Relevant bibliographies by topics / Intracellular accumulation

Academic literature on the topic 'Intracellular accumulation'

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Published: 7 July 2024

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  1. Journal articles
  2. Dissertations / Theses
  3. Books
  4. Book chapters
  5. Conference papers
  6. Reports

Journal articles on the topic "Intracellular accumulation":

1

Atabayeva, S. D., S. Sh Asrandina, R. A. Alybaeva, and S. A. Shoinbekova. "Intracellular localization, accumulation and distribution of heavy metals in plants." International Journal of Biology and Chemistry 8, no. 2 (2015): 9–12. http://dx.doi.org/10.26577/2218-7979-2015-8-2-9-12.

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Melnichenko, A., M. Iltchuk, T. Fatkhudinov, G. Bolshakova, R. Wetzker, and A. Orekhov. "Intracellular Accumulation Of Ldl Associates." Atherosclerosis 287 (August 2019): e233. http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.717.

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Vingtdeux, Valérie, Malika Hamdane, Séverine Bégard, Anne Loyens, André Delacourte, Jean-Claude Beauvillain, Luc Buée, Philippe Marambaud, and Nicolas Sergeant. "Intracellular pH regulates amyloid precursor protein intracellular domain accumulation." Neurobiology of Disease 25, no. 3 (March 2007): 686–96. http://dx.doi.org/10.1016/j.nbd.2006.09.019.

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Garringer, Holly J., Neeraja Sammeta, Adrian Oblak, Bernardino Ghetti, and Ruben Vidal. "Amyloid and intracellular accumulation of BRI2." Neurobiology of Aging 52 (April 2017): 90–97. http://dx.doi.org/10.1016/j.neurobiolaging.2016.12.018.

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Ford, Jennifer, David Cornforth, Patrick G. Hoggard, Zoe Cuthbertson, E. Rhiannon Meaden, Ian Williams, Margaret Johnson, et al. "Intracellular and Plasma Pharmacokinetics of Nelfinavir and M8 in HIV-Infected Patients: Relationship with P-Glycoprotein Expression." Antiviral Therapy 9, no. 1 (January 2004): 77–84. http://dx.doi.org/10.1177/135965350400900101.

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One of the targets of antiretroviral therapy is within cells infected with HIV. In order to improve therapeutic efficacy, it is therefore important that the intracellular pharmacokinetics of drugs, such as nelfinavir mesylate and its active metabolite M8, are studied in addition to plasma pharmacokinetics. Previously, the intracellular accumulation of protease inhibitors has been reported in vivo, displaying the following hierarchy: nelfinavir > saquinavir > ritonavir > indinavir. Multidrug resistance transporters, such as P-glycoprotein (P-gp), may result in a lower intracellular concentration of drug via an efflux mechanism, thus contributing to sanctuary site formation. The objective of this study was to determine concentrations of nelfinavir and M8 in plasma and peripheral blood mononuclear cells from HIV-infected patients, and to ascertain the relationship between intracellular accumulation and lymphocyte P-gp expression. Venous blood samples from 12 HIV-infected patients (viral load <50 copies/ml) receiving nelfinavir (1250 mg twice daily) and dual nucleoside reverse transcriptase inhibitor therapy were collected over a full dosage interval (0, 2, 4, 8 and 12 h). Plasma and intracellular (cell-associated) drug concentrations were measured by HPLC-MS/MS. Drug exposure in plasma and cells was expressed as the area under the concentration–time curve (AUC0-12h), derived from non-compartmental modelling. The ratio of intracellular AUC0-12h/total plasma AUC0-12h was calculated to determine cellular drug accumulation. P-gp expression on lymphocytes was determined by flow cytometry. The median (range) AUC0-12h of nelfinavir in plasma and cellular compartments was 21.8 mg.h.l-1 (5.64–50.8) and 104.6 mg.h.l-1 (23.1–265.7), respectively. Corresponding values for M8 in plasma and cells were 6.60 mg.h.l–1 (2.16–17.3) and 19.6 mg.h.l–1 (5.14–60.8). A ratio of plasma M8/plasma nelfinavir (AUC0–12h) and intracellular M8/intracellular nelfinavir (AUC0–12h) gave median values of 0.32 and 0.17, respectively. The cellular accumulations [median; (range)] of nelfinavir and M8 were 5.30 (2.28–16.2) and 2.32 (1.01–10.7), respectively. A significant correlation between plasma and intracellular nelfinavir minimum concentration (Cmin) (r2=0.34; P=0.049), but not between plasma and intracellular M8 Cmin was observed. C0h concentrations were higher than C12h for both nelfinavir and M8. No relationship was observed between nelfinavir or M8 accumulation and lymphocyte cell surface expression of P-gp. This study illustrates that intracellular concentrations were higher than plasma concentrations for both nelfinavir and M8, suggesting lymphocyte accumulation. The mechanism of differential intracellular accumulation of nelfinavir and M8 remains to be elucidated. It may be that affinities for influx transporters or fundamental drug characteristics play a major role in the greater accumulation of nelfinavir than M8.
6

Nguyen, Hien Thi Thu, Rikke Kristiansen, Mette Vestergaard, Reinhard Wimmer, and Per Halkjær Nielsen. "Intracellular Accumulation of Glycine in Polyphosphate-Accumulating Organisms in Activated Sludge, a Novel Storage Mechanism under Dynamic Anaerobic-Aerobic Conditions." Applied and Environmental Microbiology 81, no. 14 (May 8, 2015): 4809–18. http://dx.doi.org/10.1128/aem.01012-15.

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ABSTRACTDynamic anaerobic-aerobic feast-famine conditions are applied to wastewater treatment plants to select polyphosphate-accumulating organisms to carry out enhanced biological phosphorus removal. Acetate is a well-known substrate to stimulate this process, and here we show that different amino acids also are suitable substrates, with glycine as the most promising.13C-labeled glycine and nuclear magnetic resonance (NMR) were applied to investigate uptake and potential storage products when activated sludge was fed with glycine under anaerobic conditions. Glycine was consumed by the biomass, and the majority was stored intracellularly as free glycine and fermentation products. Subsequently, in the aerobic phase without addition of external substrate, the stored glycine was consumed. The uptake of glycine and oxidation of intracellular metabolites took place along with a release and uptake of orthophosphate, respectively. Fluorescencein situhybridization combined with microautoradiography using3H-labeled glycine revealed uncultured actinobacterialTetrasphaeraas a dominant glycine consumer. Experiments withTetrasphaera elongataas representative of unculturedTetrasphaerashowed that under anaerobic conditions it was able to take up labeled glycine and accumulate this and other labeled metabolites to an intracellular concentration of approximately 4 mM. All components were consumed under subsequent aerobic conditions. Intracellular accumulation of amino acids seems to be a novel storage strategy for polyphosphate-accumulating bacteria under dynamic anaerobic-aerobic feast-famine conditions.
7

Corti, S., J. Chevalier, and A. Cremieux. "Intracellular accumulation of norfloxacin in Mycobacterium smegmatis." Antimicrobial Agents and Chemotherapy 39, no. 11 (November 1, 1995): 2466–71. http://dx.doi.org/10.1128/aac.39.11.2466.

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8

Polti, Marta A., María Julia Amoroso, and Carlos M. Abate. "Intracellular chromium accumulation by Streptomyces sp. MC1." Water, Air, & Soil Pollution 214, no. 1-4 (March 31, 2010): 49–57. http://dx.doi.org/10.1007/s11270-010-0401-5.

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Tang, Youcai, and Anping Chen. "Curcumin Protects Hepatic Stellate Cells against Leptin-Induced Activation in Vitro by Accumulating Intracellular Lipids." Endocrinology 151, no. 9 (July 21, 2010): 4168–77. http://dx.doi.org/10.1210/en.2010-0191.

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Obesity and type II diabetes mellitus are often associated with hyperleptinemia and commonly accompanied by nonalcoholic steatohepatitis, which could cause hepatic fibrosis. During hepatic fibrogenesis, the major effectors hepatic stellate cells (HSCs) become active, coupling with depletion of cellular lipid droplets and downexpression of genes relevant to lipid accumulation. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit HSC activation. We recently reported that leptin stimulated HSC activation, which was eliminated by curcumin, a phytochemical from turmeric. The current study was designed to explore the underlying mechanisms, focusing on their effects on the level of intracellular lipids. We hypothesized that one of the mechanisms by which leptin stimulated HSC activation was to stimulate the depletion of intracellular lipids, which could be abrogated by curcumin by inducing expression of genes relevant to lipid accumulation. In this report, we observed that leptin dose dependently reduced levels of intracellular fatty acids and triglycerides in passaged HSCs, which were eliminated by curcumin. The phytochemical abrogated the impact of leptin on inhibiting the activity of AMP-activated protein kinase (AMPK) in HSCs in vitro. The activation of AMPK resulted in inducing expression of genes relevant to lipid accumulation and increasing intracellular lipids in HSCs in vitro. In summary, curcumin eliminated stimulatory effects of leptin on HSC activation and increased AMPK activity, leading to inducing expression of genes relevant to lipid accumulation and elevating the level of intracellular lipids. These results provide novel insights into mechanisms of curcumin in inhibiting leptin-induced HSC activation.
10

Khoo, Saye H., Patrick G. Hoggard, Ian Williams, E. Rhiannon Meaden, Philippa Newton, Edmund G. Wilkins, Alan Smith, et al. "Intracellular Accumulation of Human Immunodeficiency Virus Protease Inhibitors." Antimicrobial Agents and Chemotherapy 46, no. 10 (October 2002): 3228–35. http://dx.doi.org/10.1128/aac.46.10.3228-3235.2002.

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ABSTRACT Intracellular accumulation of the protease inhibitors (PIs) saquinavir (SQV), ritonavir (RTV), and indinavir (IDV) was determined in 50 human immunodeficiency virus-positive patients. Following extraction, PIs were quantified by mass spectrometry. Paired plasma and intracellular samples were collected over a full dosing interval from patients (13 on SQV, 6 on RTV, 8 on IDV, 16 on SQV plus RTV, 7 on IDV plus RTV) with a plasma viral load of <400 copies/ml. Data were expressed as intracellular/plasma drug concentration ratios. A hierarchy of intracellular accumulation was demonstrated by the following medians: 9.45 for SQV > 1.00 for RTV > 0.51 for IDV. Coadministration of RTV did not boost ratios of SQV or IDV within the cell or in plasma, although absolute plasma and intracellular SQV concentrations were increased by RTV. Seven individuals receiving SQV in hard-gel capsule form (median, 32 months) had higher intracellular/plasma drug ratios than all other patients receiving SQV (median, 17.62 versus 4.83; P = 0.04), despite consistently low plasma SQV concentrations. How this occurs may provide insight into the mechanisms that limit adequate drug penetration into sanctuary sites.
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Journal articles Dissertations / Theses

Dissertations / Theses on the topic "Intracellular accumulation":

1

Mathis, Amanda Marie Hall James E. "Accumulation and intracellular distribution of aromatic diamidines in African trypanosomes." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,985.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Dec. 18, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Pharmacy." Discipline: Pharmacy; Department/School: Pharmacy.
2

ALBERTI, MICOL. "miRNA Dysregulation Drives Neuronal Intracellular Chloride Accumulation in Down Syndrome." Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/996150.

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Down syndrome (DS) is caused by the presence of an extra-copy of chromosome 21 and is the most frequent genetic cause of mental retardation. DS cognitive disabilities primary arise from the triplication of dosage-sensitive genes on chromosome 21. However, a global dysregulation in the expression of extra-chromosome 21 genes greatly complicates the understanding of the underling pathological mechanisms. We have recently found that cognitive impairment in the Ts65Dn mouse model of DS depends on the upregulation of a non-triplicated gene encoding for the chloride importer NKCC1, which we found increased also in brain tissue from individuals with DS. Consequently, the intracellular chloride concentration is increased and GABAergic signaling, through chloride-permeable GABAA receptors, is depolarizing rather than hyperpolarizing. Here, we aimed at addressing the molecular mechanisms responsible for NKCC1 overexpression in DS. Real-time qPRC and Western Blot analysis showed that NKCC1 overexpression in trisomic neurons does not derive from greater mRNA transcription or decreased protein turnover but rather from a diminished translational repression exerted on the 3’ untranslated region (3'UTR) of the gene. As 3’ UTRs are the preferred sites of action of microRNAs (miRs), we applied a combination of bioinformatics prediction tools and gene expression screening to identify candidate miRs downregulated in trisomic samples that could mediate NKCC1 overexpression. Our results show that different candidates miRs interact with NKCC1 3’UTR and repress its expression. Additionally, overexpression of the same miRs can normalize NKCC1 levels and intracellular chloride concentration in trisomic neurons, restoring GABAergic inhibitory signaling at the network level as shown by Multi-Electrode Array recordings. Our findings will help to elucidate molecular pathways dysregulated in DS and suggest possible targets for future therapeutic intervention.
3

Jones, Kevin. "Intracellular accumulation of the HIV protease inhibitors and the effect of active transport." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366660.

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Rajendran, Lawrence, Marlen Knobloch, Kathrin D. Geiger, Stephanie Dienel, Roger Nitsch, Kai Simons, and Uwe Konietzko. "Increased Aβ Production Leads to Intracellular Accumulation of Aβ in Flotillin-1-Positive Endosomes." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136570.

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Extracellular accumulation of Aβ in β-amyloid plaques is thought to be associated with the neurodegeneration observed in Alzheimer’s disease (AD) patients, although a lack of correlation with cognitive decline raised doubts on this hypothesis. In different transgenic mouse models Aβ accumulates inside the cells and mice develop behavioral deficits well before visible extracellular β-amyloid accumulation. Here we show that intracellular Aβ accumulates in flotillin-1 positive endocytic vesicles. We also demonstrate that flotillin-1 is not only associated with intracellular Aβ in transgenic mice but also with extracellular β-amyloid plaques in AD patient brain sections
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
5

Rajendran, Lawrence, Marlen Knobloch, Kathrin D. Geiger, Stephanie Dienel, Roger Nitsch, Kai Simons, and Uwe Konietzko. "Increased Aβ Production Leads to Intracellular Accumulation of Aβ in Flotillin-1-Positive Endosomes." Karger, 2007. https://tud.qucosa.de/id/qucosa%3A27713.

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Extracellular accumulation of Aβ in β-amyloid plaques is thought to be associated with the neurodegeneration observed in Alzheimer’s disease (AD) patients, although a lack of correlation with cognitive decline raised doubts on this hypothesis. In different transgenic mouse models Aβ accumulates inside the cells and mice develop behavioral deficits well before visible extracellular β-amyloid accumulation. Here we show that intracellular Aβ accumulates in flotillin-1 positive endocytic vesicles. We also demonstrate that flotillin-1 is not only associated with intracellular Aβ in transgenic mice but also with extracellular β-amyloid plaques in AD patient brain sections.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
6

Matsui, Yoshiyuki. "Sensitizing effect of galectin-7 in urothelial cancer to cisplatin through the accumulation of intracellular reactive oxygen species." Kyoto University, 2008. http://hdl.handle.net/2433/135855.

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Mateus, André. "Intracellular unbound drug concentrations : Methodology and application for understanding cellular drug exposure." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-276095.

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Most known drug targets and metabolizing enzymes are located inside cells. Interactions with these proteins are determined by intracellular unbound drug concentrations. Assessing intracellular drug exposure is technically challenging, but essential for predicting pharmacokinetic, pharmacological, and toxicological profiles of new drugs. This thesis aims at establishing and applying a straightforward methodology to measure intracellular unbound drug concentrations. This was achieved by separately measuring cellular drug binding (fu,cell), and total intracellular drug accumulation (Kp). This allowed the calculation of intracellular drug bioavailability (Fic), which represents the fraction of the concentration added to the cells that is unbound in the cell interior. The methodology was initially developed in HEK293 cells, where the Fic of 189 drug-like compounds was measured. Binding to HEK293 cells was governed by compound lipophilicity and was correlated with binding to more complex systems, such as hepatocytes and brain. Due to negligible expression of drug transporters, Fic in this cell line was consistent with pH-dependent subcellular sequestration of lipophilic cations in low pH compartments. The methodology was then applied to study the effects of drug transporters on Fic. The uptake transporter OATP1B1 increased the Fic of its substrates in a concentration-dependent manner. In contrast, the Fic of P-gp substrates was decreased when P-gp was present. In human hepatocytes, the methodology allowed the determination of Fic without prior knowledge of transporter mechanisms or metabolic activity. Finally, the methodology was applied to measure the impact of Fic on target binding and cellular drug response. Intracellular concentrations of active metabolites of pro-drugs targeting the intracellular target thymidylate synthase were in agreement with the level of binding to this target. Further, high Fic was generally required for kinase and protease inhibitors to be active in cellular assays. In conclusion, the methodology can be used to predict if new drug candidates reach their intracellular targets in sufficient amounts. Furthermore, the methodology can improve in vitro predictions of drug clearance and drug-drug interactions, by measuring the drug available for intracellular enzymes. Finally, this work can be expanded to other xenobiotics, e.g., to predict their intracellular toxicity.
8

He, Yihua. "Interaction des radioéléments (Ra, U) avec les diatomées." Electronic Thesis or Diss., Ecole nationale supérieure Mines-Télécom Atlantique Bretagne Pays de la Loire, 2023. http://www.theses.fr/2023IMTA0376.

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Les diatomées sont des microalgues unicellulaires omniprésentes sur Terre et utilisées comme bioindicateurs pour évaluer l'impact de contaminations sur les écosystèmes aquatiques. Elles font également l'objet d'une attention croissante en tant que matériel de décontamination de métaux lourds d’effluents contaminés ou à des fins de biorestauration in situ. Cependant, les interactions entre les diatomées et les radioéléments, notamment l'uranium (U) et le radium (Ra), restent peu documentées. Ce travail vise à étudier tant au niveau macroscopique que moléculaire, les interactions de U et du Ra avec une culture xénique de diatomées Achnanthidium saprophilum, dans laquelle une communauté bactérienne est naturellement associée de manière symbiotique. Des expériences de bio-association de U et du Ra sont faites en présence de diatomées afin d’évaluer les fractions en U/Ra adsorbées et incorporées. En parallèle, diverses techniques de microscopie et de spectroscopie sont appliquées pour étudier la localisation et la spéciation de U au niveau cellulaire. Les résultats démontrent une bio-association significative de U et du Ra avec les diatomées et soulignent le rôle important des groupes carboxyliques et phosphates dans l'interaction U-diatomées. Les deux mécanismes d’adsorption et d’incorporation ont pu être mis en évidence pour U et Ra, la répartition entre les fractions adsorbées et incorporées dépendant de la phase de croissance des diatomées et du temps de contact entre les micro-algues est les radioéléments. Ce travail met également en évidence la contribution significative des bactéries symbiotiquement associées aux diatomées aux interactions globales
Diatoms are ubiquitous unicellular microalgae that are commonly used as bioindicators to evaluate the impact of contaminations on the ecological health of aquatic ecosystems. In recent decades, diatoms have received increasing attention as a decontamination material for removing heavy metals from contaminated effluents or for in situ bioremediation purposes. However, the interactions between diatoms and radioelements, e.g., uranium (U) and radium (Ra), remain relatively unclear and poorly documented. Therefore, this work aims to study, at both the macroscopic and molecular level, the interaction of U and Ra with a xenic Achnanthidium saprophilum diatom culture in which a naturally occurring bacterial community is symbiotically associated to diatoms. Batch-type U and Ra bio-association experiments are performed to evaluate the adsorbed and incorporated fractions of U/Ra in the diatom culture. Besides, various microscopic and spectroscopic techniques are applied to investigate the localization and speciation of U at the cellular level. Results demonstrate the significant bioassociation of U and Ra with the diatoms and highlight the important role of carboxylic and phosphate groups in the U-diatoms interaction. Both adsorption and incorporation are observed for U and Ra in the diatom culture, with their distribution depending on the diatom growth phase and on the contact time. This work contributes to a better understanding of the interaction of U and Ra with the xenic diatom culture and also highlights the contribution of the bacteria symbiotically associated with the diatoms to the overall interactions
9

CORTI, SANDRINE. "Accumulation intracellulaire de la norfloxacine chez les mycobacteries." Aix-Marseille 2, 1995. http://www.theses.fr/1995AIX22060.

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Les quinolones peuvent etre utilisees dans le traitement des infections par des bacteries a gram negatif ou positif, y compris les mycobacteries. Afin de determiner les mecanismes d'action de ces drogues et les mecanismes de resistance des bacteries, l'accumulation intracellulaire de la norfloxacine a ete determinee chez diverses especes bacteriennes. Dans un premier temps, l'accumulation a ete determinee chez escherichia coli et staphylococcus aureus, a l'aide de la radiometrie et la fluorimetrie. Le maximum d'accumulation est atteint rapidement avec 250 nanogramme par milligramme de poids sec pour les deux souches. Il a egalement ete verifie que le transport de la norfloxacine est passif. Dans un second temps, l'accumulation de la norfloxacine a ete etudiee chez diverses souches de mycobacteries. Les methodes ont d'abord ete appliquees a mycobacterium smegmatis, grace a un protocole permettant d'obtenir des suspensions homogenes. Apres une importante modification des techniques, notamment en fluorimetrie, l'accumulation intracellulaire de la norfloxacine est maximale apres 5 minutes d'exposition avec 45 nanogramme par milligramme de poids sec. De plus, une adsorption de la norfloxacine a la surface cellulaire a ete revelee et doit etre deduite des valeurs d'accumulation mesuree. Par ailleurs, le transport de la quinolone est passif. Les methodes d'etudes ainsi modifiees ont alors ete appliquees a d'autres souches de mycobacteries sensibles ou resistantes a la quinolone. L'adsorption a la surface cellulaire est importante et le maximum d'accumulation est atteint assez tardivement: 100 nanogramme pour les souches de mycobacterium chelonae en 10 minutes d'exposition et 40 ou 60 nanogramme pour les souches de mycobacterium avium, respectivement sensible ou resistante a la norfloxacine, en 20 minutes d'exposition. D'autre part un phenomene de resistance naturelle aux quinolones, par un systeme d'efflux actif, semble avoir ete mis en evidence chez les souches de m. Avium
10

Lambert, Catherine. "Complexes de cuivre pour le traitement de la maladie d'Alzheimer : étude de leur accumulation intracellulaire." Paris 13, 2013. http://scbd-sto.univ-paris13.fr/secure/edgalilee_th_2013_lambert.pdf.

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Les bases moléculaires de la maladie d'Alzheimer n'ont pas encore été clairement établies mais il semblerait que la dérégulation de l'homéostasie des métaux, et plus particulièrement celle du cuivre, soit étroitement liée à la pathogénèse de la maladie et à ses dépôts caractéristiques de peptide amyloïde (Aß). Des thérapies basées sur la modulation de l'homéostasie en cuivre ont vu le jour. Dans ce contexte, les complexes de cuivre et de bis(thiosemicarbazones) ([Cu(btsc)]) ont été proposés pour le traitement de la maladie d'Alzheimer. En effet, ces complexes sont supposés moduler la concentration en cuivre et modifier la production du peptide Aß dans les neurones. Par ailleurs, il est proposé que les complexes [Cu(btsc)] puissent être réduits dans la cellule. Cependant, à notre connaissance, la réduction intracellulaire de ces composés n'a jamais pas été démontrée. Ainsi, le but de notre étude était d'améliorer la compréhension du mécanisme d'accumulation intracellulaire des complexes de [Cu(btsc)]. Nos résultats révèlent que l'accumulation intracellulaire du cuivre dans les cellules est très élevée et que ces composés ne sont pas substrats de la P-glycoprotéine. Cette protéine est un élément clé dans la faible perméabilité de la barrière hémato-encéphalique. Par ailleurs, nous n'avons pas détecté de réduction intracellulaire des ions cuivriques. Enfin, une fois dans la cellule, les complexes subissent une agrégation, ce qui suggère fortement que l'agrégation des complexes est la force motrice responsable de leur accumulation intracellulaire. Leur localisation intracellulaire est en partie diffuse mais une quantité non négligeable se localise autour des gouttelettes lipidiques
The molecular basis of Alzheimer’s disease has not been clearly established, but disruption of brain metal ion homeostasis, particularly copper and zinc, might be closely involved in the pathogenesis of this disease and its characteristic ß-amyloid neuropathological features. The use of complexes of copper with bis(thiosemicarbazones) ([Cu(btsc)]) has been proposed for the treatment of Alzheimer’s disease. Their mode of action could involve the modulation of the concentration of copper or zinc, and it has been suggested that these compounds can modulate the production of ß-amyloid peptide at the neuron level. Furthermore, it has been reported that [Cu(btsc)] complexes can be reduced inside the cells. However, to our knowledge the intracellular reduction of these compounds has never been demonstrated. Thus, the goal of our study was to increase understanding of the mechanism of intracellular accumulation of [Cu(btsc)] complexes. Our results reveal that the intracellular concentration of copper inside the cells is very high and that these compounds are not P-glycoprotein substrates. This protein is a key element of the low permeability of the blood–brain barrier. Furthermore, no intracellular reduction of cupric ions was detected. Finally, once inside the cells, the complexes undergo aggregation, strongly suggesting that aggregation of complexes is the driving force responsible for their intracellular accumulation. Their intracellular localization is partly scattered but a significant amount is localized around lipid droplets
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Books on the topic "Intracellular accumulation":

1

Brooks, Andrew William. Uptake, accumulation and intracellular distribution of aluminium and iron in the terrestrial snail, Helix Aspersa. Manchester: University of Manchester, 1993.

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2

Neligan, Patrick J., and Clifford S. Deutschman. Pathophysiology and causes of metabolic acidosis in the critically ill. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199600830.003.0255.

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Critical illness is typically characterized by changes in the balance of water and electrolytes in the extracellular space, resulting in the accumulation of anionic compounds that manifests as metabolic acidosis. Metabolic acidosis manifests with tachypnoea, tachycardia, vasodilatation, headache and a variety of other non-specific symptoms and signs. It is caused by a reduction in the strong ion difference (SID) or an increase in weak acid concentration (albumin or phosphate). Increased SID results from hyperchloraemia, haemodilution or accumulation of metabolic by-products. A reduction in SID results in a corresponding reduction is serum bicarbonate. There is a corresponding increase in alveolar ventilation and reduced PaCO2. Lactic acidosis results from increased lactate production or reduced clearance. Ketoacidosis is associated with reduced intracellular glucose availability for metabolism, and is associated with insulin deficiency and starvation. Hyperchloraemic acidosis is associated with excessive administration of isotonic saline solution, renal tubular acidosis and ureteric re-implantation. Renal acidosis is associated with hyperchloraemia, hyperphosphataemia, and the accumulation of medley nitrogenous waste products.
3

Fraser, Jamie L., Frédéric Sedel, and Charles P. Vendetti. Disorders of Cobalamin and Folate Metabolism. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780199972135.003.0027.

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Cobalamin C deficiency (cblC) and related disorders of intracellular cobalamin metabolism may present at any time from the prenatal period through adolescence/adulthood and are due to deficiency of the cobalamin cofactors adenosylcobalamin and methylcobalamin. Chronic complications of cblC depend on the age at presentation and may include poor growth, renal dysfunction, neuropsychiatric manifestations, intellectual disability, strokes, progressive leukoencephalopathy and spinal cord degeneration, psychiatric manifestations and executive function deficits, and optic nerve and retinal anomalies. While less common than in isolated MMA, acute metabolic decompensation may occur in cblC patients due to accumulation of methylmalonic acid and associate metabolites and should be managed as in isolated MMA in conjunction with a metabolic consultant. The most common inborn error of folate (vitamin B9) metabolism relevant for adult patients is methylenetetrahydrofolate reductase (MTHFR) deficiency. Manifestations are primarily neurological, but the disorder may present in a substantial number of adults with psychiatric symptoms. Early recognition with adequate treatment is crucial.

Book chapters on the topic "Intracellular accumulation":

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Labro, Marie-Thérèse. "Cellular accumulation of macrolide antibiotics. Intracellular bioactivity." In Macrolide Antibiotics, 37–52. Basel: Birkhäuser Basel, 2002. http://dx.doi.org/10.1007/978-3-0348-8105-0_4.

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Rozkov, A., S. Yang, and S. O. Enfors. "Dynamics of Proteolysis and its Influence on the Accumulation of Intracellular Recombinant Protein." In Novel Frontiers in the Production of Compounds for Biomedical Use, 339–47. Dordrecht: Springer Netherlands, 2001. http://dx.doi.org/10.1007/0-306-46885-9_20.

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Cook, Julia L., and Richard N. Re. "Intracellular Accumulation and Nuclear Trafficking of Angiotensin II and the Angiotensin II Type 1 Receptor." In The Local Cardiac Renin-Angiotensin Aldosterone System, 29–41. Boston, MA: Springer US, 2009. http://dx.doi.org/10.1007/978-1-4419-0528-4_4.

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Zimmermann, Arthur. "Bile Duct Carcinomas with Marked Extracellular or Intracellular Mucin Accumulation: Mucinous and Signet Ring Cell Carcinomas." In Tumors and Tumor-Like Lesions of the Hepatobiliary Tract, 1–12. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-26587-2_35-1.

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Zimmermann, Arthur. "Bile Duct Carcinomas with Marked Extracellular or Intracellular Mucin Accumulation: Mucinous and Signet Ring Cell Carcinomas." In Tumors and Tumor-Like Lesions of the Hepatobiliary Tract, 687–97. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-26956-6_35.

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Stone, Michael, and Connie Weaver. "Improving Human Nutrition: A Critical Objective for Potassium Recommendations for Agricultural Crops." In Improving Potassium Recommendations for Agricultural Crops, 417–45. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-59197-7_15.

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AbstractPotassium (K) is the most abundant cation in intracellular fluid where it plays a key role in maintaining cell function. The majority of K consumed (60–100 mmol day−1) is lost in the urine, with the remaining excreted in the stool, and a very small amount lost in sweat. Little is known about the bioavailability of K, especially from dietary sources. Less is understood on how bioavailability may affect health outcomes. Potassium is an essential nutrient that has been labeled a shortfall nutrient by recent Dietary Guidelines for Americans Advisory Committees. Increases in K intake have been linked to improvements in cardiovascular and other metabolic health outcomes. There is growing evidence for the association between K intake and blood pressure (BP) reduction in adults; hypertension (HTN) is the leading cause of the cardiovascular disease (CVD) and a major financial burden (US$53.2 billion) to the US public health system and has a significant impact on all-cause morbidity and mortality worldwide. Evidence is also accumulating for the protective effect of adequate dietary K on age-related bone loss and glucose control. Understanding the benefit of K intake from various sources may help to reveal how specific compounds and tissues influence K movement within the body, and further the understanding of its role in health.
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Berg, Richard A. "Intracellular Turnover of Collagen." In Regulation of Matrix Accumulation, 29–52. Elsevier, 1986. http://dx.doi.org/10.1016/b978-0-12-487425-1.50007-3.

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"Hepatocellular Adaptions and Intracellular Accumulation." In Jubb, Kennedy & Palmer's Pathology of Domestic Animals, 305–16. Elsevier, 2007. http://dx.doi.org/10.1016/b978-070202823-6.50102-0.

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Yu, Xin, and Jin Wang. "Quantitative measurement of PROTAC intracellular accumulation." In Methods in Enzymology. Elsevier, 2022. http://dx.doi.org/10.1016/bs.mie.2022.11.001.

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Sortino, Maria Angela, Sara Merlo, and Simona Spampinato. "Adipokines and Alzheimer's Disease." In Extracellular and Intracellular Signaling, 130–48. The Royal Society of Chemistry, 2011. http://dx.doi.org/10.1039/bk9781849733434-00130.

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Alzheimer's disease pathology involves β-amyloid and tau. Various potential pharmacological targets are discussed that may be able to alleviate the accumulation of β-amyloid and tau. Possible causes of Alzheimer's disease are discussed involving impaired glucose and lipid metabolism and obesity. Adipokines may be involved in the etiology of Alzheimer's disease. An extensive discussion of the evidence concerning the adipokines leptin, adiponectin, resistin, visfatin, plasminogen activator inhibitor, interleukin-6 and transforming growth factor β1 as causes of Alzheimer's disease is presented.

Conference papers on the topic "Intracellular accumulation":

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Hutcheson, Joshua D., M. K. Sewell-Loftin, and W. David Merryman. "Strain and Substrate Stiffness Affect Calcium Accumulation in Aortic Valve Interstitial Cells." In ASME 2011 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2011. http://dx.doi.org/10.1115/sbc2011-53611.

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The progression of aortic valve (AV) disease is often characterized by the formation of calcific nodules on thickened AV leaflets, limiting the biomechanical function of the valve. Calcification is a major problem that often leads to the failure of bioprosthetic replacement valves [1]. In these cases, the association of extracellular Ca2+ with phosphates remaining in cellular debris within the decellularized scaffolds has been proposed to lead to the nucleation and growth of Ca3(PO4)2 nodules. In native tissue, calcification is thought to be a more active process involving AV interstitial cells (AVICs). The exact molecular mechanisms that lead to the formation of these calcific nodules in native tissue remain unclear; however, AVICs have been shown to form nodule-like structures in vitro through differentiation to a phenotype with osteogenic character [2]. Additionally, in vitro nodules are characterized by activated smooth muscle α-actin positive AVICs and high levels of apoptosis [2–3]. Mechanical strain has also been shown to influence nodule formation in excised AV leaflets [4]. Intracellular Ca2+ exhibits mechanodependency in cultured cells [5], and heightened levels of intracellular Ca2+ have been shown to be associated with apoptosis in many cell types [6] In this study, we assess the role of mechanically-induced changes in intracellular calcium and its function in modulating AVIC behavior. We hypothesized that intracellular Ca2+ will increase in strained AVICs and that over time, this will lead to apoptosis. We believe that the results from this study will help illustrate the mechanotransductive role of Ca2+ in AVICs and may elucidate early cellular changes that lead to AV calcification.
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Saha, Jhuma, Jong-Hyuk Kim, Clarissa Amaya, Caleb Witcher, Derek M. Korpela, Ali Khammanivong, Josephine Taylor, Brad A. Bryan, and Erin B. Dickerson. "Abstract LB-013: Propranolol alters the intracellular accumulation of doxorubicin and sensitizes angiosarcoma cells to chemotherapy." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-lb-013.

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Sakai, T., K. Okada, H. Bando, S. Ueshima, N. Tanaka, and O. Matsuo. "ANALYSIS OF THE SECRETION MECHANISM OF TISSUE-TYPE PLASMINOGEN ACTIVATOR IN A HUMAN MELANOMA CELL LINE (BOWES)." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1644397.

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The human melanoma cell line (Bowes) secretes tissue-type plasminogen activator (t-PA) into the culture medium. As reported previously, the secretion of t-PA was depressed and t-PA was accumulated in the intracellular compartment at alternative sodium and potassium ion concentrations and also in the presence of monensin, an ionophore for monovalent cations. In the present study, the secretion and intracellular distribution of t-PA were investigated by radioisotope labeling and fractionation of the cell organelles under normal and monensin-treated conditions. Cell homogenate was fractioneted by discontinuous sucrose density gradient ultracentrifugation. The plasminogen activator (PA) activity or t-PA antigenicity in these fractions was not uniformly distributed, but rather localized in those fractions where cell organelles were rich. This implied that t-PA was enclosed by the intracellular membranous system. Cells were incubated with 35s-methionine and/or 3H-mannose to produce labeled intracellular glycoproteins including t-PA and its premature intermediates, which were separated by immunological adsorption to rabbit anti t-PA IgG-protein A Sepharose. Pulse labeling with 35s-methionine (3 min) demonstrated that intracellular t-PA was transported from the heavier fractions (rER), via intermediate ones (Golgi complex), to lighter ones. The radioactivity of the intracellular t-PA reached a maximum in 30 min, while that of secreted t-PA was observed in 30 min and increased linearly at least for the following 20 min. Enzymography revealed the major intracellular PA activity at 72 kDa and minor activity at 50 kDa. Monensin treatment (10 μM, 6 hr) caused accumulation of the 72 kDa component which was immunologically homologous to secreted t-PA. After long term (3 hr) simultaneous 35s-methionine and 3H-mannose labeling, the radioactivity ratio (3H/35S) the intracellular t-PA was increased in the presence of monensin. These results suggest that some sugar chain(s) in the t-PA molecule are of high mannose type, which is interfered with by monensin in the course of the intracellular processing and transport of t-PA.
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Moralev, A. D., O. V. Salomatina, M. A. Zenkova, and A. V. Markov. "NEW MARKER GENES OF TUMOR CELL RESISTANCE TO DOXORUBICIN AND THE DEVELOPMENT OF DRUG CANDIDATES FOR ITS THERAPY." In X Международная конференция молодых ученых: биоинформатиков, биотехнологов, биофизиков, вирусологов и молекулярных биологов — 2023. Novosibirsk State University, 2023. http://dx.doi.org/10.25205/978-5-4437-1526-1-277.

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Key genes associated with tumor cell resistance to doxorubicin (Dox) were identified. The screening of P-glycoprotein (P-gp) inhibiting activity of 8 amides of soloxolone was carried out. Through molecular docking, we demonstrated the ability of compounds to bind the transmembrane domain of P-gp. Hit compound sg-650 enhanced the intracellular accumulation of Rhodamine 123 and Dox, synergistically increased cytotoxic effects of Dox in vitro.
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Luo, Nan, Virali Patel, Minesh Patel, Eric Conte, and Robert Campbell. "Abstract 1322: Evaluating intracellular accumulation profiles of chemotherapeutic agents using CLENs for the treatment of Y79 retinoblastoma." In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1322.

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Dzhimak, Stepan S., Anna Elkina, and Alexandr A. Basov. "MECHANISMS OF FRACTIONATION OF STABLE ISOTOPES IN LIVING SYSTEMS." In NEW TECHNOLOGIES IN MEDICINE, BIOLOGY, PHARMACOLOGY AND ECOLOGY. Institute of information technology, 2021. http://dx.doi.org/10.47501/978-5-6044060-1-4.17.

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Some physical laws are considered that provide stable fractionation of isotopes, leading to the accumulation of certain isotopic forms in the intracellular and intercellular space with the manifestation of these effects at various levels of the organism. It is suggested that for a more complete understanding of the above processes, it is necessary to study the mechanism of exchange interaction between particles with integer spin (bosons) and half-integer spin (fermions).
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Mundhara, N., D. Panda, and A. Majumder. "PO-027 Methyl-β-cyclodextrin intensifies the effect of microtubule-targeting agents by increasing their intracellular drug accumulation." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.72.

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Ma, Ruonan, Ying Tian, Qian Zhang, Jing Fang, Jue Zhang, Hongqing Feng, and Yongdong Liang. "Atmospheric pressure cold plasma leads to apoptosis in saccharomyces cerevisiae by accumulation of intracellular reactive oxygen species and calcium." In 2013 IEEE 40th International Conference on Plasma Sciences (ICOPS). IEEE, 2013. http://dx.doi.org/10.1109/plasma.2013.6634816.

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van Hell, Albert J., Dayana Martins Gueth, Manuel Nuno Melo, Siewert Jan Marrink, and Marcel Verheij. "Abstract 2750: Short-chain lipids catalyse intracellular drug accumulation by a transient molecular gateway that allows plasma membrane traversal." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2750.

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Japtap, Shubhangi Ramling, Ameeta Ravikumar, Gouri Raut, and Ravi Kumar. "Statistical Optimization of Media for Enhancing Intracellular Lipid Content in Yarrowia Lipolytica NCIM 3589 Grown on Waste Cooking Oil for Biodiesel Production." In 2022 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2022. http://dx.doi.org/10.21748/yckc2922.

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The model oleaginous yeast Yarrowia lipolytica is capable of assimilating and metabolizing hydrophobic substrates and shown the ability to accumulate high amount of lipids for biodiesel production. In the present study, an effective hybrid RSM optimization strategy for media optimization for Yarrowia lipolytica NCIM 3589 grown on waste cooking oil (WCO) and glucose were undertaken to increase its lipid content for biodiesel production. Physico-chemical properties of varied WCO batches were determined and their effect on lipid accumulation in yeast studied. Low variation in lipid content was found in different batches ranging between 25-35% of dry biomass. As lipid content was dependent on extraction methods, different methods were evaluated to maximize yields and a modified acid hydrolysis method (42% lipid content of dry biomass) employed. Lipid accumulation media (LAM) components were initially chosen for a first level of statistical optimization by Plackett-Burman Design (PBD) of experiments using glucose or WCO as carbon sources. The WCO media gave significant increase (5.25 fold) in lipid accumulation when compared to glucose. The most significant factors identified media by PBD, namely, Na2HPO4, NH4Cl, yeast extract and chosen for a second level of optimization studies with a Box-Behnken Design (BBD). Response surface analysis and ANOVA were used to obtain the best-fit quadratic model and brought out the nature of the interactions amongst the three variables. Validation experiments of the model showed that lipid content in 120 h increased from 45.1% in the pre-optimized to 64.5% in optimized media. The FAME profile and fuel properties of the biodiesel were evaluated and found to be in accordance with international standards. The results obtained here after medium optimization hold promise in biodiesel production as the carbon source WCO used is a renewable substrate which not only is abundantly available and cheap, but also addresses the problem of waste disposal.

Reports on the topic "Intracellular accumulation":

1

Ostersetzer-Biran, Oren, and Alice Barkan. Nuclear Encoded RNA Splicing Factors in Plant Mitochondria. United States Department of Agriculture, February 2009. http://dx.doi.org/10.32747/2009.7592111.bard.

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Mitochondria are the site of respiration and numerous other metabolic processes required for plant growth and development. Increased demands for metabolic energy are observed during different stages in the plants life cycle, but are particularly ample during germination and reproductive organ development. These activities are dependent upon the tight regulation of the expression and accumulation of various organellar proteins. Plant mitochondria contain their own genomes (mtDNA), which encode for a small number of genes required in organellar genome expression and respiration. Yet, the vast majority of the organellar proteins are encoded by nuclear genes, thus necessitating complex mechanisms to coordinate the expression and accumulation of proteins encoded by the two remote genomes. Many organellar genes are interrupted by intervening sequences (introns), which are removed from the primary presequences via splicing. According to conserved features of their sequences these introns are all classified as “group-II”. Their splicing is necessary for organellar activity and is dependent upon nuclear-encoded RNA-binding cofactors. However, to-date, only a tiny fraction of the proteins expected to be involved in these activities have been identified. Accordingly, this project aimed to identify nuclear-encoded proteins required for mitochondrial RNA splicing in plants, and to analyze their specific roles in the splicing of group-II intron RNAs. In non-plant systems, group-II intron splicing is mediated by proteins encoded within the introns themselves, known as maturases, which act specifically in the splicing of the introns in which they are encoded. Only one mitochondrial intron in plants has retained its maturaseORF (matR), but its roles in organellar intron splicing are unknown. Clues to other proteins required for organellar intron splicing are scarce, but these are likely encoded in the nucleus as there are no other obvious candidates among the remaining ORFs within the mtDNA. Through genetic screens in maize, the Barkan lab identified numerous nuclear genes that are required for the splicing of many of the introns within the plastid genome. Several of these genes are related to one another (i.e. crs1, caf1, caf2, and cfm2) in that they share a previously uncharacterized domain of archaeal origin, the CRM domain. The Arabidopsis genome contains 16 CRM-related genes, which contain between one and four repeats of the domain. Several of these are predicted to the mitochondria and are thus postulated to act in the splicing of group-II introns in the organelle(s) to which they are localized. In addition, plant genomes also harbor several genes that are closely related to group-II intron-encoded maturases (nMats), which exist in the nucleus as 'self-standing' ORFs, out of the context of their cognate "host" group-II introns and are predicted to reside within the mitochondria. The similarity with known group-II intron splicing factors identified in other systems and their predicted localization to mitochondria in plants suggest that nuclear-encoded CRM and nMat related proteins may function in the splicing of mitochondrial-encoded introns. In this proposal we proposed to (i) establish the intracellular locations of several CRM and nMat proteins; (ii) to test whether mutations in their genes impairs the splicing of mitochondrial introns; and to (iii) determine whether these proteins are bound to the mitochondrial introns in vivo.
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Ficht, Thomas, Gary Splitter, Menachem Banai, and Menachem Davidson. Characterization of B. Melinensis REV 1 Attenuated Mutants. United States Department of Agriculture, December 2000. http://dx.doi.org/10.32747/2000.7580667.bard.

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Brucella Mutagenesis (TAMU) The working hypothesis for this study was that survival of Brucella vaccines was directly related to their persistence in the host. This premise is based on previously published work detailing the survival of the currently employed vaccine strains S19 and Rev 1. The approach employed signature-tagged mutagenesis to construct mutants interrupted in individual genes, and the mouse model to identify mutants with attenuated virulence/survival. Intracellular survival in macrophages is the key to both reproductive disease in ruminants and reticuloendothelial disease observed in most other species. Therefore, the mouse model permitted selection of mutants of reduced intracellular survival that would limit their ability to cause reproductive disease in ruminants. Several classes of mutants were expected. Colonization/invasion requires gene products that enhance host-agent interaction or increase resistance to antibacterial activity in macrophages. The establishment of chronic infection requires gene products necessary for intracellular bacterial growth. Maintenance of chronic infection requires gene products that sustain a low-level metabolism during periods characterized little or no growth (1, 2). Of these mutants, the latter group was of greatest interest with regard to our originally stated premise. However, the results obtained do not necessarily support a simplistic model of vaccine efficacy, i.e., long-survival of vaccine strains provides better immunity. Our conclusion can only be that optimal vaccines will only be developed with a thorough understanding of host agent interaction, and will be preferable to the use of fortuitous isolates of unknown genetic background. Each mutant could be distinguished from among a group of mutants by PCR amplification of the signature tag (5). This approach permitted infection of mice with pools of different mutants (including the parental wild-type as a control) and identified 40 mutants with apparently defective survival characteristics that were tentatively assigned to three distinct classes or groups. Group I (n=13) contained organisms that exhibited reduced survival at two weeks post-infection. Organisms in this group were recovered at normal levels by eight weeks and were not studied further, since they may persist in the host. Group II (n=11) contained organisms that were reduced by 2 weeks post infection and remained at reduced levels at eight weeks post-infection. Group III (n=16) contained mutants that were normal at two weeks, but recovered at reduced levels at eight weeks. A subset of these mutants (n= 15) was confirmed to be attenuated in mixed infections (1:1) with the parental wild-type. One of these mutants was eliminated from consideration due to a reduced growth rate in vitro that may account for its apparent growth defect in the mouse model. Although the original plan involved construction of the mutant bank in B. melitensis Rev 1 the low transformability of this strain, prevented accumulation of the necessary number of mutants. In addition, the probability that Rev 1 already carries one genetic defect increases the likelihood that a second defect will severely compromise the survival of this organism. Once key genes have been identified, it is relatively easy to prepare the appropriate genetic constructs (knockouts) lacking these genes in B. melitensis Rev 1 or any other genetic background. The construction of "designer" vaccines is expected to improve immune protection resulting from minor sequence variation corresponding to geographically distinct isolates or to design vaccines for use in specific hosts. A.2 Mouse Model of Brucella Infection (UWISC) Interferon regulatory factor-1-deficient (IRF-1-/- mice have diverse immunodeficient phenotypes that are necessary for conferring proper immune protection to intracellular bacterial infection, such as a 90% reduction of CD8+ T cells, functionally impaired NK cells, as well as a deficiency in iNOS and IL-12p40 induction. Interestingly, IRF-1-/- mice infected with diverse Brucella abortus strains reacted differently in a death and survival manner depending on the dose of injection and the level of virulence. Notably, 50% of IRF-1-/- mice intraperitoneally infected with a sublethal dose in C57BL/6 mice, i.e., 5 x 105 CFU of virulent S2308 or the attenuated vaccine S19, died at 10 and 20 days post-infection, respectively. Interestingly, the same dose of RB51, an attenuated new vaccine strain, did not induce the death of IRF-1-/- mice for the 4 weeks of infection. IRF-1-/- mice infected with four more other genetically manipulated S2308 mutants at 5 x 105 CFU also reacted in a death or survival manner depending on the level of virulence. Splenic CFU from C57BL/6 mice infected with 5 x 105 CFU of S2308, S19, or RB51, as well as four different S2308 mutants supports the finding that reduced virulence correlates with survival Of IRF-1-/- mice. Therefore, these results suggest that IRF-1 regulation of multi-gene transcription plays a crucial role in controlling B. abortus infection, and IRF-1 mice could be used as an animal model to determine the degree of B. abortus virulence by examining death or survival. A3 Diagnostic Tests for Detection of B. melitensis Rev 1 (Kimron) In this project we developed an effective PCR tool that can distinguish between Rev1 field isolates and B. melitensis virulent field strains. This has allowed, for the first time, to monitor epidemiological outbreaks of Rev1 infection in vaccinated flocks and to clearly demonstrate horizontal transfer of the strain from vaccinated ewes to unvaccinated ones. Moreover, two human isolates were characterized as Rev1 isolates implying the risk of use of improperly controlled lots of the vaccine in the national campaign. Since atypical B. melitensis biotype 1 strains have been characterized in Israel, the PCR technique has unequivocally demonstrated that strain Rev1 has not diverted into a virulent mutant. In addition, we could demonstrate that very likely a new prototype biotype 1 strain has evolved in the Middle East compared to the classical strain 16M. All the Israeli field strains have been shown to differ from strain 16M in the PstI digestion profile of the omp2a gene sequence suggesting that the local strains were possibly developed as a separate branch of B. melitensis. Should this be confirmed these data suggest that the Rev1 vaccine may not be an optimal vaccine strain for the Israeli flocks as it shares the same omp2 PstI digestion profile as strain 16M.

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