P
Paul R. August
Researcher at Aventis Pharma
Publications - 44
Citations - 3284
Paul R. August is an academic researcher from Aventis Pharma. The author has contributed to research in topics: 5-HT5A receptor & Taxoid. The author has an hindex of 18, co-authored 44 publications receiving 3036 citations. Previous affiliations of Paul R. August include ARIAD Pharmaceuticals, Inc. & University of Minnesota.
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Journal ArticleDOI
Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms.
Michelle R. Rondon,Paul R. August,Alan D. Bettermann,Sean F. Brady,Trudy H Grossman,Mark R. Liles,Kara A. Loiacono,Berkley A. Lynch,Ian A. MacNeil,Minor Charles A,Choi Lai Tiong,Michael Z. Gilman,Marcia S. Osburne,Jon Clardy,Jo Handelsman,Robert M. Goodman +15 more
TL;DR: Phylogenetic analysis of 16S rRNA gene sequences recovered from one of the libraries indicates that the BAC libraries contain DNA from a wide diversity of microbial phyla, including sequences from diverse taxa such as the low-G+C, gram-positive Acidobacterium,Cytophagales, and Proteobacteria.
Journal ArticleDOI
Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.
Yingxiao Shi,Shaoyu Lin,Kim A. Staats,Yichen Li,Wen-Hsuan Chang,Shu Ting Hung,Eric Hendricks,Gabriel R. Linares,Yaoming Wang,Esther Y. Son,Xinmei Wen,Kassandra Kisler,Brent Wilkinson,Louise Menendez,Tohru Sugawara,Phillip E. Woolwine,Mickey Huang,Michael J. Cowan,Brandon B Ge,Nicole Koutsodendris,Kaitlin P. Sandor,Jacob Komberg,Vamshidhar R. Vangoor,Ketharini Senthilkumar,Valerie Hennes,Carina Seah,Amy R. Nelson,Tze-Yuan Cheng,Shih Jong J. Lee,Paul R. August,Jason A. Chen,N. Wisniewski,Victor Hanson-Smith,T. Grant Belgard,Alice Zhang,Marcelo P. Coba,Chris Grunseich,Michael E. Ward,Leonard H. van den Berg,R. Jeroen Pasterkamp,Davide Trotti,Berislav V. Zlokovic,Justin K. Ichida +42 more
Abstract: An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD
Journal ArticleDOI
Recombinant Environmental Libraries Provide Access to Microbial Diversity for Drug Discovery from Natural Products
Sophie Courtois,Carmela Cappellano,Maria M. Ball,François Francou,Philippe Normand,Gerard Helynck,Asuncion Martinez,Steven J. Kolvek,Joern Hopke,Marcia S. Osburne,Paul R. August,Renaud Nalin,Michel Guerineau,Pascale Jeannin,Pascal Simonet,Jean-Luc Pernodet +15 more
TL;DR: The data reinforce the idea that exploiting previously unknown or uncultivated microorganisms for the discovery of novel natural products has potential value and suggest a strategy for developing this technology into a realistic and effective drug discovery tool.
Journal ArticleDOI
Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699.
Paul R. August,Li Tang,Yeo J. Yoon,Sandra Ning,Rolf Müller,Tin-Wein Yu,Matthew P. Taylor,Dietmar Hoffmann,Chun-Gyu Kim,Xiaohong Zhang,C. Richard Hutchinson,Heinz G. Floss +11 more
TL;DR: Rifamycin production in A. mediterranei is governed by a single gene cluster consisting of structural, resistance and export, and regulatory genes that could be modified to produce novel forms of the rifamycins that may be effective against rif amycin-resistant microorganisms.
Journal Article
Expression and isolation of antimicrobial small molecules from soil DNA libraries.
I A MacNeil,C L Tiong,Minor Charles A,Paul R. August,Trudy H Grossman,Kara A. Loiacono,Berkley A. Lynch,T. B. Phillips,Surinder S. Narula,R Sundaramoorthi,Albert Tyler,T Aldredge,H Long,Michael Z. Gilman,Dennis A. Holt,Marcia S. Osburne +15 more
TL;DR: Results show that genes involved in natural product synthesis can be cloned directly from S-DNA and expressed in a heterologous host, supporting the idea that this technology has the potential to provide novel natural products from the wealth of environmental microbial diversity and is a potentially important new tool for drug discovery.