Speciation leads to divergent methylmercury accumulation in sympatric whitefish

Central European lake whitefish (Coregonus spp.) colonized Swiss lakes following the last glacial retreat and have undergone rapid speciation and adaptive radiation. Up to six species have been shown to coexist in some lakes, and individual species occupy specific ecological niches and have distinct feeding and reproductive ecologies. We studied methylmercury (MeHg) accumulation in sympatric whitefish species from seven Swiss lakes to determine if ecological divergence has led to different rates of MeHg bioaccumulation. In four of seven lakes, sympatric species had distinctly different MeHg levels, which varied by up to a factor of two between species. Generally, species with greater MeHg levels were smaller in body size and planktivorous, and species with lower MeHg were larger and benthivorous. While modest disparities in trophic position between species might be expected a priori to explain the divergence in MeHg, δ15N of bulk tissue did not correlate with fish MeHg in five of seven lakes. Results of a nested ANCOVA analysis across all lakes indicated that only two factors (species, lake) explained substantial portions of the variance, with species accounting for more variance (52 %) than inter-lake differences (32 %). We suggest that differences in MeHg accumulation were likely caused by diverging metabolic traits between species, such as differences in energy partitioning between anabolism and catabolism, potentially interacting with species-specific prey resource utilization. These results indicate substantial variability in MeHg accumulation between closely related fish species, illustrating that ecological speciation in fish can lead to divergent MeHg accumulation patterns.

In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Genome sequence, comparative analysis, and population genetics of the domestic horse

We report a high-quality draft sequence of the genome of the horse (Equus caballus). The genome is relatively repetitive but has little segmental duplication. Chromosomes appear to have undergone few historical rearrangements: 53% of equine chromosomes show conserved synteny to a single human chromosome. Equine chromosome 11 is shown to have an evolutionary new centromere devoid of centromeric satellite DNA, suggesting that centromeric function may arise before satellite repeat accumulation. Linkage disequilibrium, showing the influences of early domestication of large herds of female horses, is intermediate in length between dog and human, and there is long-range haplotype sharing among breeds.

Greenland accumulation and its connection to the large-scale atmospheric circulation in ERA-Interim and paleoclimate simulations

Changes in Greenland accumulation and the stability in the relationship between accumulation variability and large-scale circulation are assessed by performing time-slice simulations for the present day, the preindustrial era, the early Holocene, and the Last Glacial Maximum (LGM) with a comprehensive climate model. The stability issue is an important prerequisite for reconstructions of Northern Hemisphere atmospheric circulation variability based on accumulation or precipitation proxy records from Greenland ice cores. The analysis reveals that the relationship between accumulation variability and large-scale circulation undergoes a significant seasonal cycle. As the contributions of the individual seasons to the annual signal change, annual mean accumulation variability is not necessarily related to the same atmospheric circulation patterns during the different climate states. Interestingly, within a season, local Greenland accumulation variability is indeed linked to a consistent circulation pattern, which is observed for all studied climate periods, even for the LGM. Hence, it would be possible to deduce a reliable reconstruction of seasonal atmospheric variability (e.g., for North Atlantic winters) if an accumulation or precipitation proxy were available that resolves single seasons. We further show that the simulated impacts of orbital forcing and changes in the ice sheet topography on Greenland accumulation exhibit strong spatial differences, emphasizing that accumulation records from different ice core sites regarding both interannual and long-term (centennial to millennial) variability cannot be expected to look alike since they include a distinct local signature. The only uniform signal to external forcing is the strong decrease in Greenland accumulation during glacial (LGM) conditions and an increase associated with the recent rise in greenhouse gas concentrations.

Palynological richness and evenness: insights from the taxa accumulation curve

Palynology provides the opportunity to make inferences on changes in diversity of terrestrial vegetation over long time scales. The often coarse taxonomic level achievable in pollen analysis, differences in pollen production and dispersal, and the lack of pollen source boundaries hamper the application of diversity indices to palynology. Palynological richness, the number of pollen types at a constant pollen count, is the most robust and widely used diversity indicator for pollen data. However, this index is also influenced by the abundance distribution of pollen types in sediments. In particular, where the index is calculated by rarefaction analysis, information on taxonomic richness at low abundance may be lost. Here we explore information that can be extracted from the accumulation of taxa over consecutive samples. The log-transformed taxa accumulation curve can be broken up into linear sections with different slope and intersect parameters, describing the accumulation of new taxa within the section. The breaking points may indicate changes in the species pool or in the abundance of high versus low pollen producers. Testing this concept on three pollen diagrams from different landscapes, we find that the break points in the taxa accumulation curves provide convenient zones for identifying changes in richness and evenness. The linear regressions over consecutive samples can be used to inter- and extrapolate to low or extremely high pollen counts, indicating evenness and richness in taxonomic composition within these zones. An evenness indicator, based on the rank-order-abundance is used to assist in the evaluation of the results and the interpretation of the fossil records. Two central European pollen diagrams show major changes in the taxa accumulation curves for the Lateglacial period and the time of human induced land-use changes, while they do not indicate strong changes in the species pool with the onset of the Holocene. In contrast, a central Swedish pollen diagram shows comparatively little change, but high richness during the early Holocene forest establishment. Evenness and palynological richness are related for most periods in the three diagrams, however, sections before forest establishment and after forest clearance show high evenness, which is not necessarily accompanied by high palynological richness, encouraging efforts to separate the two.

A climatological analysis of high-precipitation events in Dronning Maud Land, Antarctica, and associated large-scale atmospheric conditions

The link between high precipitation in Dronning Maud Land (DML), Antarctica, and the large-scale atmospheric circulation is investigated using ERA-Interim data for 1979–2009. High-precipitation events are analyzed at Halvfarryggen situated in the coastal region of DML and at Kohnen Station located in its interior. This study further includes a comprehensive comparison of high precipitation in ERA-Interim with precipitation data from the Antarctic Mesoscale Prediction System (AMPS) and snow accumulation measurements from automatic weather stations (AWSs), with the limitations of such a comparison being discussed. The ERA-Interim and AMPS precipitation data agree very well. However, the correspondence between high precipitation in ERA-Interim and high snow accumulation at the AWSs is relatively weak. High-precipitation events at both Halvfarryggen and Kohnen are typically associated with amplified upper level waves. This large-scale atmospheric flow pattern is preceded by the downstream development of a Rossby wave train from the eastern South Pacific several days before the precipitation event. At the surface, a cyclone located over the Weddell Sea is the main synoptic ingredient for high precipitation both at Halvfarryggen and at Kohnen. A blocking anticyclone downstream is not a requirement for high precipitation per se, but a larger share of blocking occurrences during the highest-precipitation days in DML suggests that these blocks strengthen the vertically integrated water vapor transport (IVT) into DML. A strong link between high precipitation and the IVT perpendicular to the local orography suggests that IVT could be used as a “proxy” for high precipitation, in particular over DML's interior.

Targeting of the MET receptor tyrosine kinase by small molecule inhibitors leads to MET accumulation by impairing the receptor downregulation.

The MET receptor tyrosine kinase is deregulated primarily via overexpression or point mutations in various human cancers and different strategies for MET inhibition are currently evaluated in clinical trials. We observed by Western blot analysis and by Flow cytometry that MET inhibition by different MET small molecule inhibitors surprisingly increases in a dose-dependent manner total MET levels in treated cells. Mechanistically, this inhibition-related MET accumulation was associated with reduced Tyr1003 phosphorylation and MET physical association with the CBL ubiquitin ligase with concomitant decrease in MET ubiquitination. These data may suggest careful consideration for design of anti-MET clinical protocols.

Size-dependent accumulation of particles in lysosomes modulates dendritic cell function through impaired antigen degradation.

INTRODUCTION Nanosized particles may enable therapeutic modulation of immune responses by targeting dendritic cell (DC) networks in accessible organs such as the lung. To date, however, the effects of nanoparticles on DC function and downstream immune responses remain poorly understood. METHODS Bone marrow-derived DCs (BMDCs) were exposed in vitro to 20 or 1,000 nm polystyrene (PS) particles. Particle uptake kinetics, cell surface marker expression, soluble protein antigen uptake and degradation, as well as in vitro CD4(+) T-cell proliferation and cytokine production were analyzed by flow cytometry. In addition, co-localization of particles within the lysosomal compartment, lysosomal permeability, and endoplasmic reticulum stress were analyzed. RESULTS The frequency of PS particle-positive CD11c(+)/CD11b(+) BMDCs reached an early plateau after 20 minutes and was significantly higher for 20 nm than for 1,000 nm PS particles at all time-points analyzed. PS particles did not alter cell viability or modify expression of the surface markers CD11b, CD11c, MHC class II, CD40, and CD86. Although particle exposure did not modulate antigen uptake, 20 nm PS particles decreased the capacity of BMDCs to degrade soluble antigen, without affecting their ability to induce antigen-specific CD4(+) T-cell proliferation. Co-localization studies between PS particles and lysosomes using laser scanning confocal microscopy detected a significantly higher frequency of co-localized 20 nm particles as compared with their 1,000 nm counterparts. Neither size of PS particle caused lysosomal leakage, expression of endoplasmic reticulum stress gene markers, or changes in cytokines profiles. CONCLUSION These data indicate that although supposedly inert PS nanoparticles did not induce DC activation or alteration in CD4(+) T-cell stimulating capacity, 20 nm (but not 1,000 nm) PS particles may reduce antigen degradation through interference in the lysosomal compartment. These findings emphasize the importance of performing in-depth analysis of DC function when developing novel approaches for immune modulation with nanoparticles.

New LA-ICP-MS cryocell and calibration technique for sub-millimeter analysis of ice cores

Ice cores provide a robust reconstruction of past climate. However, development of timescales by annual-layer counting, essential to detailed climate reconstruction and interpretation, on ice cores collected at low-accumulation sites or in regions of compressed ice, is problematic due to closely spaced layers. Ice-core analysis by laser ablation–inductively coupled plasma–mass spectrometry (LA-ICP-MS) provides sub-millimeter-scale sampling resolution (on the order of 100μm in this study) and the low detection limits (ng L–1) necessary to measure the chemical constituents preserved in ice cores. We present a newly developed cryocell that can hold a 1m long section of ice core, and an alternative strategy for calibration. Using ice-core samples from central Greenland, we demonstrate the repeatability of multiple ablation passes, highlight the improved sampling resolution, verify the calibration technique and identify annual layers in the chemical profile in a deep section of an ice core where annual layers have not previously been identified using chemistry. In addition, using sections of cores from the Swiss/Italian Alps we illustrate the relationship between Ca, Na and Fe and particle concentration and conductivity, and validate the LA-ICP-MS Ca profile through a direct comparison with continuous flow analysis results.

Elevated temperature differentially affects virulence, VirB protein accumulation, and T-pilus formation in different Agrobacterium tumefaciens and Agrobacterium vitis strains.

That gene transfer to plant cells is a temperature-sensitive process has been known for more than 50 years. Previous work indicated that this sensitivity results from the inability to assemble a functional T pilus required for T-DNA and protein transfer to recipient cells. The studies reported here extend these observations and more clearly define the molecular basis of this assembly and transfer defect. T-pilus assembly and virulence protein accumulation were monitored in Agrobacterium tumefaciens strain C58 at different temperatures ranging from 20 degrees C to growth-inhibitory 37 degrees C. Incubation at 28 degrees C but not at 26 degrees C strongly inhibited extracellular assembly of the major T-pilus component VirB2 as well as of pilus-associated protein VirB5, and the highest amounts of T pili were detected at 20 degrees C. Analysis of temperature effects on the cell-bound virulence machinery revealed three classes of virulence proteins. Whereas class I proteins (VirB2, VirB7, VirB9, and VirB10) were readily detected at 28 degrees C, class II proteins (VirB1, VirB4, VirB5, VirB6, VirB8, VirB11, VirD2, and VirE2) were only detected after cell growth below 26 degrees C. Significant levels of class III proteins (VirB3 and VirD4) were only detected at 20 degrees C and not at higher temperatures. Shift of virulence-induced agrobacteria from 20 to 28 or 37 degrees C had no immediate effect on cell-bound T pili or on stability of most virulence proteins. However, the temperature shift caused a rapid decrease in the amount of cell-bound VirB3 and VirD4, and VirB4 and VirB11 levels decreased next. To assess whether destabilization of virulence proteins constitutes a general phenomenon, levels of virulence proteins and of extracellular T pili were monitored in different A. tumefaciens and Agrobacterium vitis strains grown at 20 and 28 degrees C. Levels of many virulence proteins were strongly reduced at 28 degrees C compared to 20 degrees C, and T-pilus assembly did not occur in all strains except "temperature-resistant" Ach5 and Chry5. Virulence protein levels correlated well with bacterial virulence at elevated temperature, suggesting that degradation of a limited set of virulence proteins accounts for the temperature sensitivity of gene transfer to plants.

Drosophila valois encodes a divergent WD protein that is required for Vasa localization and Oskar protein accumulation

valois (vls) was identified as a posterior group gene in the initial screens for Drosophila maternal-effect lethal mutations. Despite its early genetic identification, it has not been characterized at the molecular level until now. We show that vls encodes a divergent WD domain protein and that the three available EMS-induced point mutations cause premature stop codons in the vls ORF. We have generated a null allele that has a stronger phenotype than the EMS mutants. The vlsnull mutant shows that vls+ is required for high levels of Oskar protein to accumulate during oogenesis, for normal posterior localization of Oskar in later stages of oogenesis and for posterior localization of the Vasa protein during the entire process of pole plasm assembly. There is no evidence for vls being dependent on an upstream factor of the posterior pathway, suggesting that Valois protein (Vls) instead acts as a co-factor in the process. Based on the structure of Vls, the function of similar proteins in different systems and our phenotypic analysis, it seems likely that vls may promote posterior patterning by facilitating interactions between different molecules.

Analysis of the chlorophyll catabolism pathway in leaves of an introgression senescence mutant of Lolium temulentum

igments, proteins and enzyme activity related to chlorophyll catabolism were analysed in senescing leaves of wild-type (WT) Lolium temulentum and compared with those of an introgression line carrying a mutant gene from stay-green (SG) Festuca pratensis. During senescence of WT leaves chlorophylls a and b were continuously catabolised to colourless products and no other derivatives were observed, whereas in SG leaves there was an accumulation of dephytylated and oxidised catabolites including chlorophyllide a, phaeophorbide a and 132 OH-chlorophyllide a. Dephytylated products were absent from SG leaf tissue senescing under a light-dark cycle. Retention of pigments in SG was accompanied by significant stabilisation of light harvesting chlorophyll-proteins compared with WT, but soluble proteins such as Rubisco were degraded during senescence at a similar rate in the two genotypes. The activity of phaeophorbide a oxygenase measured in SG tissue at 3d was less than 12% of that in WT tissue at the same time-point during senescence and of the same order as that in young pre-senescent WT leaves, indicating that the metabolic lesion in SG concerns a deficiency at the ring-opening step of the catabolic pathway. In senescent L. temulentum tissue two terminal chlorophyll catabolites were identified with chromatographic characteristics that suggest they may represent hitherto undescribed catabolite structures. These data are discussed in relation to current understanding of the genetic and metabolic control of chlorophyll catabolism in leaf senescence.

Analysis of hand kinematics reveals inter-individual differences in intertemporal decision dynamics

During intertemporal decisions, the preference for smaller, sooner reward over larger-delayed rewards (temporal discounting, TD) exhibits substantial inter-subject variability; however, it is currently unclear what are the mechanisms underlying this apparently idiosyncratic behavior. To answer this question, here we recorded and analyzed mouse movement kinematics during intertemporal choices in a large sample of participants (N = 86). Results revealed a specific pattern of decision dynamics associated with the selection of “immediate” versus “delayed” response alternatives, which well discriminated between a “discounter” versus a “farsighted” behavior—thus representing a reliable behavioral marker of TD preferences. By fitting the Drift Diffusion Model to the data, we showed that differences between discounter and farsighted subjects could be explained in terms of different model parameterizations, corresponding to the use of different choice mechanisms in the two groups. While farsighted subjects were biased toward the “delayed” option, discounter subjects were not correspondingly biased toward the “immediate” option. Rather, as shown by the dynamics of evidence accumulation over time, their behavior was characterized by high choice uncertainty.

15 Years of Microstate Research in Schizophrenia - Where Are We? A Meta-Analysis

Schizophrenia patients show abnormalities in a broad range of task demands. Therefore, an explanation common to all these abnormalities has to be sought independently of any particular task, ideally in the brain dynamics before a task takes place or during resting state. For the neurobiological investigation of such baseline states, EEG microstate analysis is particularly well suited, because it identifies subsecond global states of stable connectivity patterns directly related to the recruitment of different types of information processing modes (e.g., integration of top-down and bottom-up information). Meanwhile, there is an accumulation of evidence that particular microstate networks are selectively affected in schizophrenia. To obtain an overall estimate of the effect size of these microstate abnormalities, we present a systematic meta-analysis over all studies available to date relating EEG microstates to schizophrenia. Results showed medium size effects for two classes of microstates, namely, a class labeled C that was found to be more frequent in schizophrenia and a class labeled D that was found to be shortened. These abnormalities may correspond to core symptoms of schizophrenia, e.g., insufficient reality testing and self-monitoring as during auditory verbal hallucinations. As interventional studies have shown that these microstate features may be systematically affected using antipsychotic drugs or neurofeedback interventions, these findings may help introducing novel diagnostic and treatment options.