A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence

Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl4-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB2, but not CB1, antagonists. The CB1 antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.Drug Delivery TechnologyBio-organic SynthesisMolecular Physiolog

Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe

Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process

Aedes albopictus (Diptera: Culicidae) as a potential vector of endemic and exotic arboviruses in Australia

In 2005, established populations of Aedes albopictus (Skuse) were discovered in the Torres Strait, the region that separates Papua New Guinea from northern Australia. This increased the potential for this species to be introduced to mainland Australia. Because it is an arbovirus vector elsewhere, we undertook laboratory-based infection and transmission experiments to determine the potential for Ae. albopictus from the Torres Strait to become infected with and transmit the four major Australian endemic arboviruses-Murray Valley encephalitis virus, West Nile virus Kunjin strain (WNVKUN), Ross River virus (RRV), and Barmah Forest virus-as well as the exotic Japanese encephalitis virus. Ae. albopictus is susceptible to infection with all viruses, with infection rates ranging between 8% for WNVKUN and 71% for RRV. Transmission rates of approximate to 25% were observed for RRV and Barmah Forest virus, but these were < 17% for Murray Valley encephalitis virus, WNVKUN, and Japanese encephalitis virus. Given its relative vector competence for alphaviruses, we also examined the replication kinetics and extrinsic incubation periods required for transmission of RRV and chikungunya virus. Despite lower body titers, more mosquitoes reared and maintained at 28 degrees C became infected with and transmitted the virus than those reared and maintained at 22 degrees C. The minimum time between Ae. albopictus consuming an infected bloodmeal and transmitting chikungunya virus was 2 d at 28 degrees C and 4d at 22 degrees C, and for RRV, it was 4 d, irrespective of the temperature. Given its opportunistic feeding habits and aggressive biting behavior, the establishment of Ae. albopictus on the Australian mainland could have a considerable impact on alphavirus transmission

Ability for Aedes albopictus (Diptera: Culicidae) to survive at the climatic limits of its potential range in Eastern Australia

Aedes albopictus (Skuse) is one of the most invasive mosquito species in the world and has infested islands in the Torres Strait, off the northern coast of Australia since at least 2004. This has led to fears that it may establish on the Australian mainland, including highly populated cities in southern temperate regions. To supplement theoretical projections addressing the range expansion of Ae. albopictus into Australia, laboratory-based trials were conducted to assess the performance of a Torres Strait Ae. albopictus population under a range of Australian conditions. First-instar larvae were placed in individual microcosms and maintained on a natural food resource, under average climatic conditions representing different regions of Australia's east coast. Larvae could not survive winter conditions in southern Australia. As the population performance index was >1.0 for tropical winter and summer conditions, and temperate summer conditions, populations would likely increase during these times. To test whether Ae. albopictus could overwinter during adverse conditions as eggs, we exposed cohorts to four different temperature (7, 17, 27, and 33°C) and relative humidity (35, 55, and 80%) combinations for up to 3 mo. High temperatures and low humidity were most detrimental to egg survival. However, those eggs maintained under cooler climates remained viable after 3 mo, including 17% of eggs kept at 7°C. Overall, this study suggests that a Torres Strait Ae. albopictus strain could proliferate all year round under northern tropical conditions and could overwinter in the egg stage before proliferating in the summer in southern temperate regions

Effects of cohabitation on the population performance and survivorship of the invasive mosquito Aedes albopictus and the resident mosquito Aedes notoscriptus (Diptera: Culicidae) in Australia

The presence of Aedes albopictus (Skuse) in the Torres Strait of northern Australia increases the potential for colonization and establishment on the mainland. However, there is a possibility that native species that occupy the same habitats may influence the population performance of Ae. albopictus, potentially affecting the establishment of this species in Australia. Cohabitation experiments were performed with the endemic Aedes notoscriptus (Skuse), which has been found occupying the same larval habitats as Ae. albopictus in the Torres Strait and is the most widespread container-inhabiting Aedes species in Australia. The influence of environmental factors and cohabitation between the two species was examined using different climates, food resource levels, food resource types, and species densities. Survivorship proportions and a population performance index (λ’) were calculated and compared. The consequences of increased Ae. notoscriptus densities were reduced survivorship and λ’ for Ae. albopictus. Despite this, the mean λ’ of Ae. albopictus and Ae. notoscriptus was consistently ≥ 1.06, indicating both species could increase under all conditions, potentially due to increasing conspecific densities negatively affecting Ae. notoscriptus. The outcomes from this study suggest that the preexisting presence of Ae. notoscriptus may not prevent the establishment of Ae. albopictus in Australia

Transmission of Japanese Encephalitis Virus from the Black Flying Fox, Pteropus alecto, to Culex annulirostris Mosquitoes, Despite the Absence of Detectable Viremia.

To determine the potential role of flying foxes in transmission cycles of Japanese encephalitis virus (JEV) in Australia, we exposed Pteropus alecto (Megachiroptera: Pteropididae) to JEV via infected Culex annulirostris mosquitoes or inoculation. No flying foxes developed symptoms consistent with JEV infection. Anti-JEV IgG antibodies developed in 6/10 flying foxes exposed to infected Cx. annulirostris and in 5/5 inoculated flying foxes. Low-level viremia was detected by real-time reverse transcriptase polymerase chain reaction in 1/5 inoculated flying foxes and this animal was able to infect recipient mosquitoes. Although viremia was not detected in any of the 10 flying foxes that were exposed to JEV by mosquito bite, two animals infected recipient mosquitoes. Likewise, an inoculated flying fox without detectable viremia infected recipient mosquitoes. Although infection rates in recipient mosquitoes were low, the high population densities in roosting camps, coupled with migratory behavior indicate that flying foxes could play a role in the dispersal of JEV

Estimation of sensible heat flux using the Surface Energy Balance System (SEBS) and ATSR measurements

This paper describes a modified version of the Surface Energy Balance System (SEBS) as regards the use of radiometric data from space and presents the results of a large area validation study on estimated sensible heat flux, extended over several months. The improvements were made possible by the characteristics of the Along Track Scanning Radiometer (ATSR-2) on board the European Remote Sensing satellite (ERS-2) and relate to: (a) the use of bi-angular radiometric data in two thermal infrared channels to estimate column atmospheric water vapor: (b) the use of bi-angular radiometric data in four spectral channels in the 550-1600 nm spectral regions to estimate aerosols optical depth: (c) determination of bottom of atmosphere (BOA) spectral reflectance using column water vapor, aerosols optical depth and a two-stream radiative transfer scheme to relate BOA spectral reflectance to top of atmosphere spectral radiance (d) direct and inverse modeling of radiative transfer in a vegetation canopy to relate BOA spectral reflectance to canopy properties, such as spectrally integrated hemispherical reflectance (albedo). A parameterization of the aerodynamic resistance for heat transfer (in term of kB(-1)) was applied for the first time at large spatial scales. For such large area analyses SEBS requires wind speed, potential temperature and humidity of air at an appropriate reference height. The latter was taken as being the height of the planetary boundary layer (PBL) and the data used were fields generated by an advanced numerical weather prediction model, i.e. regional atmospheric climate model (RACMO), integrated over the PBL. Validation of estimated sensible heat flux H obtained with the ATSR radiometric data was done using long-range, line-averaged measurements of H done with large aperture scintillometers (LAS) located at three sites in Spain and operated continuously between April and September 1999. The root mean square deviation of SEBS H estimates from LAS H measurements was 25.5 W m(-2). (C) 2003 Elsevier Science Ltd. All rights reserved

Flavivirus isolations from mosquitoes collected from Saibai Island in the Torres Strait, Australia, during an incursion of Japanese encephalitis virus

Adult mosquitoes (Diptera: Culicidae) were collected in January and February 2000 from Saibai Island in the Torres Strait of northern Australia, and processed for arbovirus isolation during a period of Japanese encephalitis (JE) virus activity on nearby Badu Island. A total of 84 2 10 mosquitoes were processed for virus isolation, yielding six flavivirus isolates. Viruses obtained were single isolates of JE and Kokobera (KOK) and four of Kunjin (KUN). All virus isolates were from members of the Culex sitiens Weidemann subgroup, which comprised 53.1 % of mosquitoes processed. Nucleotide sequencing and phylogenetic analysis of the pre-membrane region of the genome of JE isolate TS5313 indicated that it was closely related to other isolates from a sentinel pig and a pool of Cx. gelidus Theobald from Badu Island during the same period. Also molecular analyses of part of the envelope gene of KUN virus isolates showed that they were closely related to other KUN virus strains from Cape York Peninsula. The results indicate that flaviviruses are dynamic in the area, and suggest patterns of movement south from New Guinea and north from the Australian mainland