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We propose a GARCH model for uncorrelated, integer‐valued time series that exhibit conditional heteroskedasticity. Conditioned on past information, these observations have a two‐sided Poisson distribution with time‐varying variance. Positive and negative observations can have an asymmetric impact on conditional variance. We give conditions under which the proposed integer‐valued GARCH process is stationary, ergodic, and has finite moments. We consider maximum likelihood estimation for model parameters, and we give the limiting distribution for these estimators when the true parameter vector is in the interior of its parameter space, and when some GARCH coefficients are zero. [ABSTRACT FROM AUTHOR]

Abstract: A novel class of bacterial DNA gyrase inhibitors has been shown previously to form a ternary complex with DNA and gyrase in a site distinct from the fluoroquinolone and ATP binding sites and does not cause double-strand-cleaved complex stabilization like fluoroquinolones. We show that, unlike fluoroquinolones, a representative compound inhibits DNA-dependent ATP hydrolysis by Escherichia coli gyrase and also blocks cleaved complex stabilization by ciprofloxacin. Conversely, ciprofloxacin blocks ATPase inhibition by the novel compound. We conclude that the compound acts allosterically to inhibit ATP binding or hydrolysis and interferes with the gyrase catalytic cycle at a different point than ciprofloxacin. [Copyright &y& Elsevier]

GlmU is a bifunctional enzyme that is essential for bacterial growth, converting d-glucosamine 1-phosphate into UDP-GlcNAc via acetylation and subsequent uridyl transfer. A biochemical screen of AstraZeneca's compound library using GlmU of Escherichia coli identified novel sulfonamide inhibitors of the acetyltransferase reaction. Steady-state kinetics, ligand-observe NMR, isothermal titration calorimetry, and x-ray crystallography showed that the inhibitors were competitive with acetyl-CoA substrate. Iterative chemistry efforts improved biochemical potency against Gram-negative isozymes 300-fold and afforded antimicrobial activity against a strain of Haemophilus influenzae lacking its major efflux pump. Inhibition of precursor incorporation into bacterial macromolecules was consistent with the antimicrobial activity being caused by disruption of peptidoglycan and fatty acid biosyntheses. Isolation and characterization of two different resistant mutant strains identified the GlmU acetyltransferase domain as the molecular target. These data, along with x-ray co-crystal structures, confirmed the binding mode of the inhibitors and explained their relative lack of potency against Gram-positive GlmU isozymes. This is the first example of antimicrobial compounds mediating their growth inhibitory effects specifically via GlmU. [ABSTRACT FROM AUTHOR]

The impact of divorce on children has been well documented over the past 30 years. Divorcing parents who are also experiencing clinical depression often have a compromised ability to parent well and to give the children needed support. Children are then impacted both by the divorce itself and the effects of parental depression. They are at higher risk of numerous problems including poorer physical health, deficits in academic performance not attributable to intellectual limitations, poor social functioning, conduct disorder and other disruptive behavior problems, phobias, and other anxiety disorders. Because children of depressed parents are at higher risk for depression themselves, they should be monitored for depressive symptoms. If there are concerns, the child should be assessed by a mental health professional. [ABSTRACT FROM AUTHOR]

We establish asymptotic normality and consistency for rank-based estimators of autoregressive-moving average model parameters. The estimators are obtained by minimizing a rank-based residual dispersion function similar to the one given by L.A. Jaeckel [Ann. Math. Stat. Vol. 43 (1972) 1449–1458]. These estimators can have the same asymptotic efficiency as maximum likelihood estimators and are robust. The quality of the asymptotic approximations for finite samples is studied via simulation. [ABSTRACT FROM AUTHOR]

Abstract: An autoregressive-moving average model in which all roots of the autoregressive polynomial are reciprocals of roots of the moving average polynomial and vice versa is called an all-pass time series model. All-pass models generate uncorrelated (white noise) time series, but these series are not independent in the non-Gaussian case. An approximate likelihood for a causal all-pass model is given and used to establish asymptotic normality for maximum likelihood estimators under general conditions. Behavior of the estimators for finite samples is studied via simulation. A two-step procedure using all-pass models to identify and estimate noninvertible autoregressive-moving average models is developed and used in the deconvolution of a simulated water gun seismogram. [Copyright &y& Elsevier]

We propose autoregressive moving average (ARMA) and generalized autoregressive conditional heteroscedastic (GARCH) models driven by asymmetric Laplace (AL) noise. The AL distribution plays, in the geometric-stable class, the analogous role played by the normal in the alpha-stable class, and has shown promise in the modelling of certain types of financial and engineering data. In the case of an ARMA model we derive the marginal distribution of the process, as well as its bivariate distribution when separated by a finite number of lags. The calculation of exact confidence bands for minimum mean-squared error linear predictors is shown to be straightforward. Conditional maximum likelihood-based inference is advocated, and corresponding asymptotic results are discussed. The models are particularly suited for processes that are skewed, peaked, and leptokurtic, but which appear to have some higher order moments. A case study of a fund of real estate returns reveals that AL noise models tend to deliver a superior fit with substantially less parameters than normal noise counterparts, and provide both a competitive fit and a greater degree of numerical stability with respect to other skewed distributions. [ABSTRACT FROM AUTHOR]

We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drugresistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467-474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of super coiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of super coiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and β. [ABSTRACT FROM AUTHOR]

Background. Vitamin D deficiency impairs bone health and development. Objective. To determine the prevalence of and risk factors for vitamin D deficiency in pediatric international adoptees. Methods. A prospective cohort (N = 189) study from a single international adoption clinic was conducted. Total 25-hydroxy vitamin D [25(OH)D] level was measured at the initial clinical assessment (within 6 months of adoption). Vitamin D deficiency was defined as a 25(OH)D <20 ng/mL (<8 nmol/L) and insufficiency as 25(OH)D <30 ng/mL (<12 nmol/L). Results. Vitamin D deficiency was diagnosed in 8% and insufficiency in 27% of the cohort. Lower body mass index and longer time in an institution were associated with vitamin D deficiency and insufficiency independent of age. Conclusions. Vitamin D insufficiency was common in our cohort of international adoptees. The significance of vitamin D insufficiency on bone development during the typical “catch-up” growth following international adoption needs to be determined. [ABSTRACT FROM PUBLISHER]

ThetRNA-(N1G37) methyltransferase (TrmD) is essentialfor growth and highly conserved in both Gram-positive and Gram-negativebacterial pathogens. Additionally, TrmD is very distinct from itshuman orthologue TRM5 and thus is a suitable target for the designof novel antibacterials. Screening of a collection of compound fragmentsusing Haemophilus influenzaeTrmD identifiedinhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donorsubstrate. Guided by X-ray cocrystal structures, fragment 1was elaborated into a nanomolar inhibitor of a broad range of Gram-negativeTrmD isozymes. These compounds demonstrated no activity against representativehuman SAM utilizing enzymes, PRMT1 and SET7/9. This is the first reportof selective, nanomolar inhibitors of TrmD with demonstrated abilityto order the TrmD lid in the absence of tRNA. [ABSTRACT FROM AUTHOR]

Abstract: Pyrimidine compounds were identified as inhibitors of DNA topoisomerase IV through high-throughput screening. This study was designed to exemplify the in vitro activity of the pyrimidines against Gram-positive and Gram-negative microorganisms, to reveal the mode of action of these compounds and to demonstrate their in vivo efficacy. Frequencies of resistance to pyrimidines among Staphylococcus aureus and Streptococcus pneumoniae were <10−10 at four times their minimum inhibitory concentrations (MICs). These compounds exhibited a dual mode of action through inhibition of the ParE subunit of DNA topoisomerase IV as well as the GyrB subunit of DNA gyrase, a homologue of DNA topoisomerase IV. Pyrimidines were shown to have MIC90 values (MIC that inhibited 90% of the strains tested) of ≤2mg/L against Gram-positive pathogens, including meticillin-resistant S. aureus, quinolone- and meticillin-resistant S. aureus, vancomycin-resistant enterococci, penicillin-non-susceptible S. pneumoniae and Streptococcus pyogenes, and MIC90 values of 2- to >16mg/L and ≤0.5mg/L against the Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis, respectively. The pyrimidines were bactericidal and exhibited a ca. 1000-fold reduction of the bacterial counts at 300mg/kg in a S. pneumoniae lung infection model. The microbiological properties and in vivo efficacy of pyrimidines underscore their potential as candidates for the treatment of soft-tissue infections and hospital-acquired pneumonia. [Copyright &y& Elsevier]

Abstract: A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low Log D and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC50 <0.1μM against GlmU isozymes from Gram-negative organisms), and the lipophilicity was increased giving compounds with Log D −1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13. [Copyright &y& Elsevier]