The kinase activity of PKR represses inflammasome activity

The protein kinase R (PKR) functions in the antiviral response by controlling protein translation and inflammatory cell signaling pathways. We generated a transgenic, knock-in mouse in which the endogenous PKR is expressed with a point mutation that ablates its kinase activity. This novel animal allows us to probe the kinase-dependent and -independent functions of PKR. We used this animal together with a previously generated transgenic mouse that is ablated for PKR expression to determine the role of PKR in regulating the activity of the cryopyrin inflammasome. Our data demonstrate that, in contradiction to earlier reports, PKR represses cryopyrin inflammasome activity. We demonstrate that this control is mediated through the established function of PKR to inhibit protein translation of constituents of the inflammasome to prevent initial priming during innate immune signaling. These findings identify an important role for PKR to dampen inflammation during the innate immune response and caution against the previously proposed therapeutic strategy to inhibit PKR to treat inflammation.     

Genome-Scale Phylogenetic Analyses of Chikungunya Virus Reveal Independent Emergences of Recent Epidemics and Various Evolutionary Rates

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, has traditionally circulated in Africa and Asia, causing human febrile illness accompanied by severe, chronic joint pain. In Africa, epidemic emergence of CHIKV involves the transition from an enzootic, sylvatic cycle involving arboreal mosquito vectors and nonhuman primates, into an urban cycle where peridomestic mosquitoes transmit among humans. In Asia, however, CHIKV appears to circulate only in the endemic, urban cycle. Recently, CHIKV emerged into the Indian Ocean and the Indian subcontinent to cause major epidemics. To examine patterns of CHIKV evolution and the origins of these outbreaks, as well as to examine whether evolutionary rates that vary between enzootic and epidemic transmission, we sequenced the genomes of 40 CHIKV strains and performed a phylogenetic analysis representing the most comprehensive study of its kind to date. We inferred that extant CHIKV strains evolved from an ancestor that existed within the last 500 years and that some geographic overlap exists between two main enzootic lineages previously thought to be geographically separated within Africa. We estimated that CHIKV was introduced from Africa into Asia 70 to 90 years ago. The recent Indian Ocean and Indian subcontinent epidemics appear to have emerged independently from the mainland of East Africa. This finding underscores the importance of surveillance to rapidly detect and control African outbreaks before exportation can occur. Significantly higher rates of nucleotide substitution appear to occur during urban than during enzootic transmission. These results suggest fundamental differences in transmission modes and/or dynamics in these two transmission cycles.Chikungunya virus (CHIKV; Togaviridae: Alphavirus) is an arbovirus (arthropod-borne virus) vectored by Aedes mosquitoes to humans in tropical and subtropical regions of Africa and Asia (Fig. ​(Fig.1;1; reviewed in references 26 and 46). CHIKV has a single-stranded, positive-sense RNA genome of ∼12 kb and causes chikungunya fever (CHIK), a febrile illness associated with severe arthralgia and rash (2, 15, 31, 35); the name is derived from a Bantu language word describing the severe arthritic signs (32), which can persist for years. Thus, CHIK has enormous economic costs in addition to its public health impact (9). Because the signs and symptoms of CHIK overlap with those of dengue and because CHIKV is transmitted sympatrically in urban areas by the same mosquito vectors, it is grossly underreported in the absence of laboratory diagnostics (10, 37).Open in a separate windowFIG. 1.Distribution of the CHIKV strains used in this study. The map, based on a world map template from http://www.presentationmagazine.com, was edited with permission.CHIKV was first isolated during a 1953 outbreak in present-day Tanzania by Ross (48, 49). Since then, outbreaks have been documented in Africa and Asia, including the Indian subcontinent (Fig. ​(Fig.1)1) (1, 4). In 2005, CHIKV emerged from East Africa to cause an explosive urban epidemic in popular tourist island destinations in the Indian Ocean (Fig. ​(Fig.1;1; reviewed in reference 31). In late 2005, CHIKV spread into the Indian subcontinent, where millions of people have been affected (5). However, the geographic source of spread into India, from the mainland of Africa or from the Indian Ocean Islands, has not been delineated. India had seen large epidemics of CHIK in the past (reviewed in reference 30), but CHIKV apparently disappeared during the 1970s (5). Since 2006, CHIKV has been imported into Europe and the western hemisphere (including the United States) via many viremic travelers, and an epidemic was initiated in Italy by a traveler from India (4, 11, 47). The dramatic spread since 1980 of dengue viruses (DENV) throughout tropical America, via the same vectors, portends the severity of the public health problem if CHIKV becomes established in the western hemisphere.The first phylogenetic analysis of CHIKV (45) identified three geographically associated genotypes: the West African (WAf), East/Central/South African (ECSA), and Asian genotypes. More recent analyses indicate that the recent Indian Ocean and Indian strains form a monophyletic group within the ECSA lineage (5, 12, 14, 27, 40, 51, 52). However, most CHIKV phylogenetic studies (1, 14, 28, 29, 38, 40, 41, 47, 52) have utilized only partial sequences from the envelope glycoprotein E1 gene, preventing a robust assessment of some of the relationships among strains and of their evolutionary dynamics.The CHIKV strains represented in different geographic lineages apparently circulate in different ecological cycles. In Asia, CHIKV appears to circulate primarily in an urban transmission cycle involving the peridomestic mosquitoes Aedes aegypti and A. albopictus, as well as humans (25, 45). Asian epidemics typically infect thousands-to-millions of people over the course of several years (46). In contrast, African CHIKV circulates primarily in a sylvatic/enzootic cycle, transmitted by arboreal primatophilic Aedes mosquitoes (e.g., A. furcifer and A. africanus) and probably relies on nonhuman primates as reservoir hosts (reviewed in reference 16). Epidemics in rural Africa usually occur on a much smaller scale than in Asia, likely a result of the lower human population densities, and possibly more stable herd immunity. Although the assignments of “urban” and “sylvatic/enzootic” are based on the most common mode of transmission, CHIKV strains of African origin are capable of urban transmission by A. aegypti and A. albopictus, as evidenced by outbreaks in the Democratic Republic of the Congo (41), Nigeria (36), Kenya (27), and Gabon (42). The ecological differences between the sylvatic/enzootic (henceforth called enzootic) and urban/endemic/epidemic transmission cycles (henceforth called epidemic) such as seasonality of vector larval habitats, vertebrate host abundance and herd immunity, and vector host preferences, prompted us to hypothesize that the evolutionary dynamics of CHIKV may differ between the two transmission cycles. To test this hypothesis, to provide more robust estimates of the evolutionary relationships among the CHIKV strains including the sources of the recent epidemics, and to elucidate the temporal and spatial history of CHIKV evolution, we performed an extensive, genome-scale phylogenetic analysis, utilizing complete open reading frame (ORF) sequences of a large collection of 80 isolates with broad temporal, spatial, and host coverage.     

The Lerhamn drill core and its bearing for the graptolite biostratigraphy of the Ordovician Tøyen Shale in Scania,southern Sweden

Maletz, J. & Ahlberg, P. 2011: The Lerhamn drill core and its bearing for the graptolite biostratigraphy of the Ordovician Tøyen Shale in Scania, southern Sweden. Lethaia, Vol. 44, pp. 350–368. A drill core through the Lower Ordovician Tøyen Shale Formation at Lerhamn, NW Scania, southern Sweden, provides important new information for the precise biostratigraphic resolution of the Floian to lower Darriwilian time interval in southern Scandinavia. The Hunnegraptus copiosus, Tetragraptus phyllograptoides, Cymatograptus protobalticus (new), Baltograptus vacillans (new), Baltograptus sp. cf. Baltograptus deflexus (new), Baltograptus minutus (new), Isograptus victoriae, Undulograptus austrodentatus (Arienigraptus zhejiangensis and Undulograptus sinicus Subzones) and the (?)Corymbograptus retroflexus (new) biozones are differentiated in the core and their correlation in Scania is discussed. The Lerhamn drill core provides the most detailed graptolite record of the Floian Stage in Scandinavia. The interval is dominated by a number of species of the genus Baltograptus, endemic to the Atlantic Faunal realm and highly useful for regional biostratigraphic correlation. The biostratigraphic framework is based on endemic and pandemic faunal elements. The mixture of both elements in the drill core allows a more precise inter‐continental correlation of Lower to Middle Ordovician graptolite faunas and may – in the future – provide information as to the climatic history of regions dominated by Baltograptus faunas in the Floian. The (?)C. retroflexus Biozone is based on species originally described from Bohemia, but the record of the zone in the Lerhamn drill core indicates a wider distribution of its fauna. □Biostratigraphy, graptolites, Ordovician, Scania, Sweden.     

New snakeflies (Insecta: Raphidioptera) from the Lower Cretaceous of the UK,Spain and Brazil

Abstract: Several new taxa of snakeflies (Raphidioptera) are described from the Lower Cretaceous deposits of the Wealden, UK (Barremian), Montsec, Spain (Barremian) and the Crato Formation, Brazil (Aptian). Mesoraphidia ednae sp. nov. and M. hilli sp. nov. are described from the Wealden; Nanoraphidia lithographica sp. nov. and Iberoraphidia dividua gen. et sp. nov. are described from Montsec, and Baissoptera lisae sp. nov. is described from the Crato Formation. The geographical range of Nanoraphidia has potentially been extended.     

The identity of the Ordovician (Darriwilian) graptolite Fucoides dentatus Brongniart, 1828

Abstract: The biostratigraphically important Middle Ordovician (Darriwilian) biserial graptolite Fucoides dentatus Brongniart, 1828 is redescribed and illustrated from its type material and from additional specimens collected at the type locality – Lévis, Quebec, Canada. It is referred to Levisograptus gen. nov., which includes also the austrodentatus group of early axonophoran graptolites. The species has previously been confused with a younger, mid‐Darriwilian species, now referred to as Eoglyptograptus gerhardi sp. nov., and recognized as the type species of the genus Eoglyptograptus Mitchell. Both species can be differentiated easily by their respective proximal development types and show nonoverlapping biostratigraphical ranges. Levisograptus dentatus (Brongniart) is an important biostratigraphical index species in the early Darriwilian. Eoglyptograptus species are found in the higher Darriwilian and are biogeographically restricted to the Atlantic Faunal Realm.     

Five years of antimalarial resistance marker surveillance in Gaza Province, Mozambique, following artemisinin-based combination therapy roll out

Antimalarial drug resistance is a major obstacle to malaria control and eventual elimination. The routine surveillance for molecular marker of resistance is an efficient way to assess drug efficacy, which remains feasible in areas where malaria control interventions have succeeded in substantially reducing malaria transmission. Community based asexual parasite prevalence surveys were conducted annually in sentinel sites in Gaza Province, Mozambique from 2006 until 2010, before, during and after antimalarial policy changes to artesunate plus sulfadoxine-pyrimethamine in 2006 and to artemether-lumefantrine in 2008. Genetic analysis of dhfr, dhps, crt, and mdr1 resistant genes was conducted on 3 331 (14.4%) Plasmodium falciparum PCR positive samples collected over the study period from 23 229 children aged 2 to 15 years. The quintuple dhfr/dhps mutation associated with sulfadoxine-pyrimethamine resistance increased from 56.2% at baseline to 75.8% by 2010. At baseline the crt76T and mdr186Y mutants were approaching fixation, 96.1% and 74.7%, respectively. Following the deployment of artemisinin-based combination therapy, prevalence of both these chloroquine-resistance markers began declining, reaching 32.4% and 30.9%, respectively, by 2010. All samples analysed over the 5-year period possessed a single copy of the mdr1 gene. The high and increasing prevalence of the quintuple mutation supports the change in drug policy from artesunate plus sulfadoxine-pyrimethamine to artemether-lumefantrine in Mozambique. As chloroquine related drug pressure decreased in the region, so did the molecular markers associated with chloroquine resistance (crt76T and mdr186Y). However, this reversion to the wild-type mdr186N predisposes parasites towards developing lumefantrine resistance. Close monitoring of artemether-lumefantrine efficacy is therefore essential, particularly given the high drug pressure within the region where most countries now use artemether-lumefantrine as first line treatment.     

Phytoplankton patchiness in Winam Gulf,Lake Victoria: a study using principal component analysis of in situ fluorescent excitation spectra

1. In order to characterise phytoplankton patchiness at fine scales, a profiling multiwavelength fluorometer was cast at numerous locations throughout Winam Gulf in Lake Victoria to measure fluorescent excitation spectra, which are indicators of both phytoplankton diversity and coloured dissolved organic matter (CDOM). 2. Processing the spectral data with principal component analysis (PCA) revealed that linear combinations of four fundamental ‘base’ spectra could explain almost all of the variation in spectral measurements. Three of the base spectra were associated with spatially distinct patches of phytoplankton containing different species assemblages, while the fourth base spectrum was due to CDOM fluorescence. 3. The locations of the phytoplankton patches were traced to the south‐east of Winam Gulf, the western end of the Rusinga Channel and the open waters of Lake Victoria adjacent to Winam Gulf, respectively. The high CDOM fluorescence was traced mainly to relatively deep water in the Rusinga Channel. 4. The phytoplankton and CDOM patchiness were interpreted in the context of physical and chemical gradients that were measured at the site at the same scale as the spectral data. Strong relationships were found between the gradients in spectral data and other environmental variables, which suggested several underlying explanations for the phytoplankton and CDOM patchiness.