Monte Carlo Methods and Stochastic Processes Emmanuel Gobet Chapman & Hall/CRC, 2016, 310 pages, £44.99, hardcover ISBN: 978‐1‐498‐74622‐9

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143627/1/insr12254.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143627/2/insr12254_am.pd

Principles of Copula Theory Fabrizio Durante and Carlo Sempi CRC Press, 2015, 332 pages, £72.99, hardcover ISBN: 978‐1‐439‐88442‐3

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139078/1/insr12239_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139078/2/insr12239.pd

Semiparametric profile likelihood estimation for continuous outcomes with excess zeros in a random‐threshold damage‐resistance model

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136688/1/sim7237.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136688/2/sim7237_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136688/3/sim7237-0001-supplementary.pd

Stage-specific cancer incidence: An artificially mixed multinomial logit model

Early detection of prostate cancer using the prostate-specific antigen test led to a sharp spike in the incidence of the disease accompanied by an equally sharp improvement in patient prognoses as evaluated at the point of advanced diagnosis. Observed outcomes represent age at diagnosis and stage, a categorical prognostic variable combining the actual stage and the grade of tumor. The picture is summarized by the stage-specific cancer incidence that represents a joint survival-multinomial response regressed on factors affecting the unobserved history of the disease before diagnosis (mixture). Fitting the complex joint mixed model to large population data is a challenge. We develop a stable and structured MLE approach to the problem allowing for the estimates to be obtained iteratively. Factorization of the likelihood achieved by our method allows us to work with only a fraction of the model dimension at a time. The approach is based on generalized self-consistency and the quasi-EM algorithm used to handle the mixed multinomial part of the response through Poisson likelihood. The model provides a causal link between the screening policy in the population and the stage-specific incidence. Copyright © 2009 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63068/1/3615_ftp.pd

Eis Inhibitors

Compounds and compositions are disclosed, which are useful as inhibitors of acetyltransferase Eis, a mediator of kanamycin resistance in Mycobacterium tuberculosis

Ambiguity of structure determination from a minimum of diffraction intensities

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107547/1/S2053273314007578.pd

Eis Inhibitors

Provided herein are novel small-molecules that have use in the inhibition of Eis, which mediates kanamycin resistance in Mycobacterium tuberculosis. The presently-disclosed subject matter further includes a pharmaceutical composition including a small molecule inhibitor, as described herein, and a suitable pharmaceutical carrier. Methods of treating tuberculosis comprising administering to an individual an effective amount of the disclosed small molecule inhibitors to mediate kanamycin A resistance and treat tuberculosis are also provided

Conditional ambiguity of one‐dimensional crystal structures determined from a minimum of diffraction intensity data

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113118/1/S0108767311007616.pd

A Random Sequential Mechanism of Aminoglycoside Acetylation by \u3cem\u3eMycobacterium tuberculosis\u3c/em\u3e Eis Protein

An important cause of bacterial resistance to aminoglycoside antibiotics is the enzymatic acetylation of their amino groups by acetyltransferases, which abolishes their binding to and inhibition of the bacterial ribosome. Enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Mt) is one of such acetyltransferases, whose upregulation was recently established as a cause of resistance to aminoglycosides in clinical cases of drug-resistant tuberculosis. The mechanism of aminoglycoside acetylation by MtEis is not completely understood. A systematic analysis of steady-state kinetics of acetylation of kanamycin A and neomycin B by Eis as a function of concentrations of these aminoglycosides and the acetyl donor, acetyl coenzyme A, reveals that MtEis employs a random-sequential bisubstrate mechanism of acetylation and yields the values of the kinetic parameters of this mechanism. The implications of these mechanistic properties for the design of inhibitors of Eis and other aminoglycoside acetyltransferases are discussed

Crystal Structure of \u3cem\u3eO\u3c/em\u3e-Methyltransferase CalO6 from the Calicheamicin Biosynthetic Pathway: A Case of Challenging Structure Determination at Low Resolution

BACKGROUND: Calicheamicins (CAL) are enedyine natural products with potent antibiotic and cytotoxic activity, used in anticancer therapy. The O-methyltransferase CalO6 is proposed to catalyze methylation of the hydroxyl moiety at the C2 position of the orsellinic acid group of CAL. RESULTS: Crystals of CalO6 diffracted non-isotropically, with the usable data extending to 3.4 Å. While no single method of crystal structure determination yielded a structure of CalO6, we were able to determine its structure by using molecular replacement-guided single wavelength anomalous dispersion by using diffraction data from native crystals of CalO6 and a highly non-isomorphous mercury derivative. The structure of CalO6 reveals the methyltransferase fold and dimeric organization characteristic of small molecule O-methyltransferases involved in secondary metabolism in bacteria and plants. Uncommonly, CalO6 was crystallized in the absence of S-adenosylmethionine (SAM; the methyl donor) or S-adenosylhomocysteine (SAH; its product). CONCLUSIONS: Likely as a consequence of the dynamic nature of CalO6 in the absence of its cofactor, the central region of CalO6, which forms a helical lid-like structure near the active site in CalO6 and similar enzymes, is not observed in the electron density. We propose that this region controls the entry of SAM into and the exit of SAH from the active site of CalO6 and shapes the active site for substrate binding and catalysis