Origin of volatile organic compound emissions from subarctic tundra under global warming

Warming occurs in the Arctic twice as fast as the global average, which in turn leads to a large enhancement in terpenoid emissions from vegetation. Volatile terpenoids are the main class of biogenic volatile organic compounds (VOCs) that play crucial roles in atmospheric chemistry and climate. However, the biochemical mechanisms behind the temperature‐dependent increase in VOC emissions from subarctic ecosystems are largely unexplored. Using ¹³CO₂‐labeling, we studied the origin of VOCs and the carbon (C) allocation under global warming in the soil–plant–atmosphere system of contrasting subarctic heath tundra vegetation communities characterized by dwarf shrubs of the genera Salix or Betula. The projected temperature rise of the subarctic summer by 5°C was realistically simulated in sophisticated climate chambers. VOC emissions strongly depended on the plant species composition of the heath tundra. Warming caused increased VOC emissions and significant changes in the pattern of volatiles toward more reactive hydrocarbons. The ¹³C was incorporated to varying degrees in different monoterpene and sesquiterpene isomers. We found that de novo monoterpene biosynthesis contributed to 40%–44% (Salix) and 60%–68% (Betula) of total monoterpene emissions under the current climate, and that warming increased the contribution to 50%–58% (Salix) and 87%–95% (Betula). Analyses of above‐ and belowground ^12/13C showed shifts of C allocation in the plant–soil systems and negative effects of warming on C sequestration by lowering net ecosystem exchange of CO₂ and increasing C loss as VOCs. This comprehensive analysis provides the scientific basis for mechanistically understanding the processes controlling terpenoid emissions, required for modeling VOC emissions from terrestrial ecosystems and predicting the future chemistry of the arctic atmosphere. By changing the chemical composition and loads of VOCs into the atmosphere, the current data indicate that global warming in the Arctic may have implications for regional and global climate and for the delicate tundra ecosystems.     

Tonsilar NK Cells Restrict B Cell Transformation by the Epstein-Barr Virus via IFN-��

Cells of the innate immune system act in synergy to provide a first line of defense against pathogens. Here we describe that dendritic cells (DCs), matured with viral products or mimics thereof, including Epstein-Barr virus (EBV), activated natural killer (NK) cells more efficiently than other mature DC preparations. CD56^brightCD16⁻ NK cells, which are enriched in human secondary lymphoid tissues, responded primarily to this DC activation. DCs elicited 50-fold stronger interferon-γ (IFN-γ) secretion from tonsilar NK cells than from peripheral blood NK cells, reaching levels that inhibited B cell transformation by EBV. In fact, 100- to 1,000-fold less tonsilar than peripheral blood NK cells were required to achieve the same protection in vitro, indicating that innate immune control of EBV by NK cells is most efficient at this primary site of EBV infection. The high IFN-γ concentrations, produced by tonsilar NK cells, delayed latent EBV antigen expression, resulting in decreased B cell proliferation during the first week after EBV infection in vitro. These results suggest that NK cell activation by DCs can limit primary EBV infection in tonsils until adaptive immunity establishes immune control of this persistent and oncogenic human pathogen.     

Tonsilar NK cells restrict B cell transformation by the Epstein-Barr virus via IFN-gamma

Cells of the innate immune system act in synergy to provide a first line of defense against pathogens. Here we describe that dendritic cells (DCs), matured with viral products or mimics thereof, including Epstein-Barr virus (EBV), activated natural killer (NK) cells more efficiently than other mature DC preparations. CD56(bright)CD16(-) NK cells, which are enriched in human secondary lymphoid tissues, responded primarily to this DC activation. DCs elicited 50-fold stronger interferon-gamma (IFN-gamma) secretion from tonsilar NK cells than from peripheral blood NK cells, reaching levels that inhibited B cell transformation by EBV. In fact, 100- to 1,000-fold less tonsilar than peripheral blood NK cells were required to achieve the same protection in vitro, indicating that innate immune control of EBV by NK cells is most efficient at this primary site of EBV infection. The high IFN-gamma concentrations, produced by tonsilar NK cells, delayed latent EBV antigen expression, resulting in decreased B cell proliferation during the first week after EBV infection in vitro. These results suggest that NK cell activation by DCs can limit primary EBV infection in tonsils until adaptive immunity establishes immune control of this persistent and oncogenic human pathogen.     

A quantitative test of the relationship between parasite dose and infection probability across different host-parasite combinations

Epidemiological models generally assume that the number of susceptible individuals that become infected within a unit of time depends on the density of the hosts and the concentration of parasites (i.e. mass-action principle). However, empirical studies have found significant deviations from this assumption due to biotic and abiotic factors, such as seasonality, the spatial structure of the host population and host heterogeneity with respect to immunity and susceptibility. In this paper, we examine the effect of the dose level of the bacterial endoparasite Pasteuria ramosa on the infection rate of its host, the water flea Daphnia magna. Using seven host clones and two parasite isolates, we measure the fraction of infected hosts after exposure to eight different parasite doses to determine whether there is variation in the infection process across different host clone-parasite isolate combinations. In five combinations, a pronounced dose-dependent infection pattern was found. Using a likelihood approach, we compare the infection data of these five combinations to the fit of three mathematical models: a mass-action model, a parasite antagonism model (i.e. an increase in the parasite dose leads to an under-proportionate increase in the infection rate per host) and a heterogeneous host model. We found that the host heterogeneity model, in which we assumed the existence of non-inherited phenotypic differences in host susceptibilities to the parasite, provides the best fit. Our analysis suggests that among 5 out of the 14 host clone-parasite isolate combinations that resulted in appreciable infections, non-genetic host heterogeneity plays an important role.     

Pool desiccation and developmental thresholds in the common frog, Rana temporaria

The developmental threshold is the minimum size or condition that a developing organism must have reached in order for a life-history transition to occur. Although developmental thresholds have been observed for many organisms, inter-population variation among natural populations has not been examined. Since isolated populations can be subjected to strong divergent selection, population divergence in developmental thresholds can be predicted if environmental conditions favour fast or slow developmental time in different populations. Amphibian metamorphosis is a well-studied life-history transition, and using a common garden approach we compared the development time and the developmental threshold of metamorphosis in four island populations of the common frog Rana temporaria: two populations originating from islands with only temporary breeding pools and two from islands with permanent pools. As predicted, tadpoles from time-constrained temporary pools had a genetically shorter development time than those from permanent pools. Furthermore, the variation in development time among females from temporary pools was low, consistent with the action of selection on rapid development in this environment. However, there were no clear differences in the developmental thresholds between the populations, indicating that the main response to life in a temporary pool is to shorten the development time.     

Conservation of gene linkage in dispersed vertebrate NK homeobox clusters

Nk homeobox genes are important regulators of many different developmental processes including muscle, heart, central nervous system and sensory organ development. They are thought to have arisen as part of the ANTP megacluster, which also gave rise to Hox and ParaHox genes, and at least some NK genes remain tightly linked in all animals examined so far. The protostome–deuterostome ancestor probably contained a cluster of nine Nk genes: (Msx)–(Nk4/tinman)–(Nk3/bagpipe)–(Lbx/ladybird)–(Tlx/c15)–(Nk7)–(Nk6/hgtx)–(Nk1/slouch)–(Nk5/Hmx). Of these genes, only NKX2.6–NKX3.1, LBX1–TLX1 and LBX2–TLX2 remain tightly linked in humans. However, it is currently unclear whether this is unique to the human genome as we do not know which of these Nk genes are clustered in other vertebrates. This makes it difficult to assess whether the remaining linkages are due to selective pressures or because chance rearrangements have “missed” certain genes. In this paper, we identify all of the paralogs of these ancestrally clustered NK genes in several distinct vertebrates. We demonstrate that tight linkages of Lbx1–Tlx1, Lbx2–Tlx2 and Nkx3.1–Nkx2.6 have been widely maintained in both the ray-finned and lobe-finned fish lineages. Moreover, the recently duplicated Hmx2–Hmx3 genes are also tightly linked. Finally, we show that Lbx1–Tlx1 and Hmx2–Hmx3 are flanked by highly conserved noncoding elements, suggesting that shared regulatory regions may have resulted in evolutionary pressure to maintain these linkages. Consistent with this, these pairs of genes have overlapping expression domains. In contrast, Lbx2–Tlx2 and Nkx3.1–Nkx2.6, which do not seem to be coexpressed, are also not associated with conserved noncoding sequences, suggesting that an alternative mechanism may be responsible for the continued clustering of these genes.     

Rational confederation of genes and diseases: NGS interpretation via GeneCards,MalaCards and VarElect

Background

A key challenge in the realm of human disease research is next generation sequencing (NGS) interpretation, whereby identified filtered variant-harboring genes are associated with a patient’s disease phenotypes. This necessitates bioinformatics tools linked to comprehensive knowledgebases. The GeneCards suite databases, which include GeneCards (human genes), MalaCards (human diseases) and PathCards (human pathways) together with additional tools, are presented with the focus on MalaCards utility for NGS interpretation as well as for large scale bioinformatic analyses.

Results

VarElect, our NGS interpretation tool, leverages the broad information in the GeneCards suite databases. MalaCards algorithms unify disease-related terms and annotations from 69 sources. Further, MalaCards defines hierarchical relatedness—aliases, disease families, a related diseases network, categories and ontological classifications. GeneCards and MalaCards delineate and share a multi-tiered, scored gene-disease network, with stringency levels, including the definition of elite status—high quality gene-disease pairs, coming from manually curated trustworthy sources, that includes 4500 genes for 8000 diseases. This unique resource is key to NGS interpretation by VarElect. VarElect, a comprehensive search tool that helps infer both direct and indirect links between genes and user-supplied disease/phenotype terms, is robustly strengthened by the information found in MalaCards. The indirect mode benefits from GeneCards’ diverse gene-to-gene relationships, including SuperPaths—integrated biological pathways from 12 information sources. We are currently adding an important information layer in the form of “disease SuperPaths”, generated from the gene-disease matrix by an algorithm similar to that previously employed for biological pathway unification. This allows the discovery of novel gene-disease and disease–disease relationships. The advent of whole genome sequencing necessitates capacities to go beyond protein coding genes. GeneCards is highly useful in this respect, as it also addresses 101,976 non-protein-coding RNA genes. In a more recent development, we are currently adding an inclusive map of regulatory elements and their inferred target genes, generated by integration from 4 resources.

Conclusions

MalaCards provides a rich big-data scaffold for in silico biomedical discovery within the gene-disease universe. VarElect, which depends significantly on both GeneCards and MalaCards power, is a potent tool for supporting the interpretation of wet-lab experiments, notably NGS analyses of disease. The GeneCards suite has thus transcended its 2-decade role in biomedical research, maturing into a key player in clinical investigation.

     

A Systematic Map of Systematic Reviews in Pediatric Dentistry—What Do We Really Know?

ObjectivesTo identify, appraise and summarize existing knowledge and knowledge gaps in practice-relevant questions in pediatric dentistry.MethodsA systematic mapping of systematic reviews was undertaken for domains considered important in daily clinical practice. The literature search covered questions in the following domains: behavior management problems/dental anxiety; caries risk assessment and caries detection including radiographic technologies; prevention and non-operative treatment of caries in primary and young permanent teeth; operative treatment of caries in primary and young permanent teeth; prevention and treatment of periodontal disease; management of tooth developmental and mineralization disturbances; prevention and treatment of oral conditions in children with chronic diseases/developmental disturbances/obesity; diagnosis, prevention and treatment of dental erosion and tooth wear; treatment of traumatic injuries in primary and young permanent teeth and cost-effectiveness of these interventions. Abstracts and full text reviews were assessed independently by two reviewers and any differences were solved by consensus. AMSTAR was used to assess the risk of bias of each included systematic review. Reviews judged as having a low or moderate risk of bias were used to formulate existing knowledge and knowledge gaps.ResultsOut of 81 systematic reviews meeting the inclusion criteria, 38 were judged to have a low or moderate risk of bias. Half of them concerned caries prevention. The quality of evidence was high for a caries-preventive effect of daily use of fluoride toothpaste and moderate for fissure sealing with resin-based materials. For the rest the quality of evidence for the effects of interventions was low or very low.ConclusionThere is an urgent need for primary clinical research of good quality in most clinically-relevant domains in pediatric dentistry.