Developing a model of perceptions of security and insecurity in the context of crime.

The current study was carried out as part of the CITYCOP project exploring fear of crime, risk perception and feelings of security and insecurity. Participants (n = 272) from 11 European countries answered a questionnaire exploring measures of risk perception, fear of crime, anxiety, trust in police and related behaviours. A seven-factor structure is proposed incorporating 'Signs of Social and Physical Disorder', 'Trust in Police', 'Trait Anxiety', 'Collective Efficacy', 'Perceived Risk of Victimisation', 'Fear of Personal Harm' and 'Fear of Property Theft'. Overall findings suggest that the measures associated with feelings of insecurity are negatively related to the measures associated with feelings of security. Efforts should be made to reduce feelings of insecurity through encouraging trust in law enforcement and community interaction and reducing signs of social and physical disorder.

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Reductive conjugate addition nitro-Mannich route for the stereoselective synthesis of 1,2,3,4-tetrahydroquinoxalines.

A concise, high yielding and structurally divergent synthesis of complex 1,2,3,4-tetrahydroquinoxalines with excellent diastereoselectivity is described. A wide array of nitroalkenes and imines derived from commercially available aromatic aldehydes and 2-chloroanalines were subjected to a key reductive conjugate addition nitro-Mannich reaction to give diastereomerically pure ß-nitro amines. Sequential reduction of the nitro function followed by Pd-catalyzed intramolecular N-arylation of the resultant primary amine onto the 2-chloroanailine gives highly substituted 1,2,3,4-tetrahydroquinoxalines. Non basic imines were found to participate better in the nitro-Mannich reaction if the stronger acid methanesulfonic acid was used to promote the reaction. The 3 step reaction sequence should be useful for the array synthesis of drug like scaffolds.

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits.

The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.

Physical principles demonstrate that the biceps femoris muscle relative to the other hamstring muscles exerts the most force: implications for hamstring muscle strain injuries.

Of the hamstring muscle group the biceps femoris muscle is the most commonly injured muscle in sports requiring interval sprinting. The reason for this observation is unknown. The objective of this study was to calculate the forces of all three hamstring muscles, relative to each other, during a lengthening contraction to assess for any differences that may help explain the biceps femoris predilection for injury during interval sprinting. To calculate the displacement of each individual hamstring muscle previously performed studies on cadaveric anatomical data and hamstring kinematics during sprinting were used. From these displacement calculations for each individual hamstring muscle physical principles were then used to deduce the proportion of force exerted by each individual hamstring muscle during a lengthening muscle contraction. These deductions demonstrate that the biceps femoris muscle is required to exert proportionally more force in a lengthening muscle contraction relative to the semimembranosus and semitendinosus muscles primarily as a consequence of having to lengthen over a greater distance within the same time frame. It is hypothesized that this property maybe a factor in the known observation of the increased susceptibility of the biceps femoris muscle to injury during repeated sprints where recurrent higher force is required.

A cross-cultural study with culture fair normative indications on WAIS-III Digit Symbol-Incidental Learning.

The WAIS-III Digit Symbol-Incidental Learning optional procedure, including Pairing and Free Recall, was administered to a southern African sample (N=68, age range 19-30), which was stratified for ethnicity in association with language of origin (white English first language versus black African first language), educational level (Grade 12 and Graduate), and quality of education (advantaged and disadvantaged). ('African language' is the term used to denote the indigenous languages of black populations in southern Africa). Results yielded no significant differences for ethnicity/language of origin, level or quality of education, indicating that Digit Symbol-Incidental Learning may be a relatively culture independent task with utility as a neuropsychological screening instrument. Broad normative guidelines are provided for diagnostic purposes, and comparisons are made with available norms.