Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation

Phospholipase A(2)(PLA(2)) enzymes are considered the primary source of arachidonic acid for cyclooxygenase (COX)-mediated biosynthesis of prostaglandins. Here, we show that a distinct pathway exists in brain, where monoacylglycerol lipase (MAGL) hydrolyzes the endocannabinoid 2-arachidonoylglycerol to generate a major arachidonate precursor pool for neuroinflammatory prostaglandins. MAGL-disrupted animals show neuroprotection in a parkinsonian mouse model. These animals are spared the hemorrhaging caused by COX inhibitors in the gut, where prostaglandins are instead regulated by cytosolic PLA(2). These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.     

Supramolecular Archimedean cages assembled with 72 hydrogen bonds

Self-assembly of multiple components into well-defined and predictable structures remains one of the foremost challenges in chemistry. Here, we report on the rational design of a supramolecular cage assembled from 20 ions of three distinct species through 72 hydrogen bonds. The cage is constructed from two kinds of hexagonal molecular tiles, a tris(guanidinium)nitrate cluster and a hexa(4-sulfonatophenyl)benzene, joined at their edges through complementary and metrically matched N-H···O-S hydrogen bonds to form a truncated octahedron, one of the Archimedean polyhedra. The truncated octahedron, with an interior volume of 2200 cubic angstroms, serves as the composite building unit of a body-centered cubic zeolite-like framework, which exhibits an ability to encapsulate a wide range of differently charged species, including organic molecules, transition metal complexes, and "ship-in-a-bottle" nanoclusters not observed otherwise.     

A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila

One proposed strategy for controlling the transmission of insect-borne pathogens uses a drive mechanism to ensure the rapid spread of transgenes conferring disease refractoriness throughout wild populations. Here, we report the creation of maternal-effect selfish genetic elements in Drosophila that drive population replacement and are resistant to recombination-mediated dissociation of drive and disease refractoriness functions. These selfish elements use microRNA-mediated silencing of a maternally expressed gene essential for embryogenesis, which is coupled with early zygotic expression of a rescuing transgene.     

Patterns of rabies occurrence in Bhutan between 1996 and 2009

This study was conducted to evaluate incidence and seasonal trends of rabies in dogs and other domestic animals in Bhutan from 1996 to 2009. Time series analysis approach was used to determine the seasonal trend and temporal association between species-specific rabies cases in animals. A total of 814 rabies cases were reported during the 14-year period, of which cattle and domestic dogs accounted for 55% (447/814) and 39% (317/814) of the cases, respectively. The remaining 6% of the cases (50/814) were reported in horses (2%), cats (2%), pigs (1%) and goats (1%). Rabies cases were reported throughout the year with more reports during spring and summer months. The annual patterns of cases were stable from 1996 to 2005, but the incidence increased during 2006 and 2008. Fifty-nine of the 205 sub-districts reported rabies in animals from 1996 to 2009 with increased incidences in the four districts in southern Bhutan, an area located close to the border towns of India. A significant (P < 0.05) positive cross-correlation was observed between the number of cases in dogs and other domestic animals at time lags (months) 1-3 with the highest correlation (r = 0.94, P < 0.05) observed at time lag 0 (same month) indicating that the peak in rabies incidences occur in the same month when both dogs and other domestic animal cases are reported. Regression analysis predicted rabies in other domestic animal when there are reports of rabies in dogs during the previous months. This study provides useful information about the epidemiology of rabies that can be used to plan a rabies control programme in Bhutan.     

Quantitative exposure assessment for the combustion of meat and bone meal derived from specified risk material in the context of BSE in Ireland

The probability and severity of an adverse event can be analyzed by quantitative exposure assessment (QEA). This methodology was applied to model the human health risks associated with the combustion of specified risk material (SRM) derived meat and bone meal (MBM) in a combustion facility. The identification of MBM and SRM as significant factors in the spread of bovine spongiform encephalopathy (BSE) has resulted in restrictions on their use and movement, and this has led to a requirement for alternative end-uses for these products. A stochastic (Latin Hypercube sampling) simulation model was developed to assess the exposure and hence the risks associated with the use of SRM-derived MBM in a combustion facility. The model simulates the potential infectivity pathways that SRM-derived MBM follows, including its production from animals potentially infected with sub-clinical BSE and subsequent processing of the material with segregation and heat treatments. A failure probability was included to take account of sub-optimal operating conditions. Two scenarios, reflecting the infectivity risk in different animal tissues as defined by the European Commission's scientific steering committee (SSC), were performed with 100,000 iterations of the model. Model results showed that the societal exposure to humans resulting from the combustion of SRM-derived MBM is extremely small (mean values ranging from 7.57 x 10(-6) ID50/year to 8.38 x 10(-5) ID50/year). The resulting societal risks are significantly less than the background societal risk of approximately 2.5 cases of sporadic CJD in Ireland each year. A sensitivity analysis revealed that the species barrier had a large impact on exposure calculations and hence should be the focus of further scientific investigation to reduce our uncertainty about this parameter. The model predicts that material spillage into untreated effluent represents the biggest risk to humans, indicating that efforts for risk mitigation should be focused on reducing the potential for spillage.