Areas of expertise
Toxins and Antioxidants and Alzheimer's Disease
- Full Professor
- Holder of the Louise and André Charron Research Chair in Alzheimer’s Disease
The main goal of our laboratory is to understand the crucial role of free radicals and oxidative stress on cerebral functions during aging and in some neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. The accumulation free radicals and oxidative stress could induce cell death. On the other hand, free radicals could also be intracellular mediators by activating cell signalling pathways and regulate the expression of some genes involved in neuroprotection. The wide spectrum of activity and distribution of free radicals make them among important biological agents involved in some neurodegenerative diseases such as Alzheimer’s or Parkinson’s diseases. A better knowledge of their intracellular functions is an essential step to prevent pathology where free radicals are involved.
It is well known that free radicals can induce the oxidation of macromolecules such as proteins, lipids and DNA. In Alzheimer’s disease, these by-products of the oxidation macromolecules are detected in vulnerable regions of the brain in early stages of the disease. However, the role of these by-products of oxidation in neurodegeneration remains to be clarified. The objective of our laboratory is to investigate the contribution of these by-products of oxidation in the pathophysiology of Alzheimer’s disease.
Free radicals and oxidative stress could be produced following a dysfunction of cellular metabolism. However, they could be generated following exposure to environmental compounds such as pesticides. Another objective of our laboratory is to better understand the role of these compounds in the pathophysiology of Parkinson’s disease.
In parallel, our laboratory investigates the neuroprotective of some natural compounds such as polyphénols present in diet and in natural extracts. In addition to their antioxidant activity, these compounds could have several cellular targets likely involved in neuroprotection. Our objective is to identify polyphenols with neuroprotective activity. At long term, these compounds could be useful in the prevention and treatment of some neurodegenerative disorders.
With the aging of the population, treatment of neurodegenerative disorders associated to aging remains a challenge and an active area of research. Using an interdisciplinary approach, our laboratory investigates the development new nanoneuropharmacological tools based on polymeric biocompatible and biodegradable nanoparticles. At long term, these nanoneuropharmacological tools could be useful for the diagnostic, the prevention and the treatment of neurodegenerative disorders by enhancing the bioavailability and the efficacy of pharmacological drugs in the brain.
Publications avec comités de pairs
69- BERNARD-PATRZYNSKI F, LÉCUYER MA, PUSCAS I, BOUKHATEM I, CHARABATI M, BOURBONNIÈRE L, RAMASSAMY C, LECLAIR G, PRAT A, ROULLIN VG. (2019).
Isolation of endothelial cells, pericytes and astrocytes from mouse brain.
PLoS One. 14(12:e0226302): 1-20.
68- PERROTTE M; HADDAD M; LE PAGE A; FROST EH, FULÖP T;RAMASSAMY C.(2019).
Profile of pathogenic proteins in total circulating extracellular vesicles in mild cognitive impairment and during the progression of Alzheimer’s disease.
Neurobiology of Aging. [ahead of print]
67- MOYSE E, HADDAD M, BENLABIOD C,RAMASSAMY C, KRANTIC S. (2019).
Common Pathological Mechanisms and Risk Factors for Alzheimer’s Disease and Type-2 Diabetes: Focus on Inflammation.
Current Alzheimer Research 16(11):986-1006.
66- CHARABATI M, RABANEL JM,RAMASSAMY C,PRATT A (2019).
Overcoming the Brain Barriers: From Immune Cells to Nanoparticles.
Trends in Pharmacological Sciences 41 (1), 42-54.
65- LAMBERT de MALEZIEU M, FERRON S, SAUVAGER A, COURTEL P,RAMASSAMY C, TOMASI S, ABASQ ML. (2019).
UV-Vis Spectroelectrochemistry of Oleuropein, Tyrosol, and p-Coumaric Acid Individually and in an Equimolar Combination. Differences in LC-ESI-MS2 Profiles of Oxidation Products and their Neuroprotective Properties.
Biomolecules 9(12:E802): 1-18.
64- HADDAD M, PERROTTE M, KHEDHER MRB, DEMONGIN C, LEPAGE A,FÜLÖP T,RAMASSAMY C. (2019).
Methylglyoxal and Glyoxal as Potential Peripheral Markers for MCI Diagnosis and Their Effects on the Expression of Neurotrophic, Inflammatory and Neurodegenerative Factors in Neurons and in Neuronal Derived-Extracellular Vesicles.
International Journal of Molecular Sciences 20(19:E4906): 1-19.
63- LAMBERT de MALEZIEU M, COURTEL P, SLENO L, ABASQ M.-L,RAMASSAMY C.(2019).
Synergistic properties of bioavailable phenolic compounds from olive oil: Electron transfer and neuroprotective properties. Nutritional Neuroscience. [ahead of print] :1-14.
62- HADDAD, M.;PERROTTE, M.; LANDRI, S.; LEPAGE, A.; FULOP, T.; RAMASSAMY, C. (2019).
Circulating and Extracellular Vesicles Levels of N-(1-Carboxymethyl)-L-Lysine (CML) Differentiate Early to Moderate Alzheimer’s Disease
Journal of Alzheimers Disease , 69 (3):751-762.
61- MOYSE, E., ARSENAULT, M*., GAUDREAU, P., FERLAND, G. & RAMASSAMY, C.(2019)
Brain region-specific effects of long-term caloric restriction on redox balance of the aging rat,
Mechanisms of Ageing and Development, 179, 51-59.
60- RABANEL, J. M.*, ADIBNIA, V., TEHRANI, S. F., SANCHE, S., HILDGEN, P., BANQUY, X. & RAMASSAMY, C.(2019)
Nanoparticle heterogeneity: an emerging structural parameter influencing particle fate in biological media?,
Nanoscale, 11, 383-406.
59- PERROTTE, M.*, LE PAGE, A., FOURNET, M.*, LE SAYEC, M., RASSART, E., FULOP, T. & RAMASSAMY, C.(2019)
Blood-based redox-signature and their association to the cognitive scores in MCI and Alzheimer’s disease patients,
Free Radical Biology and Medicine, 130, 499-511.
58- SINGH, M*. & RAMASSAMY, C.(2017)
In vitro screening of neuroprotective activity of Indian medicinal plant Withania somnifera,
Journal of Nutritional Science, 6, e54, 1-5x.
57- PAKA, G. D.* &RAMASSAMY, C. (2016)
Optimization of curcumin loaded-PEG-PLGA nanoparticles by GSH functionalization. Investigation of the internalization pathway in neuronal cells,
Molecular Pharmaceutics, 14(1)`93-106.
56- DJIOKENG PAKA, G., DOGGUI, S., ZAGHMI, A., SAFAR, R., DAO, L., REISCH, A., KLYMCHENKO, A., ROULLIN, V. G., JOUBERT, O. &RAMASSAMY, C. (2016)
Neuronal Uptake and Neuroprotective Properties of Curcumin-Loaded Nanoparticles on SK-N-SH Cell Line: Role of Poly(lactide-co-glycolide) Polymeric Matrix Composition,
Molecular Pharmaceutics, 13, 2, 391-403.
55- BELKACEMI, A. &RAMASSAMY, C. (2016)
Anthocyanins Protect SK-N-SH Cells Against Acrolein-Induced Toxicity by Preserving the Cellular Redox State,
Journal of Alzheimer’s Disease, 50, 4, 981-998.
54- BELKACEMI, A. &RAMASSAMY, C.(2016)
Innovative anthocyanin/anthocyanidin formulation protects SK-N-SH cells against the amyloid-β peptide-induced toxicity: Relevance to alzheimer’s disease,
Central Nervous System Agents in Medicinal Chemistry, 16, 1, 37-49.
53- RABANEL, J. M., FAIVRE, J., PAKA, G. D.,RAMASSAMY, C., HILDGEN, P. & BANQUY, X. (2015)
Effect of polymer architecture on curcumin encapsulation and release from PEGylated polymer nanoparticles: Toward a drug delivery nano-platform to the CNS,
European Journal of Pharmaceutics and Biopharmaceutics, 96, 409-420.
52- MOYSE, E., ARSENEAULT, M., GAUDREAU, P., FERLAND, G. &RAMASSAMY, C. (2015)
Gender- and region-dependent changes of redox biomarkers in the brain of successfully aging LOU/C rats,
Mechanisms of Ageing and Development, 149, 19-30.
51- CHEN, M., TAN, M., JING, M., LIU, A., LIU, Q., WEN, S., CHEN, Z., CHAO, X., HE, X.,RAMASSAMY, C., GAO, Y. & PI, R. (2015)
Berberine protects homocysteic acid-induced HT-22 cell death: involvement of Akt pathway,
Metabolic Brain Disease, 30, 1, 137-42.
50- CHAO, X. J., CHEN, Z. W., LIU, A. M., HE, X. X., WANG, S. G., WANG, Y. T., LIU, P. Q.,RAMASSAMY, C., MAK, S. H., CUI, W., KONG, A. N., YU, Z. L., HAN, Y. F. & PI, R. B. (2014)
Effect of Tacrine-3-caffeic Acid, A Novel Multifunctional Anti-Alzheimer’s Dimer, Against Oxidative-Stress-Induced Cell Death in HT22 Hippocampal Neurons: Involvement of Nrf2/HO-1 Pathway,
CNS Neuroscience & Therapeutics, 20, 9, 840-50.
49- HUANG, Y. J., QIN, J., CHEN, M. H., CHAO, X. J., CHEN, Z. W.,RAMASSAMY, C., PI, R. B. & JIN, M. H. (2014)
Lithium Prevents Acrolein-Induced Neurotoxicity in HT22 Mouse Hippocampal Cells,
Neurochemical Research, 39, 4, 677-684.
48- M. Tan,Y. Ouyang, M Jin, M Chen, P Liu, X Chao, Z Chen, X Chen,CRamassamy C,Y Gao, R Pi.
Downregulation of Nrf2/HO-1 pathway and activation of JNK/c-Jun pathway are involved in Homocysteic acid-induced cytotoxicity in HT-22 cells.Toxicol Lett. 2013 Aug 27. S0378-4274(13) 01283-6.
47- S. Doggui, A. Belkacemi, G. Djiokeng Paka,M Perrotte, R. Pi andC. Ramassamy
Curcumin protects neuronal-like cells against acrolein by restoring Akt and redox signaling pathways.
Mol. Nutr. & Food Res. 2013 Sep;57(9): 1660-70.
46- MSingh*, V Murthy,CRamassamy.
Neuroprotective mechanisms of the standardized extract of Bacopa monniera in a paraquat/diquat-mediated acute toxicity.
Neurochem Int.2013 Apr;62(5):530-9.
45- YJHuang, MHJin, RB Pi, JJ Zhang*, Y Ouyang, XJ Chao, MH Chen, PQ Liu, JC Yu, C Ramassamy, J Dou, XH Chen, YM Jiang, J Qin.
Acrolein induces Alzheimer’s disease-like pathologies in vitro and in vivo.
Toxicol Lett. 2013; 217(3):184-91.
44- Y.Huang, M. Jin, RB. Pi, J. Zhang*, M Chen, Y Ouyang, A Liu, X Chao, P Liu, J Liu, C Ramassamy, J Qin.
Protective effects of caffeic acid and caffeic acid phenethyl ester against acrolein-induced neurotoxicity in HT22 mouse hippocampal cells.
Neurosci Lett. 2013;535:146-51.
43- S Doggui#, Lé Dao and CRamassamy
Potential of drug-loaded nanoparticles for Alzheimer’s disease: diagnosis, prevention and treatment.
Therapeutic Delivery 20123(9):1025-1027.
42- S Doggui*#, J K Sahni*#, M Arseneault, Lé Dao and CRamassamy
Neuronal uptake and neuroprotective effect of curcumin-loaded PLGA nanoparticles on the human SK-N-SH cell line.
J Alzheimers Dis. 201230(2):377-92 #: 1st co-author
41- ABelkacemi*,C Ramassamyu
Time sequence of oxidative stress in the brain from transgenic mouse models of Alzheimer’s disease related to the amyloid-βcascade.
Free Radic Biol Med. 2012; 52(3):593-600.
40- M Singh*, Ven Murthy and C Ramassamy
Standardized extracts of Bacopa monniera protect against MPP+ and Paraquat induced- toxicities bymodulating mitochondrial activities, proteasomal functions and redox pathways.
Toxcicol.Sci. 2012; 125(1):219-32.
39- ABelkacemi*, S Doggui*, L Dao andC Ramassamy
Challenges associated with curcumin therapy in Alzheimer’s disease. Expert. Rev. Molecular Med.2011; 13:e34. Review.
38- C. Ramassamy and A Belkacémi*
Nutrition and Alzheimer’s disease: is there any connection?
Cur.Alz.Res. 2011; 8: 443-444.
37- C. St-Laurent Thibault*, M. Arsenault*, and C. Ramassamy
Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against ß-amyloid toxicity. Involvement of the NF-kB signaling.
Cur.Alz.Res 2011; 8:543-551.
36- Dang Thanh*, M. Arseneault and C Ramassamy
Regulation of redox-sensitive signaling pathways in rat primary astrocytes following acrolein exposure.
J Alzheimers Dis. 2011; 21:263-277.
35- C Ramassamy, S Doggui*, L Dao
Nanoneuropharmacology: A challenging concept in pharmaceutical investigations for the next decade.
Int J Pharma Investig 2011; 1:2-3.
34- J K Sahni*, S Doggui*, J Ali, S Baboota, L Dao and C Ramassamy
Neurotherapeutic applications of Nanoparticles in Alzheimer’s disease.
J.Control.Release (IF 7), June, 2011; 152(2):208-31.
33- MSingh*, Dang Than N*, M Arseneault* and C Ramassamy
Role of by-product of lipid oxidation in Alzheimer’s disease: a focus on acrolein.
J Alzheimers Dis. 2010 21(3):741-756, 2010.
32- N.Dang Than*, M Arseneault*, N Zarkovic, G Waeg and C. Ramassamy
Molecular Regulations Induced by Acrolein in Neuroblastoma SK-N-SH Cells: Relevance to Alzheimer’s Disease.
J Alzheimers Dis. 21, 1197–1216, 2010.
31- M.Singh*, V. Murthy and C. Ramassamyi
Modulation of Hydrogen Peroxide and Acrolein-Induced Oxidative Stress, Mitochondrial Dysfunctions and Redox Regulated Pathways by the Bacopa Monniera Extract: Potential Implication in Alzheimer’s Disease.
J Alzheimers Dis. 21(1):229-247, 2010.
30- N.Dang Than*, M Arseneault*,MRV Murthy and C Ramassamy
Potential role of acrolein in neurodegeneration and in Alzheimer’s Disease.
Curr Mol Pharmacol. 3(2):66-78, 2010 (IF 3.46).
29- T. Vuong*, C. Matar,C. Ramassamy,P. S. Haddad,
Biotransformed blueberry juice protects neurons from hydrogen peroxide induced oxidative stress and MAPKs pathway alterations.
Br.J.Nutr. 12:1-8, 2010.
28- Ali J, Ali M, Baboota S, Sahni JK*,Ramassamy C, Dao L, Bhavna.
Potential of nanoparticulate drug delivery systems by intranasal administration.
Curr Pharm Des. 2010 May;16(14):1644-53.
27- Fortier, M., Frouin, H., Cloutier*, A, Arseneault*, M.,Ramassamy, C., Badiwa-Bizowe, B, St-Louis, R., Pelletier, E. and Michel Fournier.
Toxicological effects of mouse diet contaminated with TBT on the immune and neurological systems of c57bl/6 mice.
Toxicol & Environmental Chem. 92(5): 927-945, 2010.
26- M.R. Ven Murthy, Prabhakar K. Ranjekar, C. Ramassamy, M. Deshpande et al.
Scientific basis for the use of Indian Ayurvedic medicinal plants in the treatment of neurodegenerative disorders.
Central Nervous System Agents in Medicinal Chemistry (formerly”Current medicinal chemistry. Central nervous system agents”)10, 238-246, 2010.
25- Vuong T*, Benhaddou-Andaloussi A, Brault A, Harbilas D, Martineau LC, Vallerand D, Ramassamy C, Matar C, Haddad PS.
Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKA(y) mice. Int J Obes. 33(10) : 1166-73, 2009.
24- Owen JB, Opii WO,Ramassamy C, Pierce WM, Butterfield DA.
Proteomic analysis of brain protein expression levels in NF-kappabeta p50 (-/-) homozygous knockout mice. Brain Res. 1240: 22-30. 2008).
23- M. Singh*, M. Arseneault*, T. Sanderson, V. Murthy, and C. Ramassamy
Challenges for research on polyphenols in neurodegenerative diseases: Bioavailability, metabolism, cellular and molecular mechanisms.
J.Agr.Food.Chem. 56(13): 4855-73. 2008.
22- Tri Vuong*, Louis C. Martineau, C. Ramassamy, Chantal Matar, Pierre S. Haddad
Fermented Canadian lowbush blueberry juice (Vaccinium Angustifolium Ait.) stimulates glucose uptake and AMP-activated protein kinase (AMPK) in insulin-sensitive cultured muscle cells and adipocytes.
Canadian J. Physiology and Pharmacol. 85(9):956-65, 2007.
21- C. Ramassamy, F. Longpré* and Y. Christen*
Ginkgo biloba extract (EGb 761) in Alzheimer’s disease: is there any evidence?
Current Alzheimer Res 4 (3), 253-262, 2007.
20- F. Longpré*, P.Garneau*, Y. Christen and C. Ramassamy
Protection by EGb 761 against the ß-amyloid induced-neurotoxicity: involvement of NF-kB, SIRT1 and MAPKs pathways and inhibition of the amyloid fibrils formation.
Free Radical Biol.& Med . 41(12), 1781-1795, 2006.
19- C. Ramassamy
Emerging role of polyphenolic compounds in the treatment of Alzheimer’s disease.
Eur.J.Pharmacol. 545 (2006) 51–64.
18- Gagne B, Gelinas S, Bureau G, Lagace B, Ramassamy C, Chiasson K, Valastro B, Martinoli MG.
Effects of estradiol, phytoestrogens, and Ginkgo biloba extracts against 1-methyl-4-phenyl-pyridine-induced oxidative stress. Endocrine. 2003, 21(1):89-95.
17- C. Ramassamy, P. Krzywkowski, D. Averill, U. Beffert, L. Theroux, S. Lussier-Cacan, J. Davignon, Y. Christen and J. Poirier.
Influence of the absence of apolipoprotein E on lipid oxidation: an age-related study on the apoE-deficient mice model.
Mol.Brain Res .86(1-2):76-83, 2001.
16- C.B. Patrick, P. Krzywkowski, C.Ramassamy, J. Poirier and E. Murphy.
Phospholipiase A2 Activity in the hippocampus of aged apolipoprotein E deficient mice.
Neurosci. Let. 288: 211-214, 2000.
15 – S. Bastianetto, C. Ramassamy, S. Doré, Y. Christen, J. Poirier and R. Quirion.
The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid.
Eur. J. Neuroscience 12, 1882-1891, 2000.
14- C. Ramassamy, D. Averill , U. Beffert, L. Theroux, S. Lussier-Cacan, J. Davignon, Y.Christen and J. Poirier.
Oxidative insults in Alzheimer’s disease brain are associated to apolipoprotein E genotype. Neurobiol.
Dis 7, 23-37, 2000.
13- C. Ramassamy, D. Averill , U. Beffert, S. Lussier-Cacan, J. Davignon, Y. Christen and J. Poirier.
Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer’s disease is related to the apolipoprotein E genotype.
Free Rad.Biol.Med. 27, 544-553, 1999.
12- U. Beffert, J. S. Cohn, C. Petit-Turcotte, M. Tremblay, N. Aumont, C. Ramassamy, J. Davignon and J. Poirier.
Apolipoprotein E and b-amyloid levels in the hippocampus and frontal cortex of Alzheimer’s disease subjects are disease-related and apolipoprotein E genotype dependent.
Brain Res. 843, 87-94, 1999.
11- S. Bastianetto, C. Ramassamy, J. Poirier and R. Quirion.
Dehydroepiandrosterone (DHEA) protects hippocampal cells from oxidative stress-induced damage.
Mol.Brain Res. 66, 35-41, 1999x.
10- U. Beffert, M. Danik, P. Krzywkowski, C. Ramassamy, F. Berrada and J. Poirier.
The neurobiology of apolipoproteins and their receptors in the central nervous system and Alzheimer’s disease.
Brain Research Rev. 27, 119-142, 1998.
4- DOGGUI, S., DAO, L. &RAMASSAMY, C. (2012)
Potential of drug-loaded nanoparticles for Alzheimer’s disease: diagnosis, prevention and treatment,
Therapeutic Delivery, 3, 9, 1025-7.
3- M Singh* andC Ramassamy
Environmental exposure to pesticides and neurodegenerative diseases.
J. Alzheimer’s Dis & Parkinsonism 2(3), 2-3, 2012.i
2- C. Ramassamy, S Doggui*, L Dao
Nanoneuropharmacology: A challenging concept in pharmaceutical investigations for the next decade.
J.Pharm.Investigation 1(1) (2011) 2-3.
1- Ramassamy C., Belkacémi A*.
Nutrition and Alzheimer’s disease: is there any connection?
Curr Alzheimer Res. 2011 8(5):443-4.
LIVRE: Recent research on nutrition and the prevention of Alzheimer’s disease.
Scientific Editor: C. Ramassamy, editor: Research SignPost ISBN- 978-81-7895-470-7, 2010
Journal title: Current Alzheimer Research, hot topic issues on
“Nutrition and Alzheimer’s disease: is there any connection? (2010)
Guest editor: C.Ramassamy
Chapitres de livre
18- RABANEL, J. M.*, DJIOKENG-PAKA, G.* & RAMASSAMY, C.(2018)
Polymeric nanoparticles as a vehicle for delivery of antioxidants in the brain: Potential application in neurodegenerative diseases.
In: RIHN, B. H. (Ed.) Biomedical Application of Nanoparticles. Boca Raton, CRC Press 277-300.
17- Perrotte M*, Pincemail J, Haddad M*,C Ramassamy (Sous presse)
Redox based-peripheral biomarkers in Alzheimer’s disease : challenges, limits and prospects.
In: Oxidative Stress in Applied Basic Research and Clinical Practice. Scientific editors: S. Bondy and A Campbell. Editor: Springer.
16- J K Sahni*, S. Doggui*, L.H. Dao,C. Ramassamy
Nanotechnology for cerebral delivery of nutraceuticals for the treatment of neurodegenerative diseases.
In: Nutraceuticals and neurodegenerative disease prevention. Scientific editors: Dr. Gopinadhan Paliyath, Dr. Marica Bakovic, Dr. Kalidas Shetty. Editor: Wiley-Blackwell, Iowa. 263-283, 2011.
15- J. K. Sahni*, L. Letenneur, L. H. Dao,C. Ramassamy
Antioxidants and diet approach as a potential neuroprotective strategy for Alzheimer’s disease with a focus on brain targets by polyphenols
In : Lifetime nutritional influences on cognition, behaviour and psychiatric illness. Scientific editor: David Benton, Editor: Woodhead Publishing. 392-419, 2011.
14- C. Ramassamy, M. Arseneault* and D Thanh Nam*
Free radical-mediated damages to brain in Alzheimer’s disease: Role of acrolein and preclinical promise of antioxidant polyphenols.
In: Oxidative Stress in Basic Research and Clinical Practice : Aging and Age-Related Disorders
Scientific editor: S.Bondy, Editor: Springer, 417-438. 2010.
13- C. Ramassamy, S. Doggui*, M. Arsenault*and Lé Dao
Towards a nutritional approach for the prevention of Alzheimer’s disease: promise of polyphenolic components. In: Recent research on nutrition and the prevention of Alzheimer’s disease.
Chap. 1, pp.1-18, 2010.
Scientific Editor: C. Ramassamy, Editor: Research SignPost. ISBN 978-81-7895-470-7
12- M.Singh*, V.Murthy, M.Arseneault* and C. Ramassamy
Neuroprotective effects of polyphenols in Alzheimer’s disease: antioxidants activities and beyond.
In: New Research on Dietary Polyphenols & Health”. Ed. Nova Science Publishers 113-15, 2008.
11- M.Singh* and C. Ramassamy
Beneficial effects of phenolic compounds from fruits and vegetables in neurodegenerative diseases.
In: Improving the health-promoting properties of fruit and vegetable products. Ed. Pr F. Tomás Barberán and Dr. María Isabel Gil, CEBAS CSIC, Spain (in press) Woodhead Publishing Limited, Cambridge UK. chapitre 7: 145-181, 2008.