Feedback passivation of switched nonlinear systems using storage-like functions

This paper addresses the issues of passivity and feedback passivation of switched nonlinear systems via multiple storage functions. The concept of storage-like functions for switched systems is presented. A sufficient condition for passivity of switched nonlinear systems is given via multiple storage functions under some switching signal. Then, the result is extended to find conditions under which a switched system is feedback equivalent to a passive switched system. Furthermore, passivity of switched cascade systems is investigated.     

A group randomised trial of two methods for disseminating a smoking cessation programme to public antenatal clinics: effects on patient outcomes

Objective

To assess the differential effectiveness of two methods of disseminating a smoking cessation programme to public hospital antenatal clinics.

Design

Group randomised trial.

Setting

22 antenatal clinics in New South Wales, Australia.

Intervention

Clinics were allocated to a simple dissemination (SD) condition (11 clinics) which received a mail‐out of programme resources or to an intensive dissemination (ID) condition (11 clinics) which included the mail‐out plus feedback, training, and ongoing support with midwife facilitator.

Main outcome measures

Independent cross sectional surveys of women on a second or subsequent visit undertaken pre‐dissemination and 18 months after dissemination. Outcomes were: (1) levels of smoking status assessment by clinic staff; (2) proportion of women identifying as having been smokers at their first visit who reported receiving cessation advice; (3) proportion of these women who had quit (self report and expired air carbon monoxide (CO)); and (4) smoking prevalence among all women (self report and CO).

Subjects

5849 women pre‐dissemination (2374 SD, 3475 ID) and weighted sample of 5145 women post‐dissemination (2302 SD, 2843 ID).

Results

There were no significant differences between the groups on change on any outcome. Change in either group was minimal. In the post‐dissemination survey, the cessation proportions were 6.4% (SD) and 10.5% (ID).

Conclusions

Relatively modest strategies for encouraging incorporation of smoking cessation activities into antenatal care were not effective in the long term. Alternative strategies should be implemented and evaluated. The findings reinforce the importance of a whole population approach to tobacco control.     

Discovery of Inhibitors of Trypanosoma brucei by Phenotypic Screening of a Focused Protein Kinase Library

A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification of seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm . Screening of these hits in a T. b. brucei proliferation assay highlighted three compounds with a 1H‐imidazo[4,5‐b]pyrazin‐2(3H)‐one scaffold that showed sub‐micromolar activity and excellent selectivity against the MRC5 cell line. Subsequent rounds of optimisation led to the identification of compounds that exhibited good in vitro drug metabolism and pharmacokinetics (DMPK) properties, although in general this series suffered from poor solubility. A scaffold‐hopping exercise led to the identification of a 1H‐pyrazolo[3,4‐b]pyridine scaffold, which retained potency. A number of examples were assessed in a T. b. brucei growth assay, which could differentiate static and cidal action. Compounds from the 1H‐imidazo[4,5‐b]pyrazin‐2(3H)‐one series were found to be either static or growth‐slowing and not cidal. Compounds with the 1H‐pyrazolo[3,4‐b]pyridine scaffold were found to be cidal and showed an unusual biphasic nature in this assay, suggesting they act by at least two mechanisms.     

Development of Small‐Molecule Trypanosoma brucei N‐Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode

The enzyme N‐myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high‐throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X‐ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X‐ray crystallography/structure‐based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000‐fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.     

The Anthelmintic Drug Niclosamide and Its Analogues Activate the Parkinson's Disease Associated Protein Kinase PINK1

Mutations in PINK1, which impair its catalytic kinase activity, are causal for autosomal recessive early‐onset Parkinson's disease (PD). Various studies have indicated that the activation of PINK1 could be a useful strategy in treating neurodegenerative diseases, such as PD. Herein, it is shown that the anthelmintic drug niclosamide and its analogues are capable of activating PINK1 in cells through the reversible impairment of the mitochondrial membrane potential. With these compounds, for the first time, it is demonstrated that the PINK1 pathway is active and detectable in primary neurons. These findings suggest that niclosamide and its analogues are robust compounds for the study of the PINK1 pathway and may hold promise as a therapeutic strategy in PD and related disorders.     

The application of brute force logistic regression to corporate credit scoring models: Evidence from Serbian financial statements

In this paper a brute force logistic regression (LR) modeling approach is proposed and used to develop predictive credit scoring model for corporate entities. The modeling is based on 5 years of data from end-of-year financial statements of Serbian corporate entities, as well as, default event data. To the best of our knowledge, so far no relevant research about predictive power of financial ratios derived from Serbian financial statements has been published. This is also the first paper that generated 350 financial ratios to represent independent variables for 7590 corporate entities default predictions’. Many of derived financial ratios are new and were not discussed in literature before. Weight of evidence (WOE) method has been applied to transform and prepare financial ratios for brute force LR fitting simulations. Clustering method has been utilized to reduce long list of variables and to remove highly correlated financial ratios from partitioned training and validation datasets. The clustering results have revealed that number of variables can be reduced to short list of 24 financial ratios which are then analyzed in terms of default event predictive power. In this paper we propose the most predictive financial ratios from financial statements of Serbian corporate entities. The obtained short list of financial ratios has been used as a main input for brute force LR model simulations. According to literature, common practice to select variables in final model is to run stepwise, forward or backward LR. However, this research has been conducted in a way that the brute force LR simulations have to obtain all possible combinations of models that comprise of 5–14 independent variables from the short list of 24 financial ratios. The total number of simulated resulting LR models is around 14 million. Each model has been fitted through extensive and time consuming brute force LR simulations using SAS® code written by the authors. The total number of 342,016 simulated models (“well-founded” models) has satisfied the established credit scoring model validity conditions. The well-founded models have been ranked according to GINI performance on validation dataset. After all well-founded models have been ranked, the model with highest predictive power and consisting of 8 financial ratios has been selected and analyzed in terms of receiver-operating characteristic curve (ROC), GINI, AIC, SC, LR fitting statistics and correlation coefficients. The financial ratio constituents of that model have been discussed and benchmarked with several models from relevant literature.