Richard Harris

Granta Design (United Kingdom)

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Paul C. Driscoll

The Francis Crick Institute

Mark E. Girvin

Albert Einstein College of Medicine

Diego Esposito

The Francis Crick Institute

Natalia Matassova

Granta Design (United Kingdom)

Allan M. Jordan

Cancer Research UK Manchester Institute

András Kotschy

Servier (France)

D.S. Williamson

Granta Design (United Kingdom)

Olivier Geneste

Servier (France)

Patrick Casara

Servier (France)

N.E. Whitehead

Granta Design (United Kingdom)

Cooperative Institutions

University College London

Harvard University

Charité - Universitätsmedizin Berlin

Albert Einstein College of Medicine

Beijing University of Chinese Medicine

Institute of Cancer Research

Rutgers, The State University of New Jersey

Valparaiso University

Rutgers Sexual and Reproductive Health and Rights

Institute of Structural and Molecular Biology

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Benford’s Law, data mining, and financial fraud: a case study in New York State Medicaid data

WIT transactions on information and communication technologies (2008)

B. B. Little Roderick M. Rejesus Michael Schucking Richard Harris

Benford's Law was first described by an astronomer in 1881, but physicist Frank Benford lent his name to the property in a mathematical treatise published in 1938.Behaviour of numbers described by the Law defies intuition, demonstrating that one is the most frequent (30.1%), and nine is the least frequent (4.6%).The property holds for a wide variety of numbers, including but not limited to: stock indices, river lengths, road numbers, etc. Departures from the classic Benford distribution are linked to anomalies, specifically in financial data where the property has been successfully employed in financial audits.The limitation of Benford's Law is that it identifies a relatively large pool of "candidate" anomalies that must be manually evaluated.In the present analysis of Medicaid data, multivariate cluster analysis in multiple tandem analyses is used to winnow the number of anomalies to a pool of high probability anomalies for evaluation.This approach makes the application of Benford's Law more practical.

Benford's law

10.2495/data080191

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Citations (3)

Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1

ACS Omega (2019)

James B. Murray James Davidson I‐Jen Chen Ben Davis P. Dokurno

We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

Isothermal Titration Calorimetry

Heteronuclear molecule

Lead compound

10.1021/acsomega.9b00611

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Citations (49)

Film in the age of digital distribution: the challenge for Australian content

Richard Harris

Australian audiovisual production faces an uncertain future. New forms of digital delivery offer both promise and threat to filmmakers and pose challenges to established forms of government regulation. Many ambitious predictions have been made about the impact of the internet, where the explosion of user-generated sites and the investment of moguls like Murdoch and Packer warns of profound change. But how much is real and how much is hype? What are the future business models? How much of a threat does it pose for conventional media forms? And, most importantly, where will Australian content be in this new media landscape? Richard Harris attempts to navigate the internet's hype curve by examining new media trends and global developments. He finds that while the internet offers great hope for independent filmmakers, and is fundamentally changing existing business models, it is still in a nascent phase. Conventional media will not disappear but rather move increasingly cross-platform, and will need to remain the focus of content policy in the short to medium term. He argues that public broadcasting has a special role in providing a place for Australian content in a fragmenting media space, and concludes that industry and government need to plan for the future by looking in a holistic way at the broader structural issues that affect content - at development, production and delivery. It is by getting the overall settings right that Australian filmmakers will meet the challenges of new media and take advantage of the rising opportunities.

Digital content

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Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

Journal of Medicinal Chemistry (2020)

Yousuke Yamada Hajime Takashima Lee Walmsley Fumihito Ushiyama Yohei Matsuda

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Moiety

Imidazole

10.1021/acs.jmedchem.0c01215

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Citations (24)

Backbone 1H, 13C, 15N NMR assignments of the unliganded and substrate ternary complex forms of mevalonate diphosphate decarboxylase from Streptococcus pneumoniae

Biomolecular NMR Assignments (2010)

Guido Reuther Richard Harris Mark E. Girvin Thomas S. Leyh

Ternary complex

Chemical shift

Decarboxylation

Streptococcus Pyogenes

10.1007/s12104-010-9255-4

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Citations (2)

A winged helix domain in human MUS81 binds DNA and modulates the endonuclease activity of MUS81 complexes

Nucleic Acids Research (2013)

Andrew J. Fadden Stephanie Schalbetter Maureen Bowles Richard Harris John Lally

The MUS81-EME1 endonuclease maintains metazoan genomic integrity by cleaving branched DNA structures that arise during the resolution of recombination intermediates. In humans, MUS81 also forms a poorly characterized complex with EME2. Here, we identify and determine the structure of a winged helix (WH) domain from human MUS81, which binds DNA. WH domain mutations greatly reduce binding of the isolated domain to DNA and impact on incision activity of MUS81-EME1/EME2 complexes. Deletion of the WH domain reduces the endonuclease activity of both MUS81-EME1 and MUS81-EME2 complexes, and incisions made by MUS81-EME2 are made closer to the junction on substrates containing a downstream duplex, such as fork structures and nicked Holliday junctions. WH domain mutation or deletion in Schizosaccharomyces pombe phenocopies the DNA-damage sensitivity of strains deleted for mus81. Our results indicate an important role for the WH domain in both yeast and human MUS81 complexes.

Schizosaccharomyces

10.1093/nar/gkt760

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Citations (14)

Beware of Bismuth

ANZ Journal of Surgery (2003)

Richard Harris A. G. Poole

10.1046/j.1445-2197.2003.t01-1-02585.x

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Regulatory Politics in Transition. By Marc Allen Eisner. Baltimore: Johns Hopkins University Press, 1993. 246p. $45.00 cloth, $14.95 paper.

American Political Science Review (1994)

Richard Harris

An abstract is not available for this content so a preview has been provided. Please use the Get access link above for information on how to access this content.

10.2307/2944740

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Citations (1)

Book ReviewsThe New Middle Class and the Remaking of the Central City. By David Ley. New York: Oxford University Press, 1997. Pp. vii+383. $85.00.

American Journal of Sociology (1998)

Richard Harris

Reprint

10.1086/210018

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NMR structure of a complex between the VirB9/VirB7 interaction domains of the pKM101 type IV secretion system

Proceedings of the National Academy of Sciences (2007)

Richard Bayliss Richard Harris Loïc Coutte Amy Monier Rémi Fronzes

Type IV secretion (T4S) systems translocate DNA and protein effectors through the double membrane of Gram-negative bacteria. The paradigmatic T4S system in Agrobacterium tumefaciens is assembled from 11 VirB subunits and VirD4. Two subunits, VirB9 and VirB7, form an important stabilizing complex in the outer membrane. We describe here the NMR structure of a complex between the C-terminal domain of the VirB9 homolog TraO (TraO(CT)), bound to VirB7-like TraN from plasmid pKM101. TraO(CT) forms a beta-sandwich around which TraN winds. Structure-based mutations in VirB7 and VirB9 of A. tumefaciens show that the heterodimer interface is conserved. Opposite this interface, the TraO structure shows a protruding three-stranded beta-appendage, and here, we supply evidence that the corresponding region of VirB9 of A. tumefaciens inserts in the membrane and protrudes extracellularly. This complex structure elucidates the molecular basis for the interaction between two essential components of a T4S system.

Structural Biology

10.1073/pnas.0609535104

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Citations (54)