The Future of Generic Biologics: Should the United States “Follow-On” the European Pathway?

The United States is embarking on a biotechnology drug revolution. In the last few decades, biotech drugs have saved millions of lives, and the market for these miracle cures continues to grow at an astronomical rate. Unfortunately, as the market for biotech drugs is skyrocketing, drug prices are following suit. As Congress strives to make these new drugs more affordable, it must not ignore significant safety concerns unique to these revolutionary therapies. Congress should follow the lead of the European Union to create an accessible pathway for generic forms of biotech drugs that includes strict regulatory measures to ensure drug safety and efficacy

Invasiivsed vähi võõrliigid ja nende ohustav mõju jõevähi (Astacus astacus L.) asurkondadele Eestis

A Thesis for application for the degree of Doctor of Philosophy in Agricultural SciencesOnce abundant, indigenous noble crayfish stocks in Europe have suffered from a long-term population decline due to the spread of North-American crayfish species. They are latent carriers of the crayfish plague agent Aphanomyces astaci, which is lethal to all European native crayfish species. Until 2008, Estonia was one of the last countries where alien crayfish species had not been recorded in the wild. Presently, two potential plague carriers – signal and spiny cheek crayfish - are present in Estonian rivers, and the marbled crayfish is available in the Estonian aquarium trade. The objectives of this thesis were: (i) to give an overview of the status and distribution of signal crayfish and its possible role in a series of crayfish plague outbreaks in the noble crayfish populations of Estonia; (ii) to estimate survival of the marbled crayfish in Estonian winter conditions and the effect of different feeds on survival, growth, reproduction, behaviour and carapace colouration; (iii) to develop a new set of microsatellite markers for the noble crayfish that also cross-amplify in the potentially invasive narrow-clawed crayfish. Since 2008, the signal crayfish has been recorded at four sites in Estonia, and has caused the extinction of noble crayfish populations at least at two sites. The dispersed pattern of the signal crayfish distribution indicates that these populations are the result of illegal human-assisted introductions. Crayfish plague outbreaks in noble crayfish populations are caused by different A. astaci genotype groups – A, B and E. This indicates that signal crayfish, or possibly other alien crayfish species, may have spread the crayfish plague. This study showed that marbled crayfish can survive in Estonian winter conditions and successfully reproduce later on. Different levels of astaxanthine and protein in feed have a significant effect on carapace colouration, growth rate and mortality of the marbled crayfish. The marbled crayfish has a good adaptability to different environmental conditions, reproduces parthenogenetically, and their spread to the natural environment must be strictly prevented. Using next generation sequencing technology, a set of 48 tetranucleotide repeat microsatellite markers for the noble crayfish were developed that partially cross-amplify in the narrow-clawed crayfish, and can be used for the detection of possible hybrids between these sister species with largely overlapping distribution areas.Kunagised külluslikud jõevähi varud on kõikjal Euroopas kahanenud. Selle põhjuseks on peamiselt Ameerikast pärit invasiivsete vähi võõrliikide levik, kuna olles ise immuunsed, kannavad nad edasi Euroopa vähiliikidele surmavat vähikatku tekitajat Aphanomyces astaci. Kuni 2008. aastani oli Eesti üks vähestest riikidest Euroopas, kus vähi võõrliike looduses ei esinenud. Praeguseks on Eesti loodusest leitud vähikatku kandvad signaal- ja ogapõskne vähk. Akvaariumikaubanduses levib potentsiaalselt ohtlik marmorvähk. Doktoritöö eesmärk on (i) anda ülevaade signaalvähi seisundist ja levikust ning tema võimalikust rollist hiljutistes vähikatku puhangutes Eestis; (ii) hinnata marmorvähi ellujäämust Eesti talvistes tingimustes ning eri söötade mõju tema kasvule, paljunemisele, käitumisele ja kesta värvusele; (iii) töötada välja uued mikrosatelliitmarkerid jõevähi ja Eesti naaberriikides leviva potentsiaalselt ohtliku vähi võõrliigi – kitsasõralise vähi geneetilisteks uuringuteks ja nende hübriidide usaldusväärseks tuvastamiseks. Alates 2008. aastast on signaalvähke leitud Eestis neljast veekogust ning kahest neist on jõevähk tänaseks kadunud. Signaalvähi leiukohtade hajusa paiknemise järgi võib arvata, et ta on Eestisse illegaalselt sisse toodud. Vähikatku puhangud jõevähi asurkondades on põhjustanud A. astaci A, B ja E genotüübigrupid, mis näitab, et katku levitab signaalvähk ja võimalik, et ka teised vähi võõrliigid. Katsed näitasid, et marmorvähk on võimeline ellu jääma Eesti talvistes kliimatingimustes ja anda seejärel edukalt järglasi. Erineva astaksantiini- ja proteiinisisaldusega söödad mõjutasid marmorvähkide kooriku värvust, kasvu ja suremust, mis näitab nende head kohanemis- ja paljunemisvõimet erinevates keskkonnatingimustes. Seetõttu tuleb vältida tema sattumist loodusesse. Doktoritöö käigus töötati välja 48 tetranukleotiidsete kordustega mikrosatelliitmarkerit jõevähile, mis osaliselt töötavad ka Eesti jaoks võõrliigil – kitsasõralisel vähil ning on seetõttu kasutatavad nende kahe liigi hübriidide usaldusväärseks tuvastamiseks piirkondades, kus nende leviala kattub

Tõendite uurimise tähendus Euroopa riikide kriminaalmenetlusõiguses

http://tartu.ester.ee/record=b2652827~S1*es

Interface-rich Aqueous Systems for Sustainable Chemical Synthesis

Mimicking an enzyme's exquisite activity and selectivity is a long-standing goal for sustainable chemical method development in aqueous media. The use of interface-rich aqueous systems, such as single-chain polymers, micelles and vesicle membranes recently emerged as strategy to emulate the compartmentalization of natural systems. In aqueous solution, aggregates such as micelles or microemulsion droplets are formed, providing reaction environments different from bulk solutions that frequently improve selectivity and accelerate reaction rates for a wide array of chemical transformations. We present here selected examples of interface-rich aqueous systems and discuss the advantages they offer for chemical synthesis. In particular metal-catalyzed cross-coupling reactions are highlighted and future challenges to perform reactions in interface-rich aqueous media are discussed

Effet thermoélectrique dans les métaux liquides sous champ magnétique.

Lorsqu'un champ magnétique est appliqué au cours de la solidification directionnelle, une convection dans la phase liquide peut être induite par l'effet thermoélectrique. En effet la présence d'un gradient de température le long du front de solidification peut provoquer la circulation du courant thermoélectrique, qui interagit avec le champ magnétique appliqué pour créer un écoulement (convection thermo électromagnétique-TEMC). Les conditions de transport de soluté et de l'énergie sont affectées par cette convection, donc il y a influence sur l'espacement des dendrites et la macro-ségrégation des composants de l'alliage. Dans ce travail, l'influence du champ magnétique sur la solidification directionnelle d'alliages métalliques est étudiée. Des travaux expérimentaux de la solidification directionnelle de Sn-Pb et Sn-Bi alliages sont réalisés. La solidification directionnelle dans la configuration Bridgman est effectuée avec ou sans champ magnétique appliqué. L'influence, sur la solidification, du champ magnétique et d'un courant électrique (AC et DC) appliqués est étudiée. Les mouvements du liquide provoquent de fortes macro-ségrégations ainsi qu'un modification des espacements interdendritiques. Les résultats expérimentaux sont interprétés à la lumière d'une modélisation heuristique. Le cas d'un champ magnétique tournant a été aussi étudié. Ainsi, la valeur de la rotation du champ est choisie pour ralentir assez brassage électromagnétique sans pour autant supprimer les effets de TEMC. À faible vitesse de tirage et faible vitesse de rotation faible champ une macro-ségrégation en forme de spirale a pu être obtenue.If magnetic field is applied during directional solidification, liquid phase convection can be induced by means of thermoelectromagnetic effect. Temperature gradient at the solidification front can cause thermoelectric current circulation, which then interacts with field and creates convection (Thermoelectromagnetic convection-TEMC). Solute and energy transport conditions are affected by this convection, thus it influences dendrite spacing and macrosegregation of the alloys. In this work magnetic field influence on the directional solidification of metallic alloys is studied. Experimental work of directional solidification of Sn-Pb and Sn-Bi alloys is done. Alloys are directionally solidified in Bridgman setup without or with applied magnetic field. Influence on the structure by magnetic field and applied electric current (AC and DC) is studied in this work. Analytical and experimental results are compared and interpreted. Bridgman solidification under rotating transverse magnetic field is studied as well, field rotation value is chosen to be slow enough that electromagnetic stirring does not fully suppress effects of TEMC. At low pulling velocity and low field rotation velocity spiral shaped component macrosegregation can be achieved.SAVOIE-SCD - Bib.électronique (730659901) / SudocGRENOBLE1/INP-Bib.électronique (384210012) / SudocGRENOBLE2/3-Bib.électronique (384219901) / SudocSudocFranceF

Directional solidification of metallic alloys and composites under electromagnetic interaction

In this work metallic alloys with particle inclusions has been directionally solidified under electromagnetic interaction. Applied magnetic field and electric current creates melt flow which has impact on solidification structure and properties of the alloy. There are various effects taking place under electromagnetic fields during solidification. For different materials different effects can be dominant. In this work aim is to investigate aluminum alloys. Test experiments using low temperature alloys are presented as well. Experimental results are explained by analytical and numerical models

Jõevähk ja teda ohustavad võõrvähiliigid

Levik. Jõevähi looduslik levila ulatub Loode-Venemaalt Atlandi ookeani rannikuni ja Vahemerest Põhja-Skandinaaviani. Inimene on tema levikut laiendanud, viies selle liigi näiteks ka Briti saartele, kus teda varem polnud. Nimele vaatamata esineb jõevähk nii jõgedes kui järvedes. Eestis on ta praegu ainus vähiliik.Liigi kirjeldus ja tunnused. Värvus enamasti punakaspruun, kuid võib olla ka beež, must või sinine. Sõrad on suured ja tugevad, eriti isastel. Tavaliselt on sõrad kehaga sama värvi ja pealt karedad. Altpoolt on need siledad ja pu na sed kuni mustjaspruunid (mitte kunagi valged, beežid, roosad ega heleoranžid). Sõrgade lõikeservad ei ole sirged, vaid seal on kaks väljaulatuvat oga. Seljakilp on sile, kuid erinevalt signaalvähist on pea ja rindmiku liitumisko hal kummalgi küljel terav naast. Tänu vähkide võimele heita ära mõni oma kehaosa enda elu päästmise eesmärgil, võime me kohata taastuvate sõrgadega jõevähke, kelle tagasi kasvav sõrg jääb aga eelmisest kitsamaks, õhemaks ja kergemaks, mis üldkujult meenutab hoopis kitsasõralise vähi sõrga.Jõevähi tähtsus. Jõevähk on oluline lüli veekogu aineringes. Ta hoiab veekogusid kinni kasvamast ning on toiduks paljudele veeorganismidele. Suure lihasaagise ja õhukese kooriku pärast eelistavad Euroopa tarbijad seda vähiliiki teistele ja seetõttu on tema turuhind ka kõrgem.Võõrliikide kahjulikkus ja ohud. Jõevähi väike viljakus (90–260 marjatera emasvähi kohta), aeglane kasv meie jahedas kliimas, tundlikkus keskkonnaseisundi ja haiguste suhtes teevad ta kergesti haavatavaks. Võõrad vähiliigid võivad saada jõevähile hukatuslikuks, kuna nad on viljakamad, agressiivsemad ning vastupidavamad nii haiguste kui raskete keskkonnatingimuste suhtes. Ameerika vähid on immuunsed vähikatku suhtes ning kannavad seda haigust edasi. Agressiivsemad Ameerika vähi isased paarituvad emase jõevähiga, kuid sellest ei sünni järglasi ning nii väheneb jõevähi arvukus. Eesti veekogudesse võivad võõrliigid sattuda nii tahtliku kui tahtmatu inimtegevuse läbi. Tundes erinevaid vähiliike, saame seda takistada.Seadused. Looduskaitseseaduse alusel on keelatud võõrliikide loodusesse laskmine. Lisaks on keelatud Eestisse sisse tuua signaalvähi, kitsasõralise vähi ja ogapõskse vähi elusaid isendeid

Verification of thermoelectric magnetohydrodynamic flow effects on dendritic tip kinetics by in-situ observations

Magnetohydrodynamic flows can be driven by Lorentz forces acting on thermoelectric currents. Their effects on tip velocities of Pd dendrites solidifying from an undercooled melt under magnetic field intensities of up to 6 T were investigated by in-situ observations using a high-speed camera. At low undercoolings, the tip velocities are depressed by magnetic fields of low and high intensities, but recover under an intermediate magnetic field intensity. At high undercoolings, the tip velocities are also depressed, but their recovery is shifted to a higher magnetic field intensity. These observations on Pd dendrites support and extend the findings obtained in previous studies on Ni and Fe dendrites, and fully verify the convection effects on dendritic growth due to three thermoelectric magnetohydrodynamic flow patterns as predicted in recent numerical simulations

Asymmetric diastereodivergent Michael addition of 2-chloromalonate esters to conjugated imines enabled by catalyst metal change

Despite recent progress in asymmetric diastereodivergent reactions leading to products bearing two stereogenic centers, little research has been devoted to processes were a stereogenic center and a double bond are formed. Here, we report the asymmetric diastereodivergent Michael addition of 2-chloromalonate esters to N-tosyl β,γ-unsaturated α-ketimino esters to give chiral α,β-dehydro-α-aminoesters bearing either a Z or E enamine moiety, using pyBOX-metal complexes. Diastereodivergency is achieved by simply changing the metal ion from a trivalent La(III) to a divalent Ca(II) ion, providing the Z or E enamines. Computational studies reveal the crucial role of London interactions between the aromatic residues on the imine and the pyBOX ligand, which are conditioned by the different coordination modes of La(III) and Ca(II), in the change of selectivity depending on the used metal

Analytic solutions to determine critical magnetic fields for thermoelectric magnetohydrodynamics in alloy solidification

During alloy solidification, it has been observed that the morphology of microstructures can be altered by applying an external DC magnetic field. This structural change can be attributed to solutal convective transport introduced by thermoelectric magnetohydrodynamics (TEMHD) which drives fluid motion within the inter-dendritic region. Complex numerical models with grid resolutions on the microscopic scale have been constructed to solve the equations governing TEMHD. To complement these computationally intensive numerical models, analytic solutions were sought. Specifically, the analytic solutions presented herein are asymptotic solutions derived for TEMHD under low and high magnetic field intensities. Combination of these asymptotic solutions leads to simple formulae for estimating critical magnetic fields which can be readily evaluated in terms of characteristic lengths of materials that have been identified in experiments as key parameters of critical fields. Indeed, the critical magnetic fields predicted with the asymptotic solutions exhibit magnitudes consistent with those applied in current ongoing experiments where significant changes in microstructure have been observed. The capability to predict accurate results indicates that the analytic solutions described herein are valuable precursors not only for detailed numerical simulations but also for experimental design to study critical magnetic fields in alloy solidification