrial caspases, caspase 8 inhibitors should not block killing by IACs. Instead, we show that apoptosis caused by an IAC is blocked by the caspase 8 inhibitor crmA and that IAP antagonists activate NF-kappaB signaling via inhibtion of cIAP1. In sensitive tumor lines, IAP antagonist induced NF-kappaB-stimulated production of TNFalpha that killed cells in an autocrine fashion. Inhibition of NF-kappaB reduced TNFalpha production, and blocking NF-kappaB activation or TNFalpha allowed tumor cells to survive IAC-induced apoptosis. Cells treated with an IAC, or those in which cIAP1 was deleted, became sensitive to apoptosis induced by exogenous TNFalpha, suggesting novel uses of these compounds in treating cancer.

Pulmonary embolism severity index and troponin testing for the selection of low-risk patients with acute symptomatic pulmonary embolism.

Summary Background: The combination of the Pulmonary Embolism Severity Index (PESI) and troponin testing could help physicians identify appropriate patients with acute pulmonary embolism (PE) for early hospital discharge. Methods: This prospective cohort study included a total of 567 patients from a single center registry with objectively confirmed acute symptomatic PE. On the basis of the PESI, each patient was classified into 1 of 5 classes (I to V). At the time of hospital admission, patients had troponin I (cTnI) levels measured. The endpoint of the study was all-cause mortality within 30 days after diagnosis. We calculated the mortality rates in 4 patient groups: group 1: PESI class I-II plus cTnI <0.1 ng mL(-1); group 2: PESI classes III-V plus cTnI <0.1 ng mL(-1); group 3: PESI classes I-II plus cTnI >/= 0.1 ng mL(-1); and group 4: PESI classes III-V plus cTnI >/= 0.1 ng mL(-1). Results: The study cohort had a 30-day mortality of 10% (95% confidence interval [CI], 7.6 to 12.5%). Mortality rates in the 4 groups were 1.3%, 14.2%, 0% and 15.4%, respectively. Compared to non-elevated cTnl, the low-risk PESI had a higher negative predictive value (NPV) (98.9% vs 90.8%) and negative likelihood ratio (NLR) (0.1 vs 0.9) for predicting mortality. The addition of non-elevated cTnI to low-risk PESI did not improve the NPV or the NLR compared to either test alone. Conclusions: Compared to cTnl testing, PESI classification more accurately identified patients with PE who are at low risk of all-cause death within 30-days of presentation.

Cross-scale analysis of the region effect on vascular plant species diversity in southern and northern European mountain ranges.

Background: The divergent glacial histories of southern and northern Europe affect present-day species diversity at coarse-grained scales in these two regions, but do these effects also penetrate to the more fine-grained scales of local communities?Methodology/Principal Findings: We carried out a cross-scale analysis to address this question for vascular plants in two mountain regions, the Alps in southern Europe and the Scandes in northern Europe, using environmentally paired vegetation plots in the two regions (n = 403 in each region) to quantify four diversity components: (i) total number of species occurring in a region (total gamma-diversity), (ii) number of species that could occur in a target plot after environmental filtering (habitat-specific gamma-diversity), (iii) pair-wise species compositional turnover between plots (plot-to-plot beta-diversity) and (iv) number of species present per plot (plot gamma-diversity). We found strong region effects on total gamma-diversity, habitat-specific gamma-diversity and plot-to-plot beta-diversity, with a greater diversity in the Alps even towards distances smaller than 50 m between plots. In contrast, there was a slightly greater plot alpha-diversity in the Scandes, but with a tendency towards contrasting region effects on high and low soil-acidity plots.Conclusions/Significance: We conclude that there are strong regional differences between coarse-grained (landscape- to regional-scale) diversity components of the flora in the Alps and the Scandes mountain ranges,but that these differences do not necessarily penetrate to the finest-grained (plot-scale) diversity component, at least not on acidic soils. Because different processes can lead to a similar pattern, we discuss the consistency of our results with Quaternary history and other divergent features between the two regions such as habitat connectivity, selection for vagility and environmental differences not accounted for in our analyses

Metsäteollisuuden prosessien suunnittelu simulointiympäristössä

Prosessisimulointiohjelmistojen käyttö on yleistynyt paperiteollisuuden prosessien kartoituksessa ja kyseiset ohjelmistot ovat jo pitkään olleet myös Pöyry Engineering Oy:n työkaluja prosessisuunnittelussa. Tämän työn tavoitteeksi määritettiin prosessisimulointiohjelmistojen käytön selvittäminen suomalaisissa paperitehtaissa sekä prosessisimuloinnin tulevaisuuden näkymien arviointi metsäteollisuuden suunnittelupalveluissa liiketoiminnan kehittämiseksi. Työn teoriaosassa selvitetään mm. seuraavia asioita: mitä prosessisimulointi on, miksi simuloidaan ja mitkä ovat simuloinnin hyödyt ja haasteet. Teoriaosassa esitellään yleisimmät käytössä olevat prosessisimulointiohjelmistot, simulointiprosessin eteneminen sekä prosessisimuloinnin tuotteistamisen vaatimuksia. Työn kokeellisessa osassa selvitettiin kyselyn avulla prosessisimulointiohjelmistojen käyttöä Suomen paperitehtaissa. Kysely lähetettiin kaikille Suomen tärkeimmille paperitehtaille. Kyselyn avulla selvitettiin mm, mitä ohjelmia käytetään, mitä on simuloitu, mitä pitää vielä simuloida ja kuinka tarpeellisena prosessisimulointia pidetään. Työntulokset osoittavat, että kaikilla kyselyyn vastanneilla suomalaisilla paperitehtailla on käytetty prosessisimulointia. Suurin osa simuloinneista on tehty konelinjoihin sekä massa- ja vesijärjestelmiin. Tulevaisuuden tärkeimpänä kohteena pidetään energiavirtojen simulointia. Simulointimallien pitkäjänteisessä hyödyntämisessä ja ylläpidossa on kehitettävää, jossa simulointipalvelujen hankkiminen palveluna on tehtaille todennäköisin vaihtoehto. Johtopäätöksenä on se, että tehtailla on tarvetta prosessisimuloinnille. Ilmapiiri on kyselytuloksien mukaan suotuisa ja simulointi nähdään tarpeellisena työkaluna. Prosessisimuloinnin markkinointia, erillispalvelutuotteen lisäksi, kannattaisi kehittää siten, että simulointimallin ylläpito jatkuisi projektin jälkeen lähipalveluna. Markkinointi pitäisi tehdä jo projektin alkuvaiheessa tai projektin aikana. Simulointiohjelmien kirjosta suunnittelutoimiston kannattaa valita simulointiohjelmistoja, jotka sopivat sille parhaiten. Erityistapauksissa muiden ohjelmien hankintaa kannattaa harkita asiakkaan toivomusten mukaisesti.

EPCM-toimitustapamallin kehittäminen Kvaerner Power Oy:n voimalaitostoimituksiin

Tämän diplomityön päämääränäoli laatia suunnitelma voimalaitoksen toimittamiseksi EPCM-toimitustavalla. Työn keskeisiksi tavoitteiksi asetettiin EPCM-toimitustapaan perustuvan toimitustapakonseptin muodostaminen, toimituksiin liittyvien terminologian selkeyttäminen ja harmonisointi sekä voimalaitoksen suhteellisen kustannusrakenteen laatiminen. Työssä tutkittiin voimalaitostoimituksissa tavanomaisesti käytettyjä sopimustyyppejä, kiinteähintaista sopimusta ja kustannusvoittolisäsopimusta sekä harvinaisemmin käytettyjä kattohinta- ja tavoitekustannussopimusta. Vallitsevat toimitustavat, EPC- ja EPCM-toimitustavat sekä monitoimittajatapa, esiteltiin ja niiden vahvuudet sekä heikkoudet selvitettiin. Projektin ominaisuuksilla, markkinoilla ja tilaajan kyvyllä, asiantuntemuksella sekä resursseilla todettiin olevan vaikutusta toimitustavan valintaan. Lisäksi tehtiin katsaus voimalaitostoimitusten kehitystrendeihin ja projektin riskienhallintaan. Voimalaitoksen laitosjärjestelmäjako kehitettiin ja sitä soveltamalla määritettiin voimalaitoksen suhteellinen kustannusrakenne. Kattilaitoksen osuus voimalaitoksen rakentamiskustannuksista todettiin merkittävimmäksi. Laitosjärjestelmien laitekustannusten havaittiin olevan korkeimmat. EPCM-toimitustapamalli kehitettiin teoriaosan pohjalta ja sen rakenne, organisaatio, sopimustyypit ja -suhteetsekä toimituksen riskien jako kuvattiin. Voimalaitoksen rakentamiskustannuksia vertailtiin eri toimitustavoilla ja EPCM-toimitustapamalli todettiin EPC-toimitustapaa edullisemmaksi.

Market Area Selection of aSawmill Machinery Manufacturer

Tämän diplomityön tavoitteena on kartoittaa suomalaisen sahakonevalmistaja Veisto Oy:n kannalta lähitulevaisuuden merkittävimmät markkina-alueet, joiden sahateollisuuteen tehdään lähivuosina eniten korkean teknologian investointeja. Markkina-alueiden valinnassa sovelletaan sekä numeerisiin tilastoihin että asiantuntijahaastatteluihin pohjautuvia ranking-menetelmiä. Työn ensimmäinen osa käsittelee kansainvälisten teollisten markkinoiden ominaispiirteitä ja niiden analysointia. Pääpaino on kuitenkin screening-menetelmillä, markkina-alueiden vertailumenetelmilläja päätöksenteon työkaluilla. Työn toisessa osassa keskitytään markkina-alueiden screeningiin, analysointiin ja maiden eri ominaisuuksien vertailuun. Päätöksentekomatriiseja hyödyntäen valitaan Veisto Oy:lle kolme tällä hetkellä houkuttelevinta markkina-aluetta, joita ovat Venäjä, USA:n kaakkoisosan Southern Yellow Pine -alue sekä Etelä-Amerikan suurimmat sahaajamaat (Brasilia, Argentiina ja Chile) yhtenä alueena. Valituilla alueilla on Veiston kannalta omat haasteensa: USA:ssa vahvat kotimaiset kilpailijat ja uusien referenssien saaminen, Venäjällä investointien epävarmuus ja markkina-alueen laajuuden tuoma monimuotoisuus sekä Etelä-Amerikassa vahvat ruotsalaiset kilpailijat sekä etenkin Brasilian osalta tuntuvat suojatullit.

Développement et validation d'une méthode de calcul indépendant des unités moniteur basée sur les simulations Monte Carlo pour la vérification des traitements IMRT

Résumé : La radiothérapie par modulation d'intensité (IMRT) est une technique de traitement qui utilise des faisceaux dont la fluence de rayonnement est modulée. L'IMRT, largement utilisée dans les pays industrialisés, permet d'atteindre une meilleure homogénéité de la dose à l'intérieur du volume cible et de réduire la dose aux organes à risque. Une méthode usuelle pour réaliser pratiquement la modulation des faisceaux est de sommer de petits faisceaux (segments) qui ont la même incidence. Cette technique est appelée IMRT step-and-shoot. Dans le contexte clinique, il est nécessaire de vérifier les plans de traitement des patients avant la première irradiation. Cette question n'est toujours pas résolue de manière satisfaisante. En effet, un calcul indépendant des unités moniteur (représentatif de la pondération des chaque segment) ne peut pas être réalisé pour les traitements IMRT step-and-shoot, car les poids des segments ne sont pas connus à priori, mais calculés au moment de la planification inverse. Par ailleurs, la vérification des plans de traitement par comparaison avec des mesures prend du temps et ne restitue pas la géométrie exacte du traitement. Dans ce travail, une méthode indépendante de calcul des plans de traitement IMRT step-and-shoot est décrite. Cette méthode est basée sur le code Monte Carlo EGSnrc/BEAMnrc, dont la modélisation de la tête de l'accélérateur linéaire a été validée dans une large gamme de situations. Les segments d'un plan de traitement IMRT sont simulés individuellement dans la géométrie exacte du traitement. Ensuite, les distributions de dose sont converties en dose absorbée dans l'eau par unité moniteur. La dose totale du traitement dans chaque élément de volume du patient (voxel) peut être exprimée comme une équation matricielle linéaire des unités moniteur et de la dose par unité moniteur de chacun des faisceaux. La résolution de cette équation est effectuée par l'inversion d'une matrice à l'aide de l'algorithme dit Non-Negative Least Square fit (NNLS). L'ensemble des voxels contenus dans le volume patient ne pouvant être utilisés dans le calcul pour des raisons de limitations informatiques, plusieurs possibilités de sélection ont été testées. Le meilleur choix consiste à utiliser les voxels contenus dans le Volume Cible de Planification (PTV). La méthode proposée dans ce travail a été testée avec huit cas cliniques représentatifs des traitements habituels de radiothérapie. Les unités moniteur obtenues conduisent à des distributions de dose globale cliniquement équivalentes à celles issues du logiciel de planification des traitements. Ainsi, cette méthode indépendante de calcul des unités moniteur pour l'IMRT step-andshootest validée pour une utilisation clinique. Par analogie, il serait possible d'envisager d'appliquer une méthode similaire pour d'autres modalités de traitement comme par exemple la tomothérapie. Abstract : Intensity Modulated RadioTherapy (IMRT) is a treatment technique that uses modulated beam fluence. IMRT is now widespread in more advanced countries, due to its improvement of dose conformation around target volume, and its ability to lower doses to organs at risk in complex clinical cases. One way to carry out beam modulation is to sum smaller beams (beamlets) with the same incidence. This technique is called step-and-shoot IMRT. In a clinical context, it is necessary to verify treatment plans before the first irradiation. IMRT Plan verification is still an issue for this technique. Independent monitor unit calculation (representative of the weight of each beamlet) can indeed not be performed for IMRT step-and-shoot, because beamlet weights are not known a priori, but calculated by inverse planning. Besides, treatment plan verification by comparison with measured data is time consuming and performed in a simple geometry, usually in a cubic water phantom with all machine angles set to zero. In this work, an independent method for monitor unit calculation for step-and-shoot IMRT is described. This method is based on the Monte Carlo code EGSnrc/BEAMnrc. The Monte Carlo model of the head of the linear accelerator is validated by comparison of simulated and measured dose distributions in a large range of situations. The beamlets of an IMRT treatment plan are calculated individually by Monte Carlo, in the exact geometry of the treatment. Then, the dose distributions of the beamlets are converted in absorbed dose to water per monitor unit. The dose of the whole treatment in each volume element (voxel) can be expressed through a linear matrix equation of the monitor units and dose per monitor unit of every beamlets. This equation is solved by a Non-Negative Least Sqvare fif algorithm (NNLS). However, not every voxels inside the patient volume can be used in order to solve this equation, because of computer limitations. Several ways of voxel selection have been tested and the best choice consists in using voxels inside the Planning Target Volume (PTV). The method presented in this work was tested with eight clinical cases, which were representative of usual radiotherapy treatments. The monitor units obtained lead to clinically equivalent global dose distributions. Thus, this independent monitor unit calculation method for step-and-shoot IMRT is validated and can therefore be used in a clinical routine. It would be possible to consider applying a similar method for other treatment modalities, such as for instance tomotherapy or volumetric modulated arc therapy.

Synthesis and multi-target biological profiling of a novel family of rhein derivatives as disease-modifying anti-Alzheimer agents

We have synthesized a family of rheinhuprine hybrids to hit several key targets for Alzheimer"s disease. Biological screening performed in vitro and in Escherichia coli cells has shown that these hybrids exhibit potent inhibitory activities against human acetylcholinesterase butyrylcholinesterase, and BACE-1, dual Aβ42 and tau anti-aggregating activity, and brain permeability. Ex vivo studies with the leads (+)- and ()-7e in brain slices of C57bl6 mice have revealed that they efficiently protect against the Aβ-induced synaptic dysfunction , preventing the loss of synaptic proteins and/or have a positive effect on the induction of long term potentiation. In vivo studies in APP-PS1 transgenic mice treated i.p. for 4 weeks with (+)- and ()-7e have shown a central soluble Aβ lowering effect, accompanied by an increase in the levels of mature amyloid precursor protein (APP). Thus, (+)- and ()-7e emerge as very promising disease-modifying anti-Alzheimer drug candidates.