Genomic Data Reveal a Complex Making of Humans

In the last few years, two paradigms underlying human evolution have crumbled. Modern humans have not totally replaced previous hominins without any admixture, and the expected signatures of adaptations to new environments are surprisingly lacking at the genomic level. Here we review current evidence about archaic admixture and lack of strong selective sweeps in humans. We underline the need to properly model differential admixture in various populations to correctly reconstruct past demography. We also stress the importance of taking into account the spatial dimension of human evolution, which proceeded by a series of range expansions that could have promoted both the introgression of archaic genes and background selection.

Selection and recombination drive the evolution of MHC class II DRB diversity in ungulates

Major histocompatibility complex (MHC) antigen-presenting genes are the most variable loci in vertebrate genomes. Host-parasite co-evolution is assumed to maintain the excessive polymorphism in the MHC loci. However, the molecular mechanisms underlying the striking diversity in the MHC remain contentious. The extent to which recombination contributes to the diversity at MHC loci in natural populations is still controversial, and there have been only few comparative studies that make quantitative estimates of recombination rates. In this study, we performed a comparative analysis for 15 different ungulates species to estimate the population recombination rate, and to quantify levels of selection. As expected for all species, we observed signatures of strong positive selection, and identified individual residues experiencing selection that were congruent with those constituting the peptide-binding region of the human DRB gene. However, in addition for each species, we also observed recombination rates that were significantly different from zero on the basis of likelihood-permutation tests, and in other non-quantitative analyses. Patterns of synonymous and non-synonymous sequence diversity were consistent with differing demographic histories between species, but recent simulation studies by other authors suggest inference of selection and recombination is likely to be robust to such deviations from standard models. If high rates of recombination are common in MHC genes of other taxa, re-evaluation of many inference-based phylogenetic analyses of MHC loci, such as estimates of the divergence time of alleles and trans-specific polymorphism, may be required.

Met-thodology

Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. Kaposi-Novak P, Lee JS, Gomez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS. Identification of specific gene expression signatures characteristic of oncogenic pathways is an important step toward molecular classification of human malignancies. Aberrant activation of the Met signaling pathway is frequently associated with tumour progression and metastasis. In this study, we defined the Met-dependent gene expression signature using global gene expression profiling of WT and Met-deficient primary mouse hepatocytes. Newly identified transcriptional targets of the Met pathway included genes involved in the regulation of oxidative stress responses as well as cell motility, cytoskeletal organization, and angiogenesis. To assess the importance of a Met-regulated gene expression signature, a comparative functional genomic approach was applied to 242 human hepatocellular carcinomas (HCCs) and 7 metastatic liver lesions. Cluster analysis revealed that a subset of human HCCs and all liver metastases shared the Met-induced expression signature. Furthermore, the presence of the Met signature showed significant correlation with increased vascular invasion rate and microvessel density as well as with decreased mean survival time of HCC patients. We conclude that the genetically defined gene expression signatures in combination with comparative functional genomics constitute an attractive paradigm for defining both the function of oncogenic pathways and the clinically relevant subgroups of human cancers. [Abstract reproduced by permission of J Clin Invest 2006;116:1582-1595].

A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

RATIONALE: Both psychotropic drugs and mental disorders have typical signatures in quantitative electroencephalography (EEG). Previous studies found that some psychotropic drugs had EEG effects opposite to the EEG effects of the mental disorders treated with these drugs (key-lock principle). OBJECTIVES: We performed a placebo-controlled pharmaco-EEG study on two conventional antipsychotics (chlorpromazine and haloperidol) and four atypical antipsychotics (olanzapine, perospirone, quetiapine, and risperidone) in healthy volunteers. We investigated differences between conventional and atypical drug effects and whether the drug effects were compatible with the key-lock principle. METHODS: Fourteen subjects underwent seven EEG recording sessions, one for each drug (dosage equivalent of 1 mg haloperidol). In a time-domain analysis, we quantified the EEG by identifying clusters of transiently stable EEG topographies (microstates). Frequency-domain analysis used absolute power across electrodes and the location of the center of gravity (centroid) of the spatial distribution of power in different frequency bands. RESULTS: Perospirone increased duration of a microstate class typically shortened in schizophrenics. Haloperidol increased mean microstate duration of all classes, increased alpha 1 and beta 1 power, and tended to shift the beta 1 centroid posterior. Quetiapine decreased alpha 1 power and shifted the centroid anterior in both alpha bands. Olanzapine shifted the centroid anterior in alpha 2 and beta 1. CONCLUSIONS: The increased microstate duration under perospirone and haloperidol was opposite to effects previously reported in schizophrenic patients, suggesting a key-lock mechanism. The opposite centroid changes induced by olanzapine and quetiapine compared to haloperidol might characterize the difference between conventional and atypical antipsychotics.

Synchronisation of the EDML and EDC ice cores for the last 52 kyr by volcanic signature matching

A common time scale for the EPICA ice cores from Dome C (EDC) and Dronning Maud Land (EDML) has been established. Since the EDML core was not drilled on a dome, the development of the EDML1 time scale for the EPICA ice core drilled in Dronning Maud Land was based on the creation of a detailed stratigraphic link between EDML and EDC, which was dated by a simpler 1D ice-flow model. The synchronisation between the two EPICA ice cores was done through the identification of several common volcanic signatures. This paper describes the rigorous method, using the signature of volcanic sulfate, which was employed for the last 52 kyr of the record. We estimated the discrepancies between the modelled EDC and EDML glaciological age scales during the studied period, by evaluating the ratio R of the apparent duration of temporal intervals between pairs of isochrones. On average R ranges between 0.8 and 1.2 corresponding to an uncertainty of up to 20% in the estimate of the time duration in at least one of the two ice cores. Significant deviations of R up to 1.4–1.5 are observed between 18 and 28 kyr before present (BP), where present is defined as 1950. At this stage our approach does not allow us unequivocally to find out which of the models is affected by errors, but assuming that the thinning function at both sites and accumulation history at Dome C (which was drilled on a dome) are correct, this anomaly can be ascribed to a complex spatial accumulation variability (which may be different in the past compared to the present day) upstream of the EDML core.

Reactivation of rheumatoid arthritis after pregnancy: increased phagocyte and recurring lymphocyte gene activity

OBJECTIVE: Pregnancy is associated with reduced disease activity in rheumatoid arthritis (RA) and frequently with disease exacerbation after delivery. This study was undertaken to generate a systematic overview of the molecular mechanisms related to disease remission and postpartum reactivation. METHODS: Transcriptomes of peripheral blood mononuclear cells (PBMCs) were generated from RA patients and healthy women by transcription profiling during the third trimester and 24 weeks after delivery. For functional interpretation, signatures of highly purified immune cells as well as Kyoto Encyclopedia of Genes and Genomes pathway annotations were used as a reference. RESULTS: Only minor differences in gene expression in PBMCs during pregnancy were found between RA patients and controls. In contrast, RA postpartum profiles presented the most dominant changes. Systematic comparison with expression signatures of monocytes, T cells, and B cells in healthy donors revealed reduced lymphocyte and elevated monocyte gene activity during pregnancy in patients with RA and in controls. Monocyte activity decreased after delivery in controls but persisted in RA patients. Furthermore, analysis of 32 immunologically relevant cellular pathways demonstrated a significant additional activation of genes related to adhesion, migration, defense of pathogens, and cell activation, including Notch, phosphatidylinositol, mTOR, Wnt, and MAPK signaling, in RA patients postpartum. CONCLUSION: Our findings indicate that innate immune functions play an important role in postpartum reactivation of arthritis. However, this may depend not only on the monocyte itself, but also on the recurrence of lymphocyte functions postpartum and thus on a critical interaction between both arms of the immune system.

Interaction between rheumatoid arthritis and pregnancy: correlation of molecular data with clinical disease activity measures

OBJECTIVE: The factors that induce remission of RA during pregnancy and the relapse occurring after delivery remain an enigma. In a previous study, we investigated gene-expression profiles of peripheral blood mononuclear cells (PBMC) in patients with RA and healthy women in late pregnancy and postpartum. Profiles of samples from both groups were similar in late pregnancy with elevated monocyte and decreased lymphocyte signatures. Postpartum, in RA PBMC the high level of monocyte transcripts persisted. Further increase was observed in adhesion, migration and signalling processes related to monocytes but also in lymphocytes despite similar clinical activity due to intensified drug treatment. This prompted us to investigate correlations between clinical parameters of disease activity and gene profiles. METHODS: Transcriptome data were correlated with RADAI, CRP, monocyte and lymphocyte counts. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations, monocytes and lymphocytes signatures were used as reference information. RESULTS: Comparative analysis of PBMC expression profiles from RA patients during and after pregnancy with RADAI and CRP revealed a correlation of these disease activity parameters predominantly with monocyte transcripts. Genes related to cellular programs of adhesion, migration and response to infections were upregulated. Comparing clinically active and not-active RA patients postpartum revealed a cluster of 19 genes that could also identify active disease during pregnancy. CONCLUSION: The data suggest that an increase of the RADAI and an elevation of CRP is a consequence of molecular activation of monocytes. Furthermore, they indicate that molecular activation of T lymphocytes may remain clinically unrecognized postpartum. It is conceivable that a set of 19 genes may qualify as molecular disease activity marker.

Application of well log tomography to the Dundee and Rogers City Limestones, Michigan Basin, USA

The Michigan Basin is located in the upper Midwest region of the United States and is centered geographically over the Lower Peninsula of Michigan. It is filled primarily with Paleozoic carbonates and clastics, overlying Precambrian basement rocks and covered by Pleistocene glacial drift. In Michigan, more than 46,000 wells have been drilled in the basin, many producing significant quantities of oil and gas since the 1920s in addition to providing a wealth of data for subsurface visualization. Well log tomography, formerly log-curve amplitude slicing, is a visualization method recently developed at Michigan Technological University to correlate subsurface data by utilizing the high vertical resolution of well log curves. The well log tomography method was first successfully applied to the Middle Devonian Traverse Group within the Michigan Basin using gamma ray log curves. The purpose of this study is to prepare a digital data set for the Middle Devonian Dundee and Rogers City Limestones, apply the well log tomography method to this data and from this application, interpret paleogeographic trends in the natural radioactivity. Both the Dundee and Rogers City intervals directly underlie the Traverse Group and combined are the most prolific reservoir within the Michigan Basin. Differences between this study and the Traverse Group include increased well control and “slicing” of a more uniform lithology. Gamma ray log curves for the Dundee and Rogers City Limestones were obtained from 295 vertical wells distributed over the Lower Peninsula of Michigan, converted to Log ASCII Standard files, and input into the well log tomography program. The “slicing” contour results indicate that during the formation of the Dundee and Rogers City intervals, carbonates and evaporites with low natural radioactive signatures on gamma ray logs were deposited. This contrasts the higher gamma ray amplitudes from siliciclastic deltas that cyclically entered the basin during Traverse Group deposition. Additionally, a subtle north-south, low natural radioactive trend in the center of the basin may correlate with previously published Dundee facies tracts. Prominent trends associated with the distribution of limestone and dolomite are not observed because the regional range of gamma ray values for both carbonates are equivalent in the Michigan Basin and additional log curves are needed to separate these lithologies.

Synthesis of computations and experiments for obtaining pulsatile gas flow rates from dynamic pressure difference measurements across an orifice-plate meter

The use of conventional orifice-plate meter is typically restricted to measurements of steady flows. This study proposes a new and effective computational-experimental approach for measuring the time-varying (but steady-in-the-mean) nature of turbulent pulsatile gas flows. Low Mach number (effectively constant density) steady-in-the-mean gas flows with large amplitude fluctuations (whose highest significant frequency is characterized by the value fF) are termed pulsatile if the fluctuations have a direct correlation with the time-varying signature of the imposed dynamic pressure difference and, furthermore, they have fluctuation amplitudes that are significantly larger than those associated with turbulence or random acoustic wave signatures. The experimental aspect of the proposed calibration approach is based on use of Coriolis-meters (whose oscillating arm frequency fcoriolis >> fF) which are capable of effectively measuring the mean flow rate of the pulsatile flows. Together with the experimental measurements of the mean mass flow rate of these pulsatile flows, the computational approach presented here is shown to be effective in converting the dynamic pressure difference signal into the desired dynamic flow rate signal. The proposed approach is reliable because the time-varying flow rate predictions obtained for two different orifice-plate meters exhibit the approximately same qualitative, dominant features of the pulsatile flow.

Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection

Transcriptomics could contribute significantly to the early and specific diagnosis of rejection episodes by defining 'molecular Banff' signatures. Recently, the description of pathogenesis-based transcript sets offered a new opportunity for objective and quantitative diagnosis. Generating high-quality transcript panels is thus critical to define high-performance diagnostic classifier. In this study, a comparative analysis was performed across four different microarray datasets of heterogeneous sample collections from two published clinical datasets and two own datasets including biopsies for clinical indication, and samples from nonhuman primates. We characterized a common transcriptional profile of 70 genes, defined as acute rejection transcript set (ARTS). ARTS expression is significantly up-regulated in all AR samples as compared with stable allografts or healthy kidneys, and strongly correlates with the severity of Banff AR types. Similarly, ARTS were tested as a classifier in a large collection of 143 independent biopsies recently published by the University of Alberta. Results demonstrate that the 'in silico' approach applied in this study is able to identify a robust and reliable molecular signature for AR, supporting a specific and sensitive molecular diagnostic approach for renal transplant monitoring.

TERPENE AND TERPENOID EMISSIONS AND SECONDARY ORGANIC AEROSOL PRODUCTION

Approximately 90% of fine aerosol in the Midwestern United States has a regional component with a sizable fraction attributed to secondary production of organic aerosol (SOA). The Ozark Forest is an important source of biogenic SOA precursors like isoprene (> 150 mg m-2 d-1), monoterpenes (10-40 mg m-2 d-1), and sesquiterpenes (10-40 mg m-2d-1). Anthropogenic sources include secondary sulfate and nitrate and biomass burning (51-60%), vehicle emissions (17-26%), and industrial emissions (16-18%). Vehicle emissions are an important source of volatile and vapor-phase, semivolatile aliphatic and aromatic hydrocarbons that are important anthropogenic sources of SOA precursors. The short lifetime of SOA precursors and the complex mixture of functionalized oxidation products make rapid sampling, quantitative processing methods, and comprehensive organic molecular analysis essential elements of a comprehensive strategy to advance understanding of SOA formation pathways. Uncertainties in forecasting SOA production on regional scales are large and related to uncertainties in biogenic emission inventories and measurement of SOA yields under ambient conditions. This work presents a bottom-up approach to develop a conifer emission inventory based on foliar and cortical oleoresin composition, development of a model to estimate terpene and terpenoid signatures of foliar and bole emissions from conifers, development of processing and analytic techniques for comprehensive organic molecular characterization of SOA precursors and oxidation products, implementation of the high-volume sampling technique to measure OA and vapor-phase organic matter, and results from a 5 day field experiment conducted to evaluate temporal and diurnal trends in SOA precursors and oxidation products. A total of 98, 115, and 87 terpene and terpenoid species were identified and quantified in commercially available essential oils of Pinus sylvestris, Picea mariana, and Thuja occidentalis, respectively, by comprehensive, two-dimensional gas chromatography with time-of-flight mass spectrometric detection (GC × GC-ToF-MS). Analysis of the literature showed that cortical oleoresin composition was similar to foliar composition of the oldest branches. Our proposed conceptual model for estimation of signatures of terpene and terpenoid emissions from foliar and cortical oleoresin showed that emission potentials of the foliar and bole release pathways are dissimilar and should be considered for conifer species that develop resin blisters or are infested with herbivores or pathogens. Average derivatization efficiencies for Methods 1 and 2 were 87.9 and 114%, respectively. Despite the lower average derivatization efficiency of Method 1, distinct advantages included a greater certainty of derivatization yield for the entire suite of multi- and poly-functional species and fewer processing steps for sequential derivatization. Detection limits for Method 1 using GC × GC- ToF-MS were 0.09-1.89 ng μL-1. A theoretical retention index diagram was developed for a hypothetical GC × 2GC analysis of the complex mixture of SOA precursors and derivatized oxidation products. In general, species eluted (relative to the alkyl diester reference compounds) from the primary column (DB-210) in bands according to n and from the secondary columns (BPX90, SolGel-WAX) according to functionality, essentially making the GC × 2GC retention diagram a Carbon number-functionality grid. The species clustered into 35 groups by functionality and species within each group exhibited good separation by n. Average recoveries of n-alkanes and polyaromatic hydrocarbons (PAHs) by Soxhlet extraction of XAD-2 resin with dichloromethane were 80.1 ± 16.1 and 76.1 ± 17.5%, respectively. Vehicle emissions were the common source for HSVOCs [i.e., resolved alkanes, the unresolved complex mixture (UCM), alkylbenzenes, and 2- and 3-ring PAHs]. An absence of monoterpenes at 0600-1000 and high concentrations of monoterpenoids during the same period was indicative of substantial losses of monoterpenes overnight and the early morning hours. Post-collection, comprehensive organic molecular characterization of SOA precursors and products by GC × GC-ToFMS in ambient air collected with ~2 hr resolution is a promising method for determining biogenic and anthropogenic SOA yields that can be used to evaluate SOA formation models.

EXPLORATION OF THE MTSAT2 SATELLITE CAPABILITIES FOR REAL TIME DETECTION AND CHARACTERIZATION OF VOLCANIC EMISSIONS

In this report, we attempt to define the capabilities of the infrared satellite remote sensor, Multifunctional Transport Satellite-2 (MTSAT-2) (i.e. a geosynchronous instrument), in characterizing volcanic eruptive behavior in the highly active region of Indonesia. Sulfur dioxide data from NASA's Ozone Monitoring Instrument (OMI) (i.e. a polar orbiting instrument) are presented here for validation of the processes interpreted using the thermal infrared datasets. Data provided from two case studies are analyzed specifically for eruptive products producing large thermal anomalies (i.e. lava flows, lava domes, etc.), volcanic ash and SO2 clouds; three distinctly characteristic and abundant volcanic emissions. Two primary methods used for detection of heat signatures are used and compared in this report including, single-channel thermal radiance (4-µm) and the normalized thermal index (NTI) algorithm. For automated purposes, fixed thresholds must be determined for these methods. A base minimum detection limit (MDL) for single-channel thermal radiance of 2.30E+05 Wm- 2sr-1m-1 and -0.925 for NTI generate false alarm rates of 35.78% and 34.16%, respectively. A spatial comparison method, developed here specifically for use in Indonesia and used as a second parameter for detection, is implemented to address the high false alarm rate. For the single-channel thermal radiance method, the utilization of the spatial comparison method eliminated 100% of the false alarms while maintaining every true anomaly. The NTI algorithm showed similar results with only 2 false alarms remaining. No definitive difference is observed between the two thermal detection methods for automated use; however, the single-channel thermal radiance method coupled with the SO2 mass abundance data can be used to interpret volcanic processes including the identification of lava dome activity at Sinabung as well as the mechanism for the dome emplacement (i.e. endogenous or exogenous). Only one technique, the brightness temperature difference (BTD) method, is used for the detection of ash. Trends of ash area, water/ice area, and their respective concentrations yield interpretations of increased ice formation, aggregation, and sedimentation processes that only a high-temporal resolution instrument like the MTSAT-2 can analyze. A conceptual model of a secondary zone of aggregation occurring in the migrating Kelut ash cloud, which decreases the distal fine-ash component and hazards to flight paths, is presented in this report. Unfortunately, SO2 data was unable to definitively reinforce the concept of a secondary zone of aggregation due to the lack of a sufficient temporal resolution. However, a detailed study of the Kelut SO2 cloud is used to determine that there was no climatic impacts generated from this eruption due to the atmospheric residence times and e-folding rate of ~14 days for the SO2. This report applies the complementary assets offered by utilizing a high-temporal and a high-spatial resolution satellite, and it demonstrates that these two instruments can provide unparalleled observations of dynamic volcanic processes.

Identification of pathogen and host-response markers correlated with periodontal disease

BACKGROUND: Periodontitis is the major cause of tooth loss in adults and is linked to systemic illnesses, such as cardiovascular disease and stroke. The development of rapid point-of-care (POC) chairside diagnostics has the potential for the early detection of periodontal infection and progression to identify incipient disease and reduce health care costs. However, validation of effective diagnostics requires the identification and verification of biomarkers correlated with disease progression. This clinical study sought to determine the ability of putative host- and microbially derived biomarkers to identify periodontal disease status from whole saliva and plaque biofilm. METHODS: One hundred human subjects were equally recruited into a healthy/gingivitis group or a periodontitis population. Whole saliva was collected from all subjects and analyzed using antibody arrays to measure the levels of multiple proinflammatory cytokines and bone resorptive/turnover markers. RESULTS: Salivary biomarker data were correlated to comprehensive clinical, radiographic, and microbial plaque biofilm levels measured by quantitative polymerase chain reaction (qPCR) for the generation of models for periodontal disease identification. Significantly elevated levels of matrix metalloproteinase (MMP)-8 and -9 were found in subjects with advanced periodontitis with Random Forest importance scores of 7.1 and 5.1, respectively. The generation of receiver operating characteristic curves demonstrated that permutations of salivary biomarkers and pathogen biofilm values augmented the prediction of disease category. Multiple combinations of salivary biomarkers (especially MMP-8 and -9 and osteoprotegerin) combined with red-complex anaerobic periodontal pathogens (such as Porphyromonas gingivalis or Treponema denticola) provided highly accurate predictions of periodontal disease category. Elevated salivary MMP-8 and T. denticola biofilm levels displayed robust combinatorial characteristics in predicting periodontal disease severity (area under the curve = 0.88; odds ratio = 24.6; 95% confidence interval: 5.2 to 116.5). CONCLUSIONS: Using qPCR and sensitive immunoassays, we identified host- and bacterially derived biomarkers correlated with periodontal disease. This approach offers significant potential for the discovery of biomarker signatures useful in the development of rapid POC chairside diagnostics for oral and systemic diseases. Studies are ongoing to apply this approach to the longitudinal predictions of disease activity.

A three-dimensional histological atlas of the human basal ganglia. II. Atlas deformation strategy and evaluation in deep brain stimulation for Parkinson disease

OBJECT: The localization of any given target in the brain has become a challenging issue because of the increased use of deep brain stimulation to treat Parkinson disease, dystonia, and nonmotor diseases (for example, Tourette syndrome, obsessive compulsive disorders, and depression). The aim of this study was to develop an automated method of adapting an atlas of the human basal ganglia to the brains of individual patients. METHODS: Magnetic resonance images of the brain specimen were obtained before extraction from the skull and histological processing. Adaptation of the atlas to individual patient anatomy was performed by reshaping the atlas MR images to the images obtained in the individual patient using a hierarchical registration applied to a region of interest centered on the basal ganglia, and then applying the reshaping matrix to the atlas surfaces. RESULTS: Results were evaluated by direct visual inspection of the structures visible on MR images and atlas anatomy, by comparison with electrophysiological intraoperative data, and with previous atlas studies in patients with Parkinson disease. The method was both robust and accurate, never failing to provide an anatomically reliable atlas to patient registration. The registration obtained did not exceed a 1-mm mismatch with the electrophysiological signatures in the region of the subthalamic nucleus. CONCLUSIONS: This registration method applied to the basal ganglia atlas forms a powerful and reliable method for determining deep brain stimulation targets within the basal ganglia of individual patients.

Smell and taste of chewing gum affect frequency domain EEG source localizations

We investigated brain electric field signatures of subjective feelings after chewing regular gum or gum base without flavor. 19-channel eyes-closed EEG from 20 healthy males before and after 5 minutes of chewing the two gum types in random sequence was source modeled in the frequency domain using the FFT-Dipole-Approximation. 3-dimensional brain locations and strengths (Global Field Power, GFP) of the equivalent sources of five frequency bands were computed as changes from pre-chewing baseline. Gum types differed (ANOVA) in pre-post changes of source locations for the alpha-2 band (to anterior and right after regular gum, opposite after gum base) and beta-2 band (to anterior and inferior after regular gum, opposite after gum base), and of GFP for delta-theta, alpha-2 and beta-1 (regular gum: increase, gum base: decrease). Subjective feeling changed to more positive values after regular gum than gum base (ANOVA).—Thus, chewing gum with and without taste-smell activates different brain neuronal populations.