Spelling suggestions: "subject:"erowth inhibition"" "subject:"frowth inhibition""
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Combined effects of bioavailable organic contaminants in the aquatic environmentEmelogu, Emmanuel Steven January 2013 (has links)
Passive sampling, as opposed to the conventional spot or bottle water sampling technique, has shown to be reliable and efficient in monitoring the toxicologically relevant, freely dissolved (e.g. bioavaialable) concentrations of a wide range of organic contaminants in water. At the same time, partitioning controlled delivery (passive dosing; PD) techniques promise to overcome many of the challenges associated with toxicity testing of hydrophobic substances that may bias the interpretation of toxicity data. The present study investigated the feasibility of coupling silicone rubber passive sampling devices (SR-PSDs) with bioassay techniques for both chemical and ecotoxicological assessment of complex mixtures of organic contaminants in the aquatic environment. SR-PSDs were deployed in water at various locations within the Ythan catchment (north east, Scotland, UK), Forth estuary and the Firth of Forth (east coast of central Scotland, UK) for 7 to 9 weeks. Following retrieval, extracts from the SR-PSDs were analysed for dissolved concentrations of a variety of organic contaminants including PAHs and PCBs using GC-MS and GC-ECD respectively and were screened for a wide range of pesticides using GC-MS/MS and LC-MS/MS. The extracts were further evaluated for acute cytotoxicity (i.e. neutral red uptake assay) and EROD induction potential using rainbow trout liver cell line (Oncorhynchus mykiss; RTL-W1) and for phytotoxicity and developmental toxicity potential using algal growth inhibition test (with a marine phytoplankton, Diacronema lutheri) and fish embryo toxicity test (with embryos from zebrafish Danio rerio) respectively. Overall, the individual and total dissolved concentrations of PAHs (ΣPAH40; parent and branched) and PCBs (ΣPCB32; ortho and mono-ortho) measured in water from the Ythan, Forth estuary and Firth of Forth were relatively low compared with other studies using PSDs. A number and level of pesticides, including insecticides, herbicides and fungicides of varying hydrophobicity (log KOWs ~2.25 to ~5.31) were detected in the silicone rubber (SR) extracts from the Ythan catchment, the Forth estuary and the Firth of Forth, suggesting input mainly from agricultural run-off and possibly from direct discharges. No statistically significant (p<0.05) acute cytotoxicity was observed following 48 h exposure of RTL-W1 cells to SR extracts from the Ythan catchment. But, on a sublethal level, for every site, statistically significant EROD activity was observed to some degree following 72 h exposure. In addition, developmental and algal toxicities on embryos of D. rerio and D. lutheri respectively, were measured in all the deployed samples compared with the procedural controls (undeployed samples). Interestingly, extracts of SR-PSDs from the Forth estuary and the Firth of Forth exhibited growth inhibitions on D. lutheri that were similar to those of extracts from the Ythan, even though, fewer numbers of pesticides were detected in the Forth estuary and Firth of Forth than the Ythan. This suggests that pesticides were not solely responsible for the observed effects in the Ythan catchment. To further improve data from toxicity testing of hydrophobic substances, the study identified the use of SR O-rings as a suitable passive dosing format in in vitro toxicity tests and was partially validated through their use in dosing RTL-W1 cells with two individual PAHs and subsequently determining cytotoxicity and EROD-activity.
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Peptídeos RALF em tecido reprodutivo: caracterização e efeito dos AtRALF4, 25, 26 e 34 / RALF peptides in reproductive tissues: characterization and effect of AtRALFs 4, 25, 26 and 34Bergonci, Tábata 30 August 2016 (has links)
Pequenos peptídeos são importantes sinalizadores celulares e estão envolvidos na comunicação célula-a-célula em diversos aspectos do desenvolvimento da planta. Durante a reprodução sexual, moléculas sinalizadoras atuam na interação entre o gametófito feminino e o masculino, controlando processos como germinação do grão de pólen, alongamento do tubo polínico e liberação das células espermáticas, entre outros. RALF é um peptídeo de sinalização codificado por genes de expressão ubíqua ou tecido-especifica e que regulam negativamente a expansão celular. Em arabidopsis, peptídeos AtRALFs podem ser agrupados em uma família de 39 membros e, interessantemente, os maiores níveis de expressão gênica dessa família são encontrados nos AtRALFs expressos em tecidos reprodutivos. / Small peptides are important cell signaling involved in several aspects of plant development. During sexual reproduction, signaling molecules act in the interaction between female and male gametophyte, controlling processes such as pollen grains germination, pollen tube elongation and sperm cells release. RALF is a signaling peptide ubiquitous or tissuespecific that negatively regulates cell growth. In arabidopsis, AtRALFs peptides can be grouped into a family of 39 members and, interestingly, the highest levels of gene expression of this family are found in AtRALFs expressed in reproductive tissues.
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Ecotoxicité comparative de l'oxyde de graphène et d'autres nanoparticules de carbone chez des organismes aquatiques modèles : d'une évaluation en conditions monospécifiques vers l'étude d'une chaîne trophique expérimentale / Comparative ecotoxicity of graphene oxide and other carbon-based nanoparticles in freshwater model organisms : from an assessment in monospecific conditions towards the study of an experimental trophic chainLagier, Laura 08 November 2017 (has links)
L'écotoxicité de différentes nanoparticules de carbone (NPC) a été évaluée chez des organismes aquatiques, en particulier chez Xenopus laevis. Il a été montré que la surface des NPC est le paramètre le plus pertinent pour décrire l'inhibition de croissance chez le xénope, indépendamment de leur forme allotropique et de leur état de dispersion. L'induction des micronoyaux a aussi été étudiée chez le xénope, et l'oxyde de graphène (GO) s'est révélé génotoxique à faible dose, résultat corroboré par l'étude de l'expression des gènes. Les mécanismes de toxicité impliqués seraient notamment liés aux fonctions oxygénées de la particule. De plus, le GO a aussi entrainé de la génotoxicité chez Pleurodeles waltl. et de la tératogénicité, des retards de développement et de l'inhibition de croissance chez Chironomus riparius. La mise en interaction de ces organismes au sein d'un mésocosme a également conduit à l'observation de génotoxicité chez le pleurodèle en présence de GO. / The ecotoxicity of different carbon-based nanoparticles (CNPs) was assessed in freshwater organisms, especially in Xenopus laevis. The surface of the CNPs was shown to be the more relevant parameter to describe the growth inhibition in Xenopus, regardless of their allotropic form and their state of dispersion. Micronucleus induction was also studied in Xenopus and graphene oxide (GO) was found genotoxic at low dose. This result was in compliance with the study of genes expression. The involved toxicity mechanisms would be related to the oxidized functions of the CNP. Moreover, GO was also found responsible for genotoxicity in Pleurodeles waltl. and for teratogenicity, development delay and growth inhibition in Chironomus riparius. These organisms have finally been put together in a mesocosm, which has also led to genotoxicity in Pleurodeles in the presence of GO.
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Peptídeos RALF em tecido reprodutivo: caracterização e efeito dos AtRALF4, 25, 26 e 34 / RALF peptides in reproductive tissues: characterization and effect of AtRALFs 4, 25, 26 and 34Tábata Bergonci 30 August 2016 (has links)
Pequenos peptídeos são importantes sinalizadores celulares e estão envolvidos na comunicação célula-a-célula em diversos aspectos do desenvolvimento da planta. Durante a reprodução sexual, moléculas sinalizadoras atuam na interação entre o gametófito feminino e o masculino, controlando processos como germinação do grão de pólen, alongamento do tubo polínico e liberação das células espermáticas, entre outros. RALF é um peptídeo de sinalização codificado por genes de expressão ubíqua ou tecido-especifica e que regulam negativamente a expansão celular. Em arabidopsis, peptídeos AtRALFs podem ser agrupados em uma família de 39 membros e, interessantemente, os maiores níveis de expressão gênica dessa família são encontrados nos AtRALFs expressos em tecidos reprodutivos. / Small peptides are important cell signaling involved in several aspects of plant development. During sexual reproduction, signaling molecules act in the interaction between female and male gametophyte, controlling processes such as pollen grains germination, pollen tube elongation and sperm cells release. RALF is a signaling peptide ubiquitous or tissuespecific that negatively regulates cell growth. In arabidopsis, AtRALFs peptides can be grouped into a family of 39 members and, interestingly, the highest levels of gene expression of this family are found in AtRALFs expressed in reproductive tissues.
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Regulation and Characterization of Transcription Factor Activator Protein-2 Alpha (AP-2α)Nama, Srikanth January 2009 (has links) (PDF)
Introduction
AP2α is a 52 kDa retinoic acid inducible and developmentally regulated activator of
transcription, which binds to the DNA in a sequence-specific manner. Transcription factor AP-2α was isolated from HeLa cells by affinity chromatography using specific binding sites with in SV40 and human metallothionein promoters. Further screening of HeLa cDNA library with oligonucleotide probes predicted partial peptide sequence which led to the isolation of AP-2α
cDNA and subsequently it was mapped to chromosome 6 near HLA locus. A differentially spliced version of AP-2α, which lacks most of the C-terminus, encodes a dominant negative protein (AP-2B). Subsequent studies led to the identification of four more isoforms: AP-2β, AP-2γ, AP-2δ and AP-2ε. AP-2 family members can form homo or hetero dimers among themselves through the unique C-terminal helix span helix motif and bind DNA through basic domain lies N-terminus of DNA binding domain.
Several evidences suggest that AP-2α can act as a tumor suppressor gene. It has been
shown that AP-2α can activate growth suppressor genes like p21WAF1/CIP1. Transforming viral oncogenes like adenovirus E1A and SV40 large T antigen have been shown to alter AP-2α function. In addition, reduced expression of AP-2α has been reported in human breast, ovary,
colon, skin, brain and prostate cancers. Further, supporting evidences suggest that more invasiveness and tumorogenicity was observed when dominant negative mutant of AP-2α was expressed in melanoma cells.
In this work, we have carried out a systematic study to find the various signal
transduction pathways which regulate AP-2 activity as well as we attempted to demonstrate the importance of DNA binding domain in the growth inhibitory functions of AP-2α. HDAC inhibitors (HDIs) activate AP-2 activity through spleen tyrosine kinase (Syk)
In the literature, ample evidences are available that genotoxic drugs such as adriamycin, induce tumor suppressors like p53 and p73. In this study, we have screened pharmacological drugs which damage DNA and specific inhibitors of various signal transduction pathways for their ability to activate AP-2 activity. AP-2 specific reporter, 3Χ-AP2-CAT was used in this
study to measure the AP-2 activity. Of all the compounds studied, we found that Histone
Deacetylase Inhibitors (HDIs) efficiently activated AP-2 activity and was found to be specific as they failed to activate 3X-AP2 mut CAT, which contains mutated AP-2 binding sites as well as pGL tk Luc, which contains thymidine kinase minimal promoter and no AP-2 binding sites.
To understand the mechanism of HDI-mediated of AP-2 activation, AP-2 isoforms and its coactivators transcript and protein levels were analyzed. We found significant change in transcript levels of the some of the molecules tested. While the endogenous protein levels of various AP-2 isoforms were undetectable, we found stabilization of AP-2α protein expressed from exogenous
source in cells treated with HDIs. HDI stabilized AP-2α was found to be functionally active as it showed increased sequence-specific DNA-binding as well as increased apoptosis. While HDIs known for their ability to modulate the gene activities by chromatin remodeling, it is also known that they alter various signal transduction pathways. In an effort to find pathway(s) by which HDIs activate AP-2 activity, we found that HDIs failed to activate AP-2 reporter in the presence of staurosporine suggesting the involvement a staurosporine sensitive pathway(s) in
this process. Stauosporine is a non-specific kinase inhibitor of different signaling pathways.
Further studies using different pathway specific inhibitors identified that spleen tyrosine kinase (Syk) is essential for HDIs mediated activation of AP-2 activity. Syk is a non receptor tyrosine kinase which is known to be activated in stress conditions. Syk is considered to be a tumor suppressor since Syk over expression leads to growth suppression of breast cancer cells and is
also inactivated in a subset of breast cancers. These results suggest that HDI mediated activation of AP-2 involves AP-2α stabilization through Syk pathway.
Regulation of AP-2 by MAP kinase pathway
Cell growth, differentiation, and apoptosis are mediated by the activation of mitogenactivated protein kinase (MAPK) pathways. These kinases constitute MAP kinase cascades mainly regulated through phosphorylation status. In mammalian cells, at least four MAPKs, namely, extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase/stress-activated
protein kinases (JNK/SAPKs), p38 and ERK5/big MAP kinase have been identified. The ERKs are usually activated by mitogenic stimuli which in turn increase the proliferation and survival.
Over expression of any activator of this signaling cascade lead to the unregulated proliferation of cells. In many cancers, ERK pathways are known to be up regulated. In this study, we found that MEK (MEK is the immediate upstream regulator of ERK) inhibitors - PD98059 and U0126 activate 3X-AP2-CAT suggesting that AP-2 activity is repressed by activated MAP kinase pathway. MEK inhibitor mediated activation was found to be specific because they failed to
activate transcription from pGL tk Luc which contains thymidine kinase minimal promoter and no AP-2 binding sites. To understand the mechanism of MEK inhibitor-mediated of AP-2
activation, AP-2 isoforms and its coactivators transcript and protein levels were analyzed. We found significant change in transcript levels of the some of the molecules tested. The endogenous protein levels of various AP-2 isoforms were undetectable. When AP-2α was exogenously expressed, while no change in protein levels and DNA-binding ability was seen, we found evidence for appearance of post-ranslationally modified AP-2α protein in U0126 treated cells. We also found CITED2 (CBP/p300-interacting transactivator 2, co-activator of AP-2α) transcript levels were up regulated in UO126 treated cells. Post translational modifications of AP-2α and increased and increased CITED2 levels may be responsible for MEK inhibitor mediated AP-2 activation. Thus we conclude that ERK pathway, which is an oncogenic MAP kinase pathway, inhibits AP-2 activity thereby suggesting the importance of down regulation of AP-2 activity during transformation.
Essential role of DNA-binding domain of AP-2α for its growth inhibitory functions
Transcription factor AP-2α has three distinct domains, N-terminal transactivation
domain (52-108 aa), C-terminal DNA binding domain (204-408 aa) and dimerization domain
(277-395 aa) which lies within the DNA binding domain. AP-2α exerts its effects through binding to specific DNA sequence in the promoter of its target genes leading to either repression or activation. Recent evidences suggest that AP-2α represses many genes through its competitive binding to overlapping AP-2 and other transcription factor binding sites. This suggests an important role exclusively for the DNA binding domain in AP-2α mediated functions. To address the importance of DNA binding domain for AP-2α mediated apoptosis,
we have tested the ability different deletion/point mutants of AP-2α with varying DNA binding and transactivation capability to perform growth suppressor function and ability to induce apoptosis. Replication-deficient recombinant adenoviruses expressing different mutants were used in this study. We found that an intact DNA-binding domain alone even in the absence of
activation domain is sufficient for AP-2α to inhibit colony formation and to induce significant levels of apoptosis. These results suggest an important role for DNA binding domain growth inhibitory functions of AP-2α and thereby implying the importance of transcriptional repression in AP-2α functions.
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Vliv fyzikálních metod a nových chemických preparátů na bázi nanočástic na vybrané dřevokazné houby napadajících dřevěné konstrukce - možnosti a limitace moderních metod prevence / The impact of physical methods and new chemical preparations based on nanoparticles on selected wood-rotting fungi invading wooden structures - possibilities and limitations of modern techniques of preventionŠvec, Karel January 2016 (has links)
83 Abstract The work focuses on the physiology of wood-rotting fungi and the possibilities of their inhibition by physical methods (microwave and gamma irradiations, dry heat) or newly developed chemical preparatives contaning metallic nanoparticles. The effect of abovementioned treatments on mycelial growth, activities of extracellular enzymes responsible for wood degradation and on spore germination or viability was studied in selected strains of wood-rotting fungi obtained from culture collection (Coniophora puteana, Fibroporia vaillantii, Gloeophyllum sepiarium) or isolated from infected buildings (Serpula lacrymans).
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DESIGNING COMBINATION DRUG REGIMENS TO IMPROVE GLIOBLASTOMA CHEMOTHERAPY: A PHARMACOKINETIC PHARMACODYNAMIC MODELING APPROACHSaugat Adhikari (11267001) 13 August 2021 (has links)
<p>Despite advancements in therapies, such as surgery, irradiation (IR) and chemotherapy, outcome for patients suffering from glioblastoma (GBM) remains fatal; the median survival time is only about 15 months. Even with novel therapeutic targets, networks and signaling pathways being discovered, monotherapy with such agents targeting such pathways has been disappointing in clinical trials. Poor prognosis for GBM can be attributed to several factors, including failure of drugs to cross the blood-brain-barrier (BBB), tumor heterogeneity, invasiveness, and angiogenesis. Development of tumor resistance, particularly to temozolomide (TMZ) and IR, creates a substantial clinical challenge.</p><p> </p><p>The primary focus of the work described herein was to develop a modeling and simulation approach that could be applied to rationally develop novel combination therapies and dose regimens that mitigate resistance development. Specifically, TMZ was combined with small molecule inhibitors that are either currently in clinical trials or are approved drugs for other cancer types, and which target the disease at various resistance signaling pathways that are induced in response to TMZ monotherapy. To accomplish this objective, an integrated PKPD modeling approach was used. A PK model for each drug was first defined. PK models were subsequently linked to a PD model description of tumor growth dynamics in the presence of a single drug or combinations of drugs. A key outcome of these combined PKPD models was tumor static concentration (TSC) curves of TMZ in combination with small molecule inhibitors that identify combination drug exposures predicted to arrest tumor growth. This approach was applied to TMZ in combination with abemaciclib (a dual CDK4/6 small molecule inhibitor) based on data from a published study evaluating abemaciclib (ACB) efficacy in combination with TMZ in a U87 GBM xenograft model. TSC was also constructed for TMZ in combination with RG7388 (MDM2 inhibitor) based on the data from an in-vivo study that evaluated effects on tumor growth suppression of these small molecule inhibitors in combination with TMZ in GBM 10 patient derived xenografts.</p><p>In GBM 43 mouse xenografts, emergence of resistance to TMZ treatment was identified. Thus, a resistance integrated PKPD model was developed to predict tumor growth kinetics after treatment with TMZ in GBM 43 tumors. Population PK models in immune deficient NOD.Cg-<em>Prkdc<sup>scid</sup> Il2rg<sup>tm1Wjl</sup></em>/SzJ (NSG) mice for TMZ and small molecule inhibitors (GDC0068/RG7112) were developed based on a combination of data obtained from an in-vivo study and published sources. Subsequently, PK models were linked to tumor volume data obtained from GBM 43 subcutaneous xenografts. Model parameters quantifying tumor volume dynamics were precisely estimated (coefficient of variation < 40%) compared to a base tumor growth inhibition model in GBM 43 that did not incorporate resistance development. Graphical diagnostics of the resistance incorporated PKPD tumor growth inhibition model demonstrated a superior fit compared to the base model, and accurately captured the emergence of resistance to the TMZ monotherapy treatment observed in the GBM 43 patient derived xenograft model.</p>
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Utsläpp från vägmarkeringar : Toxicitetstest av lakvatten från vägmarkeringsprodukter med mikroalgen Raphidocelis subcapitata / Emissions from road markings : Toxicity tests of leachates from road marking products on the microalgae Raphidocelis subcapitataÖsterblad, Mikaela January 2021 (has links)
Ackumuleringen av plast och mikroplast i miljön är idag en globalt aktuell fråga. Forskning kring mikroplast och dess påverkan på miljö och biota har ökat kraftigt det senaste decenniet. En av de största utsläppskällorna till mikroplast är slitage från vägtrafiken, speciellt från däck, men mikroplast kan även komma från vägmarkeringar. Vägmarkeringar innehåller plastpolymerer (som bindemedel), fyllnadsmedel, pigment och tillsatsämnen (additiv), och ofta ingår även glaspärlor. Vissa ämnen kan ge en negativ påverkan på människa och miljö. I dagsläget saknas det data för att kunna kartlägga i vilken omfattning vägmarkeringsslitage bidrar till spridning av mikroplaster samt för att bedöma om och hur det skulle kunna påverka miljön och vattenlevande organismer. I detta examensarbete har toxicitetstest av lakvatten från vägmarkeringsprodukter utförts med algen Raphidocelis subcapitata för att studera om de är toxiska samt om det finns någon skillnad mellan olika vägmarkeringsprodukter. Partiklar från fyra olika typer av vägmarkeringsprodukter (prefabricerad termoplast, varmapplicerad termoplast, vattenbaserad akrylatfärg och 2-komponentsakrylatfärg) genererades och lakades var för sig med skakning i avjoniserat vatten under 24 timmar. Lakvattnen utan partiklar användes sedan till algtillväxthämningstest. Algerna exponerades under 72 timmar för lakvatten i olika koncentrationer, där den högsta motsvarade 100 g vägmarkeringspartiklar per liter, och algtillväxt mättes. Effektmåtten var maximal tillväxthastighet och lag-fas och dessutom analyserades korrelationen mellan dem som ett mått för anpassningseffektivitet. De fyra lakvattnen påverkade lag-fas och/eller tillväxthastighet i olika omfattning och medförde antingen inhibering eller stimulering av algtillväxten. Lakvattnet från den vattenbaserade akrylatfärgen påvisade störst inhibering av tillväxt och var även det mest toxiska eftersom ingen tillväxtanpassning skedde. För övriga lakvatten påvisades olika grad av anpassningseffektivitet av alger vid exponering. Dock krävs mer ingående statistisk utvärdering för att åtskilja de två lakvatten som hade minst påverkan, dvs. från den prefabricerade och den varmapplicerade termoplasten. Detta är enbart en första studie. Upprepade tester med fler vägmarkeringsprodukter och fler tester med andra organismer, såsom bakterier, kärlväxter, kräftdjur och fisk, krävs för att bättre kunna utreda om och hur olika vägmarkeringar kan påverka biota. För ytterligare studier skulle det vara intressant att utvärdera vilka ämnen i vägmarkeringar som kan påverka miljön och om dessa skulle kunna ersättas med andra, mindre giftiga ämnen. / The accumulation of plastic and microplastics in the environment is a current global issue. Research on microplastics and its impact on the environment and biota has increased rapidly in the last decade. One of the largest sources of microplastics is wear from road traffic, especially tires, but they can also originate from road markings. Road markings contain plastic polymers (as a binder), fillers, pigments, and additives, and often also glass beads. Some substances may have a negative impact on humans and the environment. At present, there are no data to map the extent to which wear from road markings contributes to the emissions of microplastics, or to assess the effect they might cause on the environment and aquatic organisms. In this thesis, toxicity tests on leachates from road marking products were conducted on the alga Raphidocelis subcapitata to study the effect on the algae and if it differs between the different products. Particles from four types of road marking products (prefabricated thermoplastic, hot-applied thermoplastic, acrylic water-based paint, and 2-component acrylic paint) were generated and leached separately by shaking in deionized water for 24 hours. The leachates without particles were used in the standard algal growth inhibition tests. The algae were exposed for 72 hours to the leachates in different concentrations, with the highest corresponding to 100 g road marking particles per liter, and algal growth was monitored. Endpoints used were maximum growth rate and lag phase and, in addition, their correlation was analyzed as an indicator for adaptation capacity. The four leachates affected lag phase and/or growth rate to a varying extent and caused inhibition or stimulation of algae growth. Exposure to leachate from the water-based acrylic paint showed most inhibition of growth and was also the most toxic as no growth adaptation was observed. For the other tests, different rates of adaptation efficiency of the algae growth were found. However, more detailed statistical evaluation is needed to differentiate between the two leachates that had the least effect, i.e. the prefabricated and the hot-applied thermoplastic. This is only a first study. More tests with more road marking products and with other organisms, such as bacteria, vascular plants, crustaceans, and fish, are required to better understand if and how different road markings could affect biota. Additionally, an evaluation of what substances in road marking materials may cause effects and whether these can be replaced by other, less toxic substances, would be of interest.
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Actions of lignocellulolytic enzymes on Abies grandis(grand fir) wood for application in biofuel productionCherdchim, Banyat 27 October 2010 (has links)
No description available.
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