The dynamics of measles in sub-Saharan Africa.

Although vaccination has almost eliminated measles in parts of the world, the disease remains a major killer in some high birth rate countries of the Sahel. On the basis of measles dynamics for industrialized countries, high birth rate regions should experience regular annual epidemics. Here, however, we show that measles epidemics in Niger are highly episodic, particularly in the capital Niamey. Models demonstrate that this variability arises from powerful seasonality in transmission-generating high amplitude epidemics-within the chaotic domain of deterministic dynamics. In practice, this leads to frequent stochastic fadeouts, interspersed with irregular, large epidemics. A metapopulation model illustrates how increased vaccine coverage, but still below the local elimination threshold, could lead to increasingly variable major outbreaks in highly seasonally forced contexts. Such erratic dynamics emphasize the importance both of control strategies that address build-up of susceptible individuals and efforts to mitigate the impact of large outbreaks when they occur

2-Arylamino-6-ethynylpurines are cysteine-targeting irreversible inhibitors of Nek2 kinase

Renewed interest in covalent inhibitors of enzymes implicated in disease states has afforded several agents targeted at protein kinases of relevance to cancers. We now report the design, synthesis and biological evaluation of 6-ethynylpurines that act as covalent inhibitors of Nek2 by capturing a cysteine residue (Cys22) close to the catalytic domain of this protein kinase. Examination of the crystal structure of the non-covalent inhibitor 3-((6-cyclohexylmethoxy-7H-purin-2-yl)amino)benzamide in complex with Nek2 indicated that replacing the alkoxy with an ethynyl group places the terminus of the alkyne close to Cys22 and in a position compatible with the stereoelectronic requirements of a Michael addition. A series of 6-ethynylpurines was prepared and a structure activity relationship (SAR) established for inhibition of Nek2. 6-Ethynyl-N-phenyl-7H-purin-2-amine [IC50 0.15 μM (Nek2)] and 4-((6-ethynyl-7H-purin-2-yl)amino)benzenesulfonamide (IC50 0.14 μM) were selected for determination of the mode of inhibition of Nek2, which was shown to be time-dependent, not reversed by addition of ATP and negated by site directed mutagenesis of Cys22 to alanine. Replacement of the ethynyl group by ethyl or cyano abrogated activity. Variation of substituents on the N-phenyl moiety for 6-ethynylpurines gave further SAR data for Nek2 inhibition. The data showed little correlation of activity with the nature of the substituent, indicating that after sufficient initial competitive binding to Nek2 subsequent covalent modification of Cys22 occurs in all cases. A typical activity profile was that for 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide [IC50 0.06 μM (Nek2); GI50 (SKBR3) 2.2 μM] which exhibited >5–10-fold selectivity for Nek2 over other kinases; it also showed > 50% growth inhibition at 10 μM concentration against selected breast and leukaemia cell lines. X-ray crystallographic analysis confirmed that binding of the compound to the Nek2 ATP-binding site resulted in covalent modification of Cys22. Further studies confirmed that 2-(3-((6-ethynyl-9H-purin-2-yl)amino)phenyl)acetamide has the attributes of a drug-like compound with good aqueous solubility, no inhibition of hERG at 25 μM and a good stability profile in human liver microsomes. It is concluded that 6-ethynylpurines are promising agents for cancer treatment by virtue of their selective inhibition of Nek2

Structure-guided design of purine-based probes for selective Nek2 inhibition

Nek2 (NIMA-related kinase 2) is a cell cycle-dependent serine/threonine protein kinase that regulates centrosome separation at the onset of mitosis. Overexpression of Nek2 is common in human cancers and suppression can restrict tumor cell growth and promote apoptosis. Nek2 inhibition with small molecules, therefore, offers the prospect of a new therapy for cancer. To achieve this goal, a better understanding of the requirements for selective-inhibition of Nek2 is required. 6-Alkoxypurines were identified as ATP-competitive inhibitors of Nek2 and CDK2. Comparison with CDK2-inhibitor structures indicated that judicious modification of the 6-alkoxy and 2-arylamino substituents could achieve discrimination between Nek2 and CDK2. In this study, a library of 6-cyclohexylmethoxy-2-arylaminopurines bearing carboxamide, sulfonamide and urea substituents on the 2-arylamino ring was synthesized. Few of these compounds were selective for Nek2 over CDK2, with the best result being obtained for 3-((6-(cyclohexylmethoxy)-9H-purin-2-yl)amino)-N,N-dimethylbenzamide (CDK2 IC50 = 7.0 μM; Nek2 IC50 = 0.62 μM) with >10-fold selectivity. Deletion of the 6-substituent abrogated activity against both Nek2 and CDK2. Nine compounds containing an (E)-dialkylaminovinyl substituent at C-6, all showed selectivity for Nek2, e.g. (E)-6-(2-(azepan-1-yl)vinyl)-N-phenyl-9H-purin-2-amine (CDK2 IC50 = 2.70 μM; Nek2 IC50 = 0.27 μM). Structural biology of selected compounds enabled a partial rationalization of the observed structure activity relationships and mechanism of Nek2 activation. This showed that carboxamide 11 is the first reported inhibitor of Nek2 in the DFG-in conformation

A Systematic Review of Mosquito Coils and Passive Emanators: Defining Recommendations for Spatial Repellency Testing Methodologies.

Mosquito coils, vaporizer mats and emanators confer protection against mosquito bites through the spatial action of emanated vapor or airborne pyrethroid particles. These products dominate the pest control market; therefore, it is vital to characterize mosquito responses elicited by the chemical actives and their potential for disease prevention. The aim of this review was to determine effects of mosquito coils and emanators on mosquito responses that reduce human-vector contact and to propose scientific consensus on terminologies and methodologies used for evaluation of product formats that could contain spatial chemical actives, including indoor residual spraying (IRS), long lasting insecticide treated nets (LLINs) and insecticide treated materials (ITMs). PubMed, (National Centre for Biotechnology Information (NCBI), U.S. National Library of Medicine, NIH), MEDLINE, LILAC, Cochrane library, IBECS and Armed Forces Pest Management Board Literature Retrieval System search engines were used to identify studies of pyrethroid based coils and emanators with key-words "Mosquito coils" "Mosquito emanators" and "Spatial repellents". It was concluded that there is need to improve statistical reporting of studies, and reach consensus in the methodologies and terminologies used through standardized testing guidelines. Despite differing evaluation methodologies, data showed that coils and emanators induce mortality, deterrence, repellency as well as reduce the ability of mosquitoes to feed on humans. Available data on efficacy outdoors, dose-response relationships and effective distance of coils and emanators is inadequate for developing a target product profile (TPP), which will be required for such chemicals before optimized implementation can occur for maximum benefits in disease control

Effectiveness of Biosecurity Measures in Preventing Badger Visits to Farm Buildings

This is the final version of the article. Available from Public Library of Science via the DOI in this record.BACKGROUND: Bovine tuberculosis caused by Mycobacterium bovis is a serious and economically important disease of cattle. Badgers have been implicated in the transmission and maintenance of the disease in the UK since the 1970s. Recent studies have provided substantial evidence of widespread and frequent visits by badgers to farm buildings during which there is the potential for close direct contact with cattle and contamination of cattle feed. METHODOLOGY: Here we evaluated the effectiveness of simple exclusion measures in improving farm biosecurity and preventing badger visits to farm buildings. In the first phase of the study, 32 farms were surveyed using motion-triggered infrared cameras on potential entrances to farm buildings to determine the background level of badger visits experienced by each farm. In the second phase, they were divided into four treatment groups; "Control", "Feed Storage", "Cattle Housing" and "Both", whereby no exclusion measures were installed, exclusion measures were installed on feed storage areas only, cattle housing only or both feed storage and cattle housing, respectively. Badger exclusion measures included sheet metal gates, adjustable metal panels for gates, sheet metal fencing, feed bins and electric fencing. Cameras were deployed for at least 365 nights in each phase on each farm. RESULTS: Badger visits to farm buildings occurred on 19 of the 32 farms in phase one. In phase two, the simple exclusion measures were 100% effective in preventing badger entry into farm buildings, as long as they were appropriately deployed. Furthermore, the installation of exclusion measures also reduced the level of badger visits to the rest of the farmyard. The findings of the present study clearly demonstrate how relatively simple practical measures can substantially reduce the likelihood of badger visits to buildings and reduce some of the potential for contact and disease transmission between badgers and cattle.This work was funded by Defra project number SE3119, http://www.defra.gov.uk/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

CMB Telescopes and Optical Systems

The cosmic microwave background radiation (CMB) is now firmly established as a fundamental and essential probe of the geometry, constituents, and birth of the Universe. The CMB is a potent observable because it can be measured with precision and accuracy. Just as importantly, theoretical models of the Universe can predict the characteristics of the CMB to high accuracy, and those predictions can be directly compared to observations. There are multiple aspects associated with making a precise measurement. In this review, we focus on optical components for the instrumentation used to measure the CMB polarization and temperature anisotropy. We begin with an overview of general considerations for CMB observations and discuss common concepts used in the community. We next consider a variety of alternatives available for a designer of a CMB telescope. Our discussion is guided by the ground and balloon-based instruments that have been implemented over the years. In the same vein, we compare the arc-minute resolution Atacama Cosmology Telescope (ACT) and the South Pole Telescope (SPT). CMB interferometers are presented briefly. We conclude with a comparison of the four CMB satellites, Relikt, COBE, WMAP, and Planck, to demonstrate a remarkable evolution in design, sensitivity, resolution, and complexity over the past thirty years.Comment: To appear in: Planets, Stars and Stellar Systems (PSSS), Volume 1: Telescopes and Instrumentatio

The Effects of Stress at Work and at Home on Inflammation and Endothelial Dysfunction

This study examined whether stress at work and at home may be related to dysregulation of inflammation and endothelial function, two important contributors to the development of cardiovascular disease. In order to explore potential biological mechanisms linking stress with cardiovascular health, we investigated cross-sectional associations between stress at work and at home with an inflammation score (n's range from 406–433) and with two endothelial biomarkers (intercellular and vascular adhesion molecules, sICAM-1 and sVCAM-1; n's range from 205–235) in a cohort of healthy US male health professionals. No associations were found between stress at work or at home and inflammation. Men with high or medium levels of stress at work had significantly higher levels of sVCAM-1 (13% increase) and marginally higher levels of sICAM-1 (9% increase), relative to those reporting low stress at work, independent of health behaviors. Men with high levels of stress at home had marginally higher levels of both sVCAM-1 and sICAM-1 than those with low stress at home. While lack of findings related to inflammation are somewhat surprising, if replicated in future studies, these findings may suggest that endothelial dysfunction is an important biological mechanism linking stress at work with cardiovascular health outcomes in men

Hip abduction weakness in elite junior footballers is common but easy to correct quickly: a prospective sports team cohort based study

Background: Hip abduction weakness has never been documented on a population basis as a common finding in a healthy group of athletes and would not normally be found in an elite adolescent athlete. This study aimed to show that hip abduction weakness not only occurs in this group but also is common and easy to correct with an unsupervised home based program. Methods: A prospective sports team cohort based study was performed with thirty elite adolescent under-17 Australian Rules Footballers in the Australian Institute of Sport/Australian Football League Under-17 training academy. The players had their hip abduction performance assessed and were then instructed in a hip abduction muscle training exercise. This was performed on a daily basis for two months and then they were reassessed.Results: The results showed 14 of 28 athletes who completed the protocol had marked weakness or a side-to-side difference of more than 25% at baseline. Two months later ten players recorded an improvement of ≥ 80% in their recorded scores. The mean muscle performance on the right side improved from 151 Newton (N) to 202 N (p<0.001) while on the left, the recorded results improved from 158 N to 223 N (p<0.001). Conclusions: The baseline values show widespread profound deficiencies in hip abduction performance not previously reported. Very large performance increases can be achieved, unsupervised, in a short period of time to potentially allow large clinically significant gains. This assessment should be an integral part of preparticipation screening and assessed in those with lower limb injuries. This particular exercise should be used clinically and more research is needed to determine its injury prevention and performance enhancement implications

Development of an Acute and Highly Pathogenic Nonhuman Primate Model of Nipah Virus Infection

Nipah virus (NiV) is an enigmatic emerging pathogen that causes severe and often fatal neurologic and/or respiratory disease in both animals and humans. Amongst people, case fatality rates range between 40 and 75 percent and there are no vaccines or treatments approved for human use. Guinea pigs, hamsters, cats, ferrets, pigs and most recently squirrel monkeys (New World monkey) have been evaluated as animal models of human NiV infection, and with the exception of the ferret, no model recapitulates all aspects of NiV-mediated disease seen in humans. To identify a more viable nonhuman primate (NHP) model, we examined the pathogenesis of NiV in African green monkeys (AGM). Exposure of eight monkeys to NiV produced a severe systemic infection in all eight animals with seven of the animals succumbing to infection. Viral RNA was detected in the plasma of challenged animals and occurred in two of three subjects as a peak between days 7 and 21, providing the first clear demonstration of plasma-associated viremia in NiV experimentally infected animals and suggested a progressive infection that seeded multiple organs simultaneously from the initial site of virus replication. Unlike the cat, hamster and squirrel monkey models of NiV infection, severe respiratory pathology, neurological disease and generalized vasculitis all manifested in NiV-infected AGMs, providing an accurate reflection of what is observed in NiV-infected humans. Our findings demonstrate the first consistent and highly pathogenic NHP model of NiV infection, providing a new and critical platform in the evaluation and licensure of either passive and active immunization or therapeutic strategies for human use