Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

We elucidate the detailed effects of gut microbial depletion on the bile acid sub-metabolome of multiple body compartments (liver, kidney, heart, and blood plasma) in rats. We use a targeted ultraperformance liquid chromatography with time of flight mass-spectrometry assay to characterize the differential primary and secondary bile acid profiles in each tissue and show a major increase in the proportion of taurine-conjugated bile acids in germ-free (GF) and antibiotic (streptomycin/penicillin)-treated rats.Although conjugated bile acids dominate the hepatic profile (97.0 ± 1.5%) of conventional animals, unconjugated bile acids comprise the largest proportion of the total measured bile acid profile in kidney (60.0±10.4%) andheart (53.0 ± 18.5%) tissues. In contrast, in the GF animal, taurine-conjugated bile acids (especially taurocholic acid and tauro-β-muricholic acid) dominated the bile acid profiles (liver: 96.0 ± 14.5%; kidney: 96 ± 1%; heart: 93 ± 1%; plasma: 93.0 ± 2.3%), with unconjugated and glycine-conjugated species representing a small proportion of the profile. Higher free taurine levels were found in GF livers compared with the conventional liver (5.1-fold; P < 0.001). Bile acid diversity was also lower in GF and antibiotic-treated tissues compared with conventional animals. Because bile acids perform important signaling functions, it is clear that these chemical communication networks are strongly influencedbymicrobial activitiesormodulation, as evidenced by farnesoid X receptor-regulated pathway transcripts. The presence of specific microbial bile acid co-metabolite patterns in peripheral tissues (including heart and kidney) implies a broader signaling role for these compounds and emphasizes the extent of symbiotic microbial influences in mammalian homeostasis.

Wheat archive links long-term population dynamics of pathogens to air pollution

We used the PCR to study the presence of two plant pathogens in archived wheat samples from a long-term experiment started in 1843. The data were used to construct a unique 160-yr time-series of the abundance of Phaeosphaeria nodorum and Mycosphaerella graminicola, two important pathogens of wheat. During the period since 1970, the relative abundance of DNA of these two pathogens in the samples has reflected the relative importance of the two wheat diseases they cause in U.K. disease surveys. Unexpectedly, changes in the ratio of the pathogens over the 160-yr period were very strongly correlated with changes in atmospheric pollution, as measured by SO2 emissions. This finding suggests that long-term, economically important, changes in pathogen populations can be influenced by anthropogenically induced environmental changes.

Theoretical and experimental investigation of wall confluent jets ventilation and comparison with wall displacement ventilation

This paper reports CFD and experimental results of the characteristics of wall confluent jets in a room. The results presented show the behaviour of wall confluent jets in the form of velocity profiles, the spreading rate of jets on the surface, jets decay, etc. The empirical equations derived are compared with other types of air jets. In addition, the flow in wall confluent jets is compared with the flow in displacement ventilation supply, with regards to the vertical and horizontal spreading on the floor. It is concluded that the jet momentum of wall confluent jets can be more conserved than other jets. Thus, wall confluent jets have a greater spread over the floor than displacement flow.

Regulation of cell cycle and stress responses to hydrostatic pressure in fission yeast

We have investigated the cellular responses to hydrostatic pressure by using the fission yeast Schizosaccharomyces pombe as a model system. Exposure to sublethal levels of hydrostatic pressure resulted in G2 cell cycle delay. This delay resulted from Cdc2 tyrosine-15 (Y-15) phosphorylation, and it was abrogated by simultaneous disruption of the Cdc2 kinase regulators Cdc25 and Wee1. However, cell cycle delay was independent of the DNA damage, cytokinesis, and cell size checkpoints, suggesting a novel mechanism of Cdc2-Y15 phosphorylation in response to hydrostatic pressure. Spc1/Sty1 mitogen-activated protein (MAP) kinase, a conserved member of the eukaryotic stress-activated p38, mitogen-activated protein (MAP) kinase family, was rapidly activated after pressure stress, and it was required for cell cycle recovery under these conditions, in part through promoting polo kinase (Plo1) phosphorylation on serine 402. Moreover, the Spc1 MAP kinase pathway played a key role in maintaining cell viability under hydrostatic pressure stress through the bZip transcription factor, Atf1. Further analysis revealed that prestressing cells with heat increased barotolerance, suggesting adaptational cross-talk between these stress responses. These findings provide new insight into eukaryotic homeostasis after exposure to pressure stress.

Independent and reciprocal accommodation in anisometropic amblyopia

Accommodation is considered to be a symmetrical response and to be driven by the least ametropic and nonamblyopic eye in anisometropia. We report the case of a 4-year-old child with anisometropic amblyopia who accommodates asymmetrically, reliably demonstrating normal accommodation in the nonamblyopic eye and antiaccommodation of the amblyopic eye to near targets. The abnormal accommodation of the amblyopic eye remained largely unchanged during 7 subsequent testing sessions undertaken over the course of therapy. We suggest that a congenital dysinnervation syndrome may result in relaxation of accommodation in relation to near cues and might be a hitherto unconsidered additional etiological factor in anisometropic amblyopia.

Temporal relations of column water vapor and tropical precipitation

Empirical studies using satellite data and radiosondes have shown that precipitation increases with column water vapor (CWV) in the tropics, and that this increase is much steeper above some critical CWV value. Here, eight years of 1-min-resolution microwave radiometer and optical gauge data at Nauru Island are analyzed to better understand the relationships among CWV, column liquid water (CLW), and precipitation at small time scales. CWV is found to have large autocorrelation times compared with CLW and precipitation. Before precipitation events, CWV increases on both a synoptic-scale time period and a subsequent shorter time period consistent with mesoscale convective activity; the latter period is associated with the highest CWV levels. Probabilities of precipitation increase greatly with CWV. Given initial high CWV, this increased probability of precipitation persists at least 10–12 h. Even in periods of high CWV, however, probabilities of initial precipitation in a 5-min period remain low enough that there tends to be a lag before the start of the next precipitation event. This is consistent with precipitation occurring stochastically within environments containing high CWV, with the latter being established by a combination of synoptic-scale and mesoscale forcing.

Structure determination of an intercalating ruthenium dipyridophenazine complex which kinks DNA by semiintercalation of a tetraazaphenanthrene ligand

We describe a crystal structure, at atomic resolution (1.1 Å, 100 K), of a ruthenium polypyridyl complex bound to duplex DNA, in which one ligand acts as a wedge in the minor groove, resulting in the 51° kinking of the double helix. The complex cation Λ-[Ru(1,4,5,8-tetraazaphenanthrene)2(dipyridophenazine)]2+ crystallizes in a 1∶1 ratio with the oligonucleotide d(TCGGCGCCGA) in the presence of barium ions. Each complex binds to one duplex by intercalation of the dipyridophenazine ligand and also by semiintercalation of one of the orthogonal tetraazaphenanthrene ligands into a second symmetrically equivalent duplex. The result is noncovalent cross-linking and marked kinking of DNA.

Phylogenies reveal predictive power of traditional medicine in bioprospecting

There is controversy about whether traditional medicine can guide drug discovery, and investment in ethnobotanically led research has fluctuated. One view is that traditionally used plants are not necessarily efficacious and there are no robust methods for distinguishing the ones that are most likely to be bioactive when selecting species for further testing. Here, we reconstruct a genus-level molecular phylogeny representing the 20,000 species found in the floras of three disparate biodiversity hotspots: Nepal, New Zealand and the Cape of South Africa. Borrowing phylogenetic methods from community ecology, we reveal significant clustering of the 1,500 traditionally used species, and provide a direct measure of the relatedness of the three medicinal floras. We demonstrate shared phylogenetic patterns across the floras: related plants from these regions are used to treat medical conditions in the same therapeutic areas. This strongly suggests independent discovery of plant efficacy, an interpretation corroborated by the presence of a significantly greater proportion of known bioactive species in these plant groups than in a random sample. Phylogenetic cross-cultural comparison can focus screening efforts on a subset of traditionally used plants that are richer in bioactive compounds, and could revitalise the use of traditional knowledge in bioprospecting.

Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex proteins (ROC) domain that may act as a GTPase to regulate its protein kinase activity. The structure of ROC and the mechanism(s) by which it regulates kinase activity are not known. Here, we report the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg2+ at 2.0-Å resolution. The structure displays a dimeric fold generated by extensive domain-swapping, resulting in a pair of active sites constructed with essential functional groups contributed from both monomers. Two PD-associated pathogenic residues, R1441 and I1371, are located at the interface of two monomers and provide exquisite interactions to stabilize the ROC dimer. The structure demonstrates that loss of stabilizing forces in the ROC dimer is likely related to decreased GTPase activity resulting from mutations at these sites. Our data suggest that the ROC domain may regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC domain also represents a signature from a previously undescribed class of GTPases from complex proteins and results may provide a unique molecular target for therapeutics in PD.

Wildfire responses to abrupt climate change in North America

It is widely accepted, based on data from the last few decades and on model simulations, that anthropogenic climate change will cause increased fire activity. However, less attention has been paid to the relationship between abrupt climate changes and heightened fire activity in the paleorecord. We use 35 charcoal and pollen records to assess how fire regimes in North America changed during the last glacial–interglacial transition (15 to 10 ka), a time of large and rapid climate changes. We also test the hypothesis that a comet impact initiated continental-scale wildfires at 12.9 ka; the data do not support this idea, nor are continent-wide fires indicated at any time during deglaciation. There are, however, clear links between large climate changes and fire activity. Biomass burning gradually increased from the glacial period to the beginning of the Younger Dryas. Although there are changes in biomass burning during the Younger Dryas, there is no systematic trend. There is a further increase in biomass burning after the Younger Dryas. Intervals of rapid climate change at 13.9, 13.2, and 11.7 ka are marked by large increases in fire activity. The timing of changes in fire is not coincident with changes in human population density or the timing of the extinction of the megafauna. Although these factors could have contributed to fire-regime changes at individual sites or at specific times, the charcoal data indicate an important role for climate, and particularly rapid climate change, in determining broad-scale levels of fire activity.

Endosomes: a legitimate platform for the signaling train

Although long regarded as a conduit for the degradation or recycling of cell surface receptors, the endosomal system is also an essential site of signal transduction. Activated receptors accumulate in endosomes, and certain signaling components are exclusively localized to endosomes. Receptors can continue to transmit signals from endosomes that are different from those that arise from the plasma membrane, resulting in distinct physiological responses. Endosomal signaling is widespread in metazoans and plants, where it transmits signals for diverse receptor families that regulate essential processes including growth, differentiation and survival. Receptor signaling at endosomal membranes is tightly regulated by mechanisms that control agonist availability, receptor coupling to signaling machinery, and the subcellular localization of signaling components. Drugs that target mechanisms that initiate and terminate receptor signaling at the plasma membrane are widespread and effective treatments for disease. Selective disruption of receptor signaling in endosomes, which can be accomplished by targeting endosomal-specific signaling pathways or by selective delivery of drugs to the endosomal network, may provide novel therapies for disease.

Genome-wide association mapping to candidate polymorphism resolution in the unsequenced barley genome

Although commonplace in human disease genetics, genome-wide association (GWA) studies have only relatively recently been applied to plants. Using 32 phenotypes in the inbreeding crop barley, we report GWA mapping of 15 morphological traits across ∼500 cultivars genotyped with 1,536 SNPs. In contrast to the majority of human GWA studies, we observe high levels of linkage disequilibrium within and between chromosomes. Despite this, GWA analysis readily detected common alleles of high penetrance. To investigate the potential of combining GWA mapping with comparative analysis to resolve traits to candidate polymorphism level in unsequenced genomes, we fine-mapped a selected phenotype (anthocyanin pigmentation) within a 140-kb interval containing three genes. Of these, resequencing the putative anthocyanin pathway gene HvbHLH1 identified a deletion resulting in a premature stop codon upstream of the basic helix-loop-helix domain, which was diagnostic for lack of anthocyanin in our association and biparental mapping populations. The methodology described here is transferable to species with limited genomic resources, providing a paradigm for reducing the threshold of map-based cloning in unsequenced crops.

Fire-free land use in pre-1492 Amazonian savannas

The nature and scale of pre-Columbian land use and the consequences of the 1492 “Columbian Encounter” (CE) on Amazonia are among the more debated topics in New World archaeology and paleoecology. However, pre-Columbian human impact in Amazonian savannas remains poorly understood. Most paleoecological studies have been conducted in neotropical forest contexts. Of studies done in Amazonian savannas, none has the temporal resolution needed to detect changes induced by either climate or humans before and after A.D. 1492, and only a few closely integrate paleoecological and archaeological data. We report a high-resolution 2,150-y paleoecological record from a French Guianan coastal savanna that forces reconsideration of how pre-Columbian savanna peoples practiced raised-field agriculture and how the CE impacted these societies and environments. Our combined pollen, phytolith, and charcoal analyses reveal unexpectedly low levels of biomass burning associated with pre-A.D. 1492 savanna raised-field agriculture and a sharp increase in fires following the arrival of Europeans. We show that pre-Columbian raised-field farmers limited burning to improve agricultural production, contrasting with extensive use of fire in pre-Columbian tropical forest and Central American savanna environments, as well as in present-day savannas. The charcoal record indicates that extensive fires in the seasonally flooded savannas of French Guiana are a post-Columbian phenomenon, postdating the collapse of indigenous populations. The discovery that pre-Columbian farmers practiced fire-free savanna management calls into question the widely held assumption that pre-Columbian Amazonian farmers pervasively used fire to manage and alter ecosystems and offers fresh perspectives on an emerging alternative approach to savanna land use and conservation that can help reduce carbon emissions.

Default perception of high-speed motion

When human observers are exposed to even slight motion signals followed by brief visual transients—stimuli containing no detectable coherent motion signals—they perceive large and salient illusory jumps. This novel effect, which we call “high phi”, challenges well-entrenched assumptions about the perception of motion, namely the minimal-motion principle and the breakdown of coherent motion perception with steps above an upper limit. Our experiments with transients such as texture randomization or contrast reversal show that the magnitude of the jump depends on spatial frequency and transient duration, but not on the speed of the inducing motion signals, and the direction of the jump depends on the duration of the inducer. Jump magnitude is robust across jump directions and different types of transient. In addition, when a texture is actually displaced by a large step beyond dmax, a breakdown of coherent motion perception is expected, but in the presence of an inducer observers again perceive coherent displacements at or just above dmax. In sum, across a large variety of stimuli, we find that when incoherent motion noise is preceded by a small bias, instead of perceiving little or no motion, as suggested by the minimal-motion principle, observers perceive jumps whose amplitude closely follows their own dmax limits.

Late Pleistocene climate change and the global expansion of anatomically modern humans

The extent to which past climate change has dictated the pattern and timing of the out-of-Africa expansion by anatomically modern humans is currently unclear [Stewart JR, Stringer CB (2012) Science 335:1317–1321]. In particular, the incompleteness of the fossil record makes it difficult to quantify the effect of climate. Here, we take a different approach to this problem; rather than relying on the appearance of fossils or archaeological evidence to determine arrival times in different parts of the world, we use patterns of genetic variation in modern human populations to determine the plausibility of past demographic parameters. We develop a spatially explicit model of the expansion of anatomically modern humans and use climate reconstructions over the past 120 ky based on the Hadley Centre global climate model HadCM3 to quantify the possible effects of climate on human demography. The combinations of demographic parameters compatible with the current genetic makeup of worldwide populations indicate a clear effect of climate on past population densities. Our estimates of this effect, based on population genetics, capture the observed relationship between current climate and population density in modern hunter–gatherers worldwide, providing supporting evidence for the realism of our approach. Furthermore, although we did not use any archaeological and anthropological data to inform the model, the arrival times in different continents predicted by our model are also broadly consistent with the fossil and archaeological records. Our framework provides the most accurate spatiotemporal reconstruction of human demographic history available at present and will allow for a greater integration of genetic and archaeological evidence.