Markstein M, Dettorre S, Cho J, Neumüller RA, Craig-Müller S, Perrimon N. Systematic screen of chemotherapeutics in Drosophila stem cell tumors. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4530-5. doi: 10.1073/pnas.1401160111. PMID: 24616500; PMCID: PMC3970492.
From the abstract: "Here we report the development of an in vivo system to study the
interaction of stem cells with drugs using a tumor model in the adult Drosophila
intestine. ... An immediate implication
of our findings is that supplementing traditional chemotherapeutics
with anti-inflammatories may reduce tumor recurrence."
Tuesday, June 24, 2014
Thursday, June 12, 2014
Fly study relevant to Parkinson's disease links LRRK2 with Akt, FOXO1 and apoptosis
Chuang CL, Lu YN, Wang HC, Chang HY. Genetic dissection reveals that Akt is the critical kinase downstream of LRRK2 to phosphorylate and inhibit FOXO1, and promotes neuron survival. Hum Mol Genet. 2014 Jun 10. PMID: 24916379.
From the abstract: "... Here, we show that LRRK2 protects neurons against apoptosis induced by the Drosophila genes grim, hid and reaper. ... These data establish that LRRK2 can protect neurons from apoptotic insult through a survival pathway in which LRRK2 signals to activate Akt, and then inhibits FOXO1. These results might indicate that a therapeutic pathway to promote neuron survival and to prevent neurodegeneration in Parkinson's disease."
From the abstract: "... Here, we show that LRRK2 protects neurons against apoptosis induced by the Drosophila genes grim, hid and reaper. ... These data establish that LRRK2 can protect neurons from apoptotic insult through a survival pathway in which LRRK2 signals to activate Akt, and then inhibits FOXO1. These results might indicate that a therapeutic pathway to promote neuron survival and to prevent neurodegeneration in Parkinson's disease."
Tuesday, June 10, 2014
Study of normal function of Tau in flies includes report of partial rescue of Tau mutant with human Tau
Bolkan BJ, Kretzschmar D. Loss of Tau results in defects in photoreceptor development and progressive neuronal degeneration in Drosophila. Dev Neurobiol. 2014 Jun 7. PMID: 24909306.
From the abstract: "... Expression of wild type human Tau partially rescued the neurodegenerative phenotype caused by the loss of endogenous dTau, suggesting that the functions of Tau proteins are functionally conserved from flies to humans."
From the abstract: "... Expression of wild type human Tau partially rescued the neurodegenerative phenotype caused by the loss of endogenous dTau, suggesting that the functions of Tau proteins are functionally conserved from flies to humans."
Monday, June 9, 2014
Cold temperature & fly models of Hereditary Spastic Paraplegia
Baxter SL, Allard DE, Crowl C, Sherwood NT. Cold temperature improves mobility and survival in drosophila models of Autosomal-Dominant Hereditary Spastic Paraplegia (AD-HSP). Dis Model Mech. 2014 Jun 6. pii: dmm.013987. PMID: 24906373.
Friday, June 6, 2014
Two new reports related to Parkinson's disease
Yun J, Puri R, Yang H, Lizzio MA, Wu C, Sheng ZH, Guo M. MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. Elife. 2014 Jun 4;3:e01958. PMID: 24898855.
From the abstract: "In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. ... We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone ... Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD."
Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y. PINK1-Mediated Phosphorylation of Parkin Boosts Parkin Activity in Drosophila. PLoS Genet. 2014 Jun 5;10(6):e1004391. PMID: 24901221.
From the abstract: "Two genes linked to early onset Parkinson's disease, PINK1 and Parkin, encode a protein kinase and a ubiquitin-ligase, respectively. Both enzymes have been suggested to support mitochondrial quality control. ... Our data reveal that Parkin phosphorylation regulates not only mitochondrial function but also the neuronal activity of dopaminergic neurons in vivo, suggesting that the appropriate regulation of Parkin phosphorylation is important for muscular and dopaminergic functions."
From the abstract: "In this study, we show that MUL1 suppresses PINK1 or parkin mutant phenotypes in Drosophila. ... We further show that removing MUL1 in PINK1 or parkin loss-of-function mutant aggravates phenotypes caused by loss of either gene alone ... Together, these observations show that MUL1 acts in parallel to the PINK1/parkin pathway on a shared target mitofusin to maintain mitochondrial integrity. The MUL1 pathway compensates for loss of PINK1/parkin in both Drosophila and mammals and is a promising therapeutic target for PD."
Shiba-Fukushima K, Inoshita T, Hattori N, Imai Y. PINK1-Mediated Phosphorylation of Parkin Boosts Parkin Activity in Drosophila. PLoS Genet. 2014 Jun 5;10(6):e1004391. PMID: 24901221.
From the abstract: "Two genes linked to early onset Parkinson's disease, PINK1 and Parkin, encode a protein kinase and a ubiquitin-ligase, respectively. Both enzymes have been suggested to support mitochondrial quality control. ... Our data reveal that Parkin phosphorylation regulates not only mitochondrial function but also the neuronal activity of dopaminergic neurons in vivo, suggesting that the appropriate regulation of Parkin phosphorylation is important for muscular and dopaminergic functions."
Wednesday, June 4, 2014
Fly model included in new study related to familial encephalopathy with neuroserpin inclusion bodies (FENIB)
Roussel BD, Newton TM, Malzer E, Simecek N, Haq I, Thomas SE, Burr ML, Lehner PJ, Crowther DC, Marciniak SJ, Lomas DA. Sterol metabolism regulates neuroserpin polymer degradation in the absence of the unfolded protein response in the dementia FENIB. Hum Mol Genet. 2013 Nov 15;22(22):4616-26. PMID: 23814041; PMCID: PMC3889810.
Cancer review includes "intriguing new systems using Drosophila and zebrafish"
Kegelman TP, Hu B, Emdad L, Das SK, Sarkar D, Fisher PB. In vivo modeling of malignant glioma: the road to effective therapy. Adv Cancer Res. 2014;121:261-330. PMID: 24889534.
From the abstract: "... This review examines recent developments in the animal modeling of glioma, from more established rat models to intriguing new systems using Drosophila and zebrafish that set the stage for higher throughput studies of potentially useful targets. It also addresses the versatility of mouse modeling ..."
From the abstract: "... This review examines recent developments in the animal modeling of glioma, from more established rat models to intriguing new systems using Drosophila and zebrafish that set the stage for higher throughput studies of potentially useful targets. It also addresses the versatility of mouse modeling ..."
Monday, June 2, 2014
Review--Drosophila as a model for development of novel therapeutics to fight infection
Tzelepis I, Kapsetaki SE, Panayidou S, Apidianakis Y. Drosophila melanogaster: a first step and a stepping-stone to anti-infectives. Curr Opin Pharmacol. 2013 Oct;13(5):763-8. PMID: 23992884.
From the abstract: "Following an expansion in the antibiotic drug discovery in the previous century, we now face a bottleneck in the production of new anti-infective drugs. ... Drug screening in Drosophila offers to fill the gap between in vitro and mammalian model host testing ... alternative screening methods in Drosophila, while low-throughput, may reduce the cost and increase the success rate of preclinical trials."
From the abstract: "Following an expansion in the antibiotic drug discovery in the previous century, we now face a bottleneck in the production of new anti-infective drugs. ... Drug screening in Drosophila offers to fill the gap between in vitro and mammalian model host testing ... alternative screening methods in Drosophila, while low-throughput, may reduce the cost and increase the success rate of preclinical trials."
Review on NPT2b in chronic kidney disease includes discussion of fly studies
Sabbagh Y, Schiavi SC. Role of NPT2b in health and chronic kidney disease. Curr Opin Nephrol Hypertens. 2014 May 20. PMID: 24848935.
Recent fly studies and reviews related to cancer
Sechi S, Colotti G, Belloni G, Mattei V, Frappaolo A, Raffa GD, Fuller MT, Giansanti MG. GOLPH3 Is Essential for Contractile Ring Formation and Rab11 Localization to the Cleavage Site during Cytokinesis in Drosophila melanogaster. PLoS Genet. 2014 May 1;10(5):e1004305. PMID: 24786584; PubMed Central PMCID: PMC4006750.
Huo G, Lu J, Qu Z, Lin Z, Zhang D, Yang Y, Li B. [The applications and advantages of Drosophila melanogaster in cancer research]. Yi Chuan. 2014 Jan;36(1):30-40. Chinese. PubMed PMID: 24846916.
Reddy BA, van der Knaap JA, Bot AG, Mohd-Sarip A, Dekkers DH, Timmermans MA, Martens JW, Demmers JA, Verrijzer CP. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell. 2014 Feb 6;53(3):458-70. PMID: 24462112. From the abstract: "... Here, we show that guanosine 5'-monophosphate synthase (GMPS) is required for USP7-mediated stabilization of p53. ... Intriguingly, cytoplasmic sequestration of GMPS requires ubiquitylation by TRIM21, a ubiquitin ligase associated with autoimmune disease. These results implicate a classic nucleotide biosynthetic enzyme and a ubiquitin ligase, better known for its role in autoimmune disease, in p53 control."
Markstein M. Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies. Drug Discov Today Technol. 2013 Spring;10(1):e73-81. PMID: 24050233. From the abstract: "This review discusses recent shifts in the understanding of colorectal cancer ... recent advances in the culturing of colorectal stem cells using mammalian organoids, zebrafish, and Drosophila offer promising avenues for anti-CSC drug discovery."
Das TK, Cagan RL. A Drosophila approach to thyroid cancer therapeutics. Drug Discov Today Technol. 2013 Spring;10(1):e65-71. doi: 10.1016/j.ddtec.2012.09.004. PMID: 24050232; PubMed Central PMCID: PMC3779345. From the abstract: "Thyroid neoplasias represent among the fastest growing cancers. ... recent Drosophila models have proven useful both for understanding disease mechanism as well as helping identify new generation therapeutics"
Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut. 2014 Mar;63(3):480-93. PMID: 23585469; PubMed Central PMCID: PMC3932979.
Huo G, Lu J, Qu Z, Lin Z, Zhang D, Yang Y, Li B. [The applications and advantages of Drosophila melanogaster in cancer research]. Yi Chuan. 2014 Jan;36(1):30-40. Chinese. PubMed PMID: 24846916.
Reddy BA, van der Knaap JA, Bot AG, Mohd-Sarip A, Dekkers DH, Timmermans MA, Martens JW, Demmers JA, Verrijzer CP. Nucleotide biosynthetic enzyme GMP synthase is a TRIM21-controlled relay of p53 stabilization. Mol Cell. 2014 Feb 6;53(3):458-70. PMID: 24462112. From the abstract: "... Here, we show that guanosine 5'-monophosphate synthase (GMPS) is required for USP7-mediated stabilization of p53. ... Intriguingly, cytoplasmic sequestration of GMPS requires ubiquitylation by TRIM21, a ubiquitin ligase associated with autoimmune disease. These results implicate a classic nucleotide biosynthetic enzyme and a ubiquitin ligase, better known for its role in autoimmune disease, in p53 control."
Markstein M. Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies. Drug Discov Today Technol. 2013 Spring;10(1):e73-81. PMID: 24050233. From the abstract: "This review discusses recent shifts in the understanding of colorectal cancer ... recent advances in the culturing of colorectal stem cells using mammalian organoids, zebrafish, and Drosophila offer promising avenues for anti-CSC drug discovery."
Das TK, Cagan RL. A Drosophila approach to thyroid cancer therapeutics. Drug Discov Today Technol. 2013 Spring;10(1):e65-71. doi: 10.1016/j.ddtec.2012.09.004. PMID: 24050232; PubMed Central PMCID: PMC3779345. From the abstract: "Thyroid neoplasias represent among the fastest growing cancers. ... recent Drosophila models have proven useful both for understanding disease mechanism as well as helping identify new generation therapeutics"
Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut. 2014 Mar;63(3):480-93. PMID: 23585469; PubMed Central PMCID: PMC3932979.
Methods review--use of Drosophila for heart-disease related studies
Ocorr K, Vogler G, Bodmer R. Methods to assess Drosophila heart development, function and aging. Methods. 2014 Apr 12. pii: S1046-2023(14)00133-9. PMID: 24727147.
From the abstract: "In recent years the Drosophila heart has become an established model for many different aspects of human cardiac disease. This model has allowed identification of disease-causing mechanisms underlying congenital heart disease and cardiomyopathies and has permitted the study of underlying genetic, metabolic and age-related contributions to heart function. In this review we discuss methods currently employed in the analysis of the Drosophila heart structure and function ..."
From the abstract: "In recent years the Drosophila heart has become an established model for many different aspects of human cardiac disease. This model has allowed identification of disease-causing mechanisms underlying congenital heart disease and cardiomyopathies and has permitted the study of underlying genetic, metabolic and age-related contributions to heart function. In this review we discuss methods currently employed in the analysis of the Drosophila heart structure and function ..."
New fly studies and review related to neurodegenerative diseases
Parkinson's-related studies:
Thomas RE, Andrews LA, Burman JL, Lin WY, Pallanck LJ. PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial Matrix. PLoS Genet. 2014 May 29;10(5):e1004279. PMID: 24874806.
Chen AY, Xia S, Wilburn P, Tully T. Olfactory Deficits in an Alpha-Synuclein Fly Model of Parkinson's Disease. PLoS One. 2014 May 30;9(5):e97758. PMID: 24879013.
Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell. 2014 Apr 10;157(2):472-85. PMID: 24725412.
Cornelissen T, Haddad D, Wauters F, Van Humbeeck C, Mandemakers W, Koentjoro B, Sue C, Gevaert K, De Strooper B, Verstreken P, Vandenberghe W. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum Mol Genet. 2014 May 22. PMID: 24852371.
Siddique YH, Naz F, Jyoti S. Effect of curcumin on lifespan, activity pattern, oxidative stress, and apoptosis in the brains of transgenic Drosophila model of Parkinson's disease. Biomed Res Int. 2014;2014:606928. PMID: 24860828; PubMed Central PMCID: PMC4016861.
Shukla AK, Pragya P, Chaouhan HS, Tiwari AK, Patel DK, Abdin MZ, Chowdhuri DK. Heat Shock Protein-70 (Hsp-70) Suppresses Paraquat-Induced Neurodegeneration by Inhibiting JNK and Caspase-3 Activation in Drosophila Model of Parkinson's Disease. PLoS One. 2014 Jun 2;9(6):e98886. PMID: 24887138.
Knight AL, Yan X, Hamamichi S, Ajjuri RR, Mazzulli JR, Zhang MW, Daigle JG, Zhang S, Borom AR, Roberts LR, Lee SK, DeLeon SM, Viollet-Djelassi C, Krainc D, O'Donnell JM, Caldwell KA, Caldwell GA. The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson's Models. Cell Metab. 2014 May 28. PMID: 24882066.
ALS-related studies:
Hans F, Fiesel FC, Strong JC, Jäckel S, Rasse TM, Geisler S, Springer W, Schulz JB, Voigt A, Kahle PJ. UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y regulate TDP-43 ubiquitinylation. J Biol Chem. 2014 May 13. PMID: 24825905.
Salado IG, Redondo M, Bello ML, Perez C, Liachko NF, Kraemer BC, Miguel L, Lecourtois M, Gil C, Martinez A, Perez DI. Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J Med Chem. 2014 Mar 27;57(6):2755-72. PMID: 24592867; PubMed Central PMCID: PMC3969104.
Huntington's-related studies:
O'Rourke JG, Gareau JR, Ochaba J, Song W, Raskó T, Reverter D, Lee J, Monteys AM, Pallos J, Mee L, Vashishtha M, Apostol BL, Nicholson TP, Illes K, Zhu YZ, Dasso M, Bates GP, Difiglia M, Davidson B, Wanker EE, Marsh JL, Lima CD, Steffan JS, Thompson LM. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep. 2013 Jul 25;4(2):362-75. PMID: 23871671; PubMed Central PMCID: PMC3931302.
SCA-related study:
Jia DD, Zhang L, Chen Z, Wang CR, Huang FZ, Duan RH, Xia K, Tang BS, Jiang H. Lithium chloride alleviates neurodegeneration partly by inhibiting activity of GSK3β in a SCA3 Drosophila model. Cerebellum. 2013 Dec;12(6):892-901. PMID: 23812869.
SMA-related study:
Wishart TM, Mutsaers CA, Riessland M, Reimer MM, Hunter G, Hannam ML, Eaton SL, Fuller HR, Roche SL, Somers E, Morse R, Young PJ, Lamont DJ, Hammerschmidt M, Joshi A, Hohenstein P, Morris GE, Parson SH, Skehel PA, Becker T, Robinson IM, Becker CG, Wirth B, Gillingwater TH. Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy. J Clin Invest. 2014 Apr 1;124(4):1821-34. PMID: 24590288; PubMed Central PMCID: PMC3973095.
Review:
Lee S, Bang SM, Lee JW, Cho KS. Evaluation of Traditional Medicines for Neurodegenerative Diseases Using Drosophila Models. Evid Based Complement Alternat Med. 2014;2014:967462. Review. PubMed PMID: 24790636; PubMed Central PMCID: PMC3984789.
Thomas RE, Andrews LA, Burman JL, Lin WY, Pallanck LJ. PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial Matrix. PLoS Genet. 2014 May 29;10(5):e1004279. PMID: 24874806.
Chen AY, Xia S, Wilburn P, Tully T. Olfactory Deficits in an Alpha-Synuclein Fly Model of Parkinson's Disease. PLoS One. 2014 May 30;9(5):e97758. PMID: 24879013.
Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell. 2014 Apr 10;157(2):472-85. PMID: 24725412.
Cornelissen T, Haddad D, Wauters F, Van Humbeeck C, Mandemakers W, Koentjoro B, Sue C, Gevaert K, De Strooper B, Verstreken P, Vandenberghe W. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum Mol Genet. 2014 May 22. PMID: 24852371.
Siddique YH, Naz F, Jyoti S. Effect of curcumin on lifespan, activity pattern, oxidative stress, and apoptosis in the brains of transgenic Drosophila model of Parkinson's disease. Biomed Res Int. 2014;2014:606928. PMID: 24860828; PubMed Central PMCID: PMC4016861.
Shukla AK, Pragya P, Chaouhan HS, Tiwari AK, Patel DK, Abdin MZ, Chowdhuri DK. Heat Shock Protein-70 (Hsp-70) Suppresses Paraquat-Induced Neurodegeneration by Inhibiting JNK and Caspase-3 Activation in Drosophila Model of Parkinson's Disease. PLoS One. 2014 Jun 2;9(6):e98886. PMID: 24887138.
Knight AL, Yan X, Hamamichi S, Ajjuri RR, Mazzulli JR, Zhang MW, Daigle JG, Zhang S, Borom AR, Roberts LR, Lee SK, DeLeon SM, Viollet-Djelassi C, Krainc D, O'Donnell JM, Caldwell KA, Caldwell GA. The Glycolytic Enzyme, GPI, Is a Functionally Conserved Modifier of Dopaminergic Neurodegeneration in Parkinson's Models. Cell Metab. 2014 May 28. PMID: 24882066.
ALS-related studies:
Hans F, Fiesel FC, Strong JC, Jäckel S, Rasse TM, Geisler S, Springer W, Schulz JB, Voigt A, Kahle PJ. UBE2E ubiquitin-conjugating enzymes and ubiquitin isopeptidase Y regulate TDP-43 ubiquitinylation. J Biol Chem. 2014 May 13. PMID: 24825905.
Salado IG, Redondo M, Bello ML, Perez C, Liachko NF, Kraemer BC, Miguel L, Lecourtois M, Gil C, Martinez A, Perez DI. Protein kinase CK-1 inhibitors as new potential drugs for amyotrophic lateral sclerosis. J Med Chem. 2014 Mar 27;57(6):2755-72. PMID: 24592867; PubMed Central PMCID: PMC3969104.
Huntington's-related studies:
O'Rourke JG, Gareau JR, Ochaba J, Song W, Raskó T, Reverter D, Lee J, Monteys AM, Pallos J, Mee L, Vashishtha M, Apostol BL, Nicholson TP, Illes K, Zhu YZ, Dasso M, Bates GP, Difiglia M, Davidson B, Wanker EE, Marsh JL, Lima CD, Steffan JS, Thompson LM. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep. 2013 Jul 25;4(2):362-75. PMID: 23871671; PubMed Central PMCID: PMC3931302.
SCA-related study:
Jia DD, Zhang L, Chen Z, Wang CR, Huang FZ, Duan RH, Xia K, Tang BS, Jiang H. Lithium chloride alleviates neurodegeneration partly by inhibiting activity of GSK3β in a SCA3 Drosophila model. Cerebellum. 2013 Dec;12(6):892-901. PMID: 23812869.
SMA-related study:
Wishart TM, Mutsaers CA, Riessland M, Reimer MM, Hunter G, Hannam ML, Eaton SL, Fuller HR, Roche SL, Somers E, Morse R, Young PJ, Lamont DJ, Hammerschmidt M, Joshi A, Hohenstein P, Morris GE, Parson SH, Skehel PA, Becker T, Robinson IM, Becker CG, Wirth B, Gillingwater TH. Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy. J Clin Invest. 2014 Apr 1;124(4):1821-34. PMID: 24590288; PubMed Central PMCID: PMC3973095.
Review:
Lee S, Bang SM, Lee JW, Cho KS. Evaluation of Traditional Medicines for Neurodegenerative Diseases Using Drosophila Models. Evid Based Complement Alternat Med. 2014;2014:967462. Review. PubMed PMID: 24790636; PubMed Central PMCID: PMC3984789.
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