Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck

The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes

LPS preconditioning redirects TLR signaling following stroke: TRIF-IRF3 plays a seminal role in mediating tolerance to ischemic injury

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 4 (TLR4) is activated in response to cerebral ischemia leading to substantial brain damage. In contrast, mild activation of TLR4 by preconditioning with low dose exposure to lipopolysaccharide (LPS) prior to cerebral ischemia dramatically improves outcome by reprogramming the signaling response to injury. This suggests that TLR4 signaling can be altered to induce an endogenously neuroprotective phenotype. However, the TLR4 signaling events involved in this neuroprotective response are poorly understood. Here we define several molecular mediators of the primary signaling cascades induced by LPS preconditioning that give rise to the reprogrammed response to cerebral ischemia and confer the neuroprotective phenotype.</p> <p>Methods</p> <p>C57BL6 mice were preconditioned with low dose LPS prior to transient middle cerebral artery occlusion (MCAO). Cortical tissue and blood were collected following MCAO. Microarray and qtPCR were performed to analyze gene expression associated with TLR4 signaling. EMSA and DNA binding ELISA were used to evaluate NFκB and IRF3 activity. Protein expression was determined using Western blot or ELISA. MyD88-/- and TRIF-/- mice were utilized to evaluate signaling in LPS preconditioning-induced neuroprotection.</p> <p>Results</p> <p>Gene expression analyses revealed that LPS preconditioning resulted in a marked upregulation of anti-inflammatory/type I IFN-associated genes following ischemia while pro-inflammatory genes induced following ischemia were present but not differentially modulated by LPS. Interestingly, although expression of pro-inflammatory genes was observed, there was decreased activity of NFκB p65 and increased presence of NFκB inhibitors, including Ship1, Tollip, and p105, in LPS-preconditioned mice following stroke. In contrast, IRF3 activity was enhanced in LPS-preconditioned mice following stroke. TRIF and MyD88 deficient mice revealed that neuroprotection induced by LPS depends on TLR4 signaling via TRIF, which activates IRF3, but does not depend on MyD88 signaling.</p> <p>Conclusion</p> <p>Our results characterize several critical mediators of the TLR4 signaling events associated with neuroprotection. LPS preconditioning redirects TLR4 signaling in response to stroke through suppression of NFκB activity, enhanced IRF3 activity, and increased anti-inflammatory/type I IFN gene expression. Interestingly, this protective phenotype does not require the suppression of pro-inflammatory mediators. Furthermore, our results highlight a critical role for TRIF-IRF3 signaling as the governing mechanism in the neuroprotective response to stroke.</p

Atmospheric Density Uncertainty Quantification for Satellite Conjunction Assessment

Conjunction assessment requires knowledge of the uncertainty in the predicted orbit. Errors in the atmospheric density are a major source of error in the prediction of low Earth orbits. Therefore, accurate estimation of the density and quantification of the uncertainty in the density is required. Most atmospheric density models, however, do not provide an estimate of the uncertainty in the density. In this work, we present a new approach to quantify uncertainties in the density and to include these for calculating the probability of collision Pc. For this, we employ a recently developed dynamic reduced-order density model that enables efficient prediction of the thermospheric density. First, the model is used to obtain accurate estimates of the density and of the uncertainty in the estimates. Second, the density uncertainties are propagated forward simultaneously with orbit propagation to include the density uncertainties for Pc calculation. For this, we account for the effect of cross-correlation in position uncertainties due to density errors on the Pc. Finally, the effect of density uncertainties and cross-correlation on the Pc is assessed. The presented approach provides the distinctive capability to quantify the uncertainty in atmospheric density and to include this uncertainty for conjunction assessment while taking into account the dependence of the density errors on location and time. In addition, the results show that it is important to consider the effect of cross-correlation on the Pc, because ignoring this effect can result in severe underestimation of the collision probability.Comment: 15 pages, 6 figures, 5 table

Global coordination and standardisation in marine biodiversity through the World Register of Marine Species (WoRMS) and related databases

The World Register of Marine Species is an over 90% complete open-access inventory of all marine species names. Here we illustrate the scale of the problems with species names, synonyms, and their classification, and describe how WoRMS publishes online quality assured information on marine species.Within WoRMS, over 100 global, 12 regional and 4 thematic species databases are integrated with a common taxonomy. Over 240 editors from 133 institutions and 31 countries manage the content. To avoid duplication of effort, content is exchanged with 10 external databases. At present WoRMS contains 460,000 taxonomic names (from Kingdom to subspecies), 368,000 species level combinations of which 215,000 are currently accepted marine species names, and 26,000 related but non-marine species. Associated information includes 150,000 literature sources, 20,000 images, and locations of 44,000 specimens. Usage has grown linearly since its launch in 2007, with about 600,000 unique visitors to the website in 2011, and at least 90 organisations from 12 countries using WoRMS for their data management.By providing easy access to expert-validated content, WoRMS improves quality control in the use of species names, with consequent benefits to taxonomy, ecology, conservation and marine biodiversity research and management. The service manages information on species names that would otherwise be overly costly for individuals, and thus minimises errors in the application of nomenclature standards. WoRMS' content is expanding to include host-parasite relationships, additional literature sources, locations of specimens, images, distribution range, ecological, and biological data. Species are being categorised as introduced (alien, invasive), of conservation importance, and on other attributes. These developments have a multiplier effect on its potential as a resource for biodiversity research and management. As a consequence of WoRMS, we are witnessing improved communication within the scientific community, and anticipate increased taxonomic efficiency and quality control in marine biodiversity research and management

Marine Biodiversity in the Australian Region

The entire Australian marine jurisdictional area, including offshore and sub-Antarctic islands, is considered in this paper. Most records, however, come from the Exclusive Economic Zone (EEZ) around the continent of Australia itself. The counts of species have been obtained from four primary databases (the Australian Faunal Directory, Codes for Australian Aquatic Biota, Online Zoological Collections of Australian Museums, and the Australian node of the Ocean Biogeographic Information System), but even these are an underestimate of described species. In addition, some partially completed databases for particular taxonomic groups, and specialized databases (for introduced and threatened species) have been used. Experts also provided estimates of the number of known species not yet in the major databases. For only some groups could we obtain an (expert opinion) estimate of undiscovered species. The databases provide patchy information about endemism, levels of threat, and introductions. We conclude that there are about 33,000 marine species (mainly animals) in the major databases, of which 130 are introduced, 58 listed as threatened and an unknown percentage endemic. An estimated 17,000 more named species are either known from the Australian EEZ but not in the present databases, or potentially occur there. It is crudely estimated that there may be as many as 250,000 species (known and yet to be discovered) in the Australian EEZ. For 17 higher taxa, there is sufficient detail for subdivision by Large Marine Domains, for comparison with other National and Regional Implementation Committees of the Census of Marine Life. Taxonomic expertise in Australia is unevenly distributed across taxa, and declining. Comments are given briefly on biodiversity management measures in Australia, including but not limited to marine protected areas

Confirmation of beach accretion by grain-size trend analysis: Camposoto beach, Cádiz, SW Spain

An application of the grain size trend analysis (GSTA) is used in an exploratory approach to characterize sediment transport on Camposoto beach (Cádiz, SW Spain). In May 2009 the mesotidal beach showed a well-developed swash bar on the upper foreshore, which was associated with fair-weather conditions prevailing just before and during the field survey. The results were tested by means of an autocorrelation statistical test (index I of Moran). Two sedimentological trends were recognized, i.e. development towards finer, better sorted and more negatively skewed sediment (FB–), and towards finer, better sorted and less negatively or more positively skewed sediment (FB+). Both vector fields were compared with results obtained from more classical approaches (sand tracers, microtopography and current measurements). This revealed that both trends can be considered as realistic, the FB+ trend being identified for the first time in a beach environment. The data demonstrate that, on the well-developed swash bar, sediment transported onshore becomes both finer and better sorted towards the coast. On the lower foreshore, which exhibits a steeper slope produced by breaking waves, the higherenergy processes winnow out finer particles and thereby produce negatively skewed grain-size distributions. The upper foreshore, which has a flatter and smoother slope, is controlled by lower-energy swash-backwash and overwash processes. As a result, the skewness of the grain-size distributions evolves towards less negative or more positive values. The skewness parameter appears to be distributed as a function of the beach slope and, thus, reflects variations in hydrodynamic energy. This has novel implications for coastal management

How Many Species Are There on Earth and in the Ocean?

The diversity of life is one of the most striking aspects of our planet; hence knowing how many species inhabit Earth is among the most fundamental questions in science. Yet the answer to this question remains enigmatic, as efforts to sample the world's biodiversity to date have been limited and thus have precluded direct quantification of global species richness, and because indirect estimates rely on assumptions that have proven highly controversial. Here we show that the higher taxonomic classification of species (i.e., the assignment of species to phylum, class, order, family, and genus) follows a consistent and predictable pattern from which the total number of species in a taxonomic group can be estimated. This approach was validated against well-known taxa, and when applied to all domains of life, it predicts ∼8.7 million (±1.3 million SE) eukaryotic species globally, of which ∼2.2 million (±0.18 million SE) are marine. In spite of 250 years of taxonomic classification and over 1.2 million species already catalogued in a central database, our results suggest that some 86% of existing species on Earth and 91% of species in the ocean still await description. Renewed interest in further exploration and taxonomy is required if this significant gap in our knowledge of life on Earth is to be closed

Persistent export of 231Pa from the deep central Arctic Ocean over the past 35,000 years

The Arctic Ocean has an important role in Earth’s climate, both through surface processes such as sea-ice formation and transport, and through the production and export of waters at depth that contribute to the global thermohaline circulation. Deciphering the deep Arctic Ocean’s palaeo-oceanographic history is a crucial part of understanding its role in climatic change. Here we show that sedimentary ratios of the radionuclides thorium-230 (230Th) and protactinium-231 (231Pa), which are produced in sea water and removed by particle scavenging on timescales of decades to centuries, respectively, record consistent evidence for the export of 231Pa from the deep Arctic and may indicate continuous deep-water exchange between the Arctic and Atlantic oceans throughout the past 35,000 years. Seven well-dated box-core records provide a comprehensive overview of 231Pa and 230Th burial in Arctic sediments during glacial, deglacial and interglacial conditions. Sedimentary 231Pa/230Th ratios decrease nearly linearly with increasing water depth above the core sites, indicating efficient particle scavenging in the upper water column and greater influence of removal by lateral transport at depth. Although the measured 230Th burial is in balance with its production in Arctic sea water, integrated depth profiles for all time intervals reveal a deficit in 231Pa burial that can be balanced only by lateral export in the water column. Because no enhanced sink for 231Pa has yet been found in the Arctic, our records suggest that deep-water exchange through the Fram strait may export 231Pa. Such export may have continued for the past 35,000 years, suggesting a century-scale replacement time for deep waters in the Arctic Ocean since the most recent glaciation and a persistent contribution of Arctic waters to the global ocean circulation

Metabolic responses to high pCO2 conditions at a CO2 vent site in juveniles of a marine isopod species assemblage

We are starting to understand the relationship between metabolic rate responses and species' ability to respond to exposure to high pCO2. However, most of our knowledge has come from investigations of single species. The examination of metabolic responses of closely related species with differing distributions around natural elevated CO2 areas may be useful to inform our understanding of their adaptive significance. Furthermore, little is known about the physiological responses of marine invertebrate juveniles to high pCO2, despite the fact they are known to be sensitive to other stressors, often acting as bottlenecks for future species success. We conducted an in situ transplant experiment using juveniles of isopods found living inside and around a high pCO2 vent (Ischia, Italy): the CO2 'tolerant' Dynamene bifida and 'sensitive' Cymodoce truncata and Dynamene torelliae. This allowed us to test for any generality of the hypothesis that pCO2 sensitive marine invertebrates may be those that experience trade-offs between energy metabolism and cellular homoeostasis under high pCO2 conditions. Both sensitive species were able to maintain their energy metabolism under high pCO2 conditions, but in C. truncata this may occur at the expense of [carbonic anhydrase], confirming our hypothesis. By comparison, the tolerant D. bifida appeared metabolically well adapted to high pCO2, being able to upregulate ATP production without recourse to anaerobiosis. These isopods are important keystone species; however, given they differ in their metabolic responses to future pCO2, shifts in the structure of the marine ecosystems they inhabit may be expected under future ocean acidification conditions