Automated calibration of consensus weighted distance-based clustering approaches using sharp

Motivation: In consensus clustering, a clustering algorithm is used in combination with a subsampling procedure to detect stable clusters. Previous studies on both simulated and real data suggest that consensus clustering outperforms native algorithms. Results: We extend here consensus clustering to allow for attribute weighting in the calculation of pairwise distances using existing regularised approaches. We propose a procedure for the calibration of the number of clusters (and regularisation parameter) by maximising the sharp score, a novel stability score calculated directly from consensus clustering outputs, making it extremely computationally competitive. Our simulation study shows better clustering performances of (i) approaches calibrated by maximising the sharp score compared to existing calibration scores, and (ii) weighted compared to unweighted approaches in the presence of features that do not contribute to cluster definition. Application on real gene expression data measured in lung tissue reveals clear clusters corresponding to different lung cancer subtypes. Availability and implementation: The R package sharp (version ≥ 1.4.3) is available on CRAN at https://CRAN.R-project.org/package=sharp

RNA-seq transcriptome analysis reveals long terminal repeat retrotransposon modulation in human peripheral blood mononuclear cells after in vivo lipopolysaccharide injection

Human endogenous retroviruses (HERVs) and mammalian apparent long terminal repeat (LTR) retrotransposons (MaLRs) are retroviral sequences that integrated into germ line cells millions of years ago. Transcripts of these LTR retrotransposons are present in several tissues, and their expression is modulated in pathological conditions, although their function remains often far from being understood. Here, we focused on the HERV/MaLR expression and modulation in a scenario of immune system activation. We used a public data set of human peripheral blood mononuclear cells (PBMCs) RNA-Seq from 15 healthy participants to a clinical trial before and after exposure to lipopolysaccharide (LPS), for which we established an RNA-Seq workflow for the identification of expressed and modulated cellular genes and LTR retrotransposon elements. IMPORTANCE We described the HERV and MaLR transcriptome in PBMCs, finding that about 8.4% of the LTR retrotransposon loci were expressed and identifying the betaretrovirus-like HERVs as those with the highest percentage of expressed loci. We found 4,607 HERV and MaLR loci that were modulated as a result of in vivo stimulation with LPS. The HERV-H group showed the highest number of differentially expressed most intact proviruses. We characterized the HERV and MaLR loci as differentially expressed, checking their genomic context of insertion and observing a general colocalization with genes that are involved and modulated in the immune response, as a consequence of LPS stimulation. The analyses of HERV and MaLR expression and modulation show that these LTR retrotransposons are expressed in PBMCs and regulated in inflammatory settings. The similar regulation of HERVs/MaLRs and genes after LPS stimulation suggests possible interactions of LTR retrotransposons and the immune host response

Cryptic variations in abyssal peridotite compositions : evidence for shallow-level melt infiltration in the oceanic lithosphere

Author Posting. © The Authors, 2009. This is the author's version of the work. It is posted here by permission of Oxford University Press for personal use, not for redistribution. The definitive version was published in Journal of Petrology 51 (2010): 395-423, doi:10.1093/petrology/egp096.Ranges in clinopyroxene trace elements of 2-3 orders of magnitude occur over <2 cm distance in peridotite samples from the Atlantis II Fracture Zone on the Southwest Indian Ridge. This represents the smallest length-scale at which clinopyroxene trace element concentrations have been observed to vary in abyssal peridotites. Due to the absence of any accompanying veins or other macroscopic features of melt-rock interaction, these peridotites are interpreted as being the result of cryptic metasomatism by a low volume melt. The small length-scale of the variations, including porphyroclastic clinopyroxene grains of 2 mm diameter with an order of magnitude variation in light rare earth elements, precludes an ancient origin for these anomalies. Calculation of diffusive homogenization timescales suggests that for the trace element variations to be preserved, metasomatism occurred in the oceanic lithospheric mantle at 1000-1200°C and 10-20 km depth. This observation provides constraints for the on-axis thickness of the lithospheric mantle at an ultra-slow spreading ridge. Trace amounts of plagioclase are present in at least two of the metasomatized samples. Textural and trace element observations indicate that it formed following the trace element metasomatism, indicating that the mantle can be infiltrated multiple times by melt during the final stages of uplift at the ridge axis. The peridotites in this study are from two oceanic core complexes on the Atlantis II Fracture Zone. Our observations of multiple late-stage metasomatic events in the lithospheric mantle agree with current models and observations of melt intrusion into the mantle during oceanic core complex formation. These observations also indicate that heterogeneous lithospheric mantle can be created at ultra-slow spreading ridges.This research was supported by EAR0115433 and EAR0106578 (NS) and the WHOI Academic Programs Office (JMW)

Translithospheric Mantle Diapirism: Geological Evidence and Numerical Modelling of the Kondyor Zoned Ultramafic Complex (Russian Far-East)

We report new structural, microstructural, petrological, and major- and trace-element data on ultramafic rocks from the Kondyor zoned ultramafic complex in Far-East Russia. The ultramafic rocks are subdivided into three subconcentric lithologies, from core to rim: (1) a metasomatic domain where generally phlogopite-rich dykes pervasively intrude dunite; (2) a main dunite core; (3) a pyroxenite rim. The ultramafic rocks have nearly vertical contacts with the surrounding Archaean basement (gneisses, quartzites and marbles) and hornfelsed Riphean sediments. The hornfelsed sediments show a relatively steep (> 60°), outward dipping layering, which rapidly flattens to horizontal away from the inner contact. Although the Riphean sediments define a dome-like structure, the inward, shallow dipping foliation of the dunites indicates a synformal structure. Detailed petro-structural investigations indicate that the Kondyor dunites were deformed by solid-state flow under asthenospheric mantle conditions. The outward textural change from coarse- to fine-grained equigranular dunite and the outward-increasing abundance of subgrains and recrystallized olivine grains suggest dynamic recrystallization while fluid circulation was channelized within the core metasomatic zone, with a decreasing melt fraction from core to rim, and also suggest that solid-state deformation induced grain-size reduction towards the cooling border of the Kondyor massif. Based on their geochemistry, the dunites are interpreted as mantle rocks strongly affected by reaction with melts similar to the Jurassic-Cretaceous Aldan Shield lamproites. Rim pyroxenites were formed by a melt-consuming peritectic reaction, implying the existence of at least a small, conductive thermal gradient around the dunite body while the latter was still at near-solidus temperature conditions. This suggests that the zoned structure of Kondyor was initiated at mantle depths, most probably within the subcontinental lithosphere. Upon cooling, the lamproitic melts were progressively focused in the central part of the massif and drained into vein conduits where they reacted with the wall-rock dunite. Two-dimensional numerical modelling based on finite-differences with a marker-in-cell technique incorporates temperature-dependent rheologies for both molten and non-molten host rocks. The modelling consolidates the structural, petrological and geochemical interpretations, which show that the dunites represent the synformal, flat-lying apex of an asthenospheric mantle diapir, triggered by fluid pressure channelized in the core, which nearly reached the Earth's surface. We conclude that translithospheric mantle diapirism is an important mode of mass transfer in theEart

Transplacental innate immune training via maternal microbial exposure: role of XBP1-ERN1 axis in dendritic cell precursor programming

We recently reported that offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance to allergic airways inflammation, and localized the potential treatment target to fetal conventional dendritic cell (cDC) progenitors. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis. Additionally, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has been shown to be crucial for tissue survival of cDC, particularly within the lungs. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. We suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of OM-85-mediated transplacental innate immune training which results in postnatal resistance to airway inflammatory disease

Petrogenesis of Mafic Garnet Granulite in the Lower Crust of the Kohistan Paleo-arc Complex (Northern Pakistan): Implications for Intra-crustal Differentiation of Island Arcs and Generation of Continental Crust

We report the results of a geochemical study of the Jijal and Sarangar complexes, which constitute the lower crust of the Mesozoic Kohistan paleo-island arc (Northern Pakistan). The Jijal complex is composed of basal peridotites topped by a gabbroic section made up of mafic garnet granulite with minor lenses of garnet hornblendite and granite, grading up-section to hornblende gabbronorite. The Sarangar complex is composed of metagabbro. The Sarangar gabbro and Jijal hornblende gabbronorite have melt-like, light rare earth element (LREE)-enriched REE patterns similar to those of island arc basalts. Together with the Jijal garnet granulite, they define negative covariations of LaN, YbN and (La/Sm)N with Eu* [Eu* = 2 × EuN/(SmN + GdN), where N indicates chondrite normalized], and positive covariations of (Yb/Gd)N with Eu*. REE modeling indicates that these covariations cannot be accounted for by high-pressure crystal fractionation of hydrous primitive or derivative andesites. They are consistent with formation of the garnet granulites as plagioclase-garnet assemblages with variable trapped melt fractions via either high-pressure crystallization of primitive island arc basalts or dehydration-melting of hornblende gabbronorite, provided that the amount of segregated or restitic garnet was low (30 km (equivalent to c. 1·0 GPa), together with the hot geotherms now postulated for lower island arc crust, should cause dehydration-melting of amphibole-bearing plutonic rocks generating dense garnet granulitic roots in island arcs. Dehydration-melting of hornblende-bearing plutonic rocks may, hence, be a common intracrustal chemical and physical differentiation process in island arcs and a natural consequence of their maturation, leading to the addition of granitic partial melts to the middle-upper arc crust and formation of dense, unstable garnet granulite roots in the lower arc crust. Addition of LREE-enriched granitic melts produced by this process to the middle-upper island arc crust may drive its basaltic composition toward that of andesite, affording a plausible solution to the ‘arc paradox' of formation of andesitic continental-like crust in island arc setting

Education, biological ageing, all-cause and cause-specific mortality and morbidity : UK biobank cohort study

Background: Socioeconomic position as measured by education may be embodied and affect the functioning of key physiological systems. Links between social disadvantage, its biological imprint, and cause-specific mortality and morbidity have not been investigated in large populations, and yet may point towards areas for public health interventions beyond targeting individual behaviours. Methods: Using data from 366,748 UK Biobank participants with 13 biomarker measurements, we calculated a Biological Health Score (BHS, ranging from 0 to 1) capturing the level of functioning of five physiological systems. Associations between BHS and incidence of cardiovascular disease (CVD) and cancer, and mortality from all, CVD, cancer, and external causes were examined. We explored the role of education in these associations. Mendelian randomisation using genetic evidence was used to triangulate these findings. Findings: An increase in BHS of 0.1 was associated with all-cause (HR = 1.14 [1.12–1.16] and 1.09 [1.07–1.12] in men and women respectively), cancer (HR = 1.11 [1.09–1.14] and 1.07 [1.04–1.10]) and CVD (HR = 1.25 [1.20–1.31] and 1.21 [1.11–1.31]) mortality, CVD incidence (HR = 1.15 [1.13–1.16] and 1.17 [1.15–1.19]). These associations survived adjustment for education, lifestyle-behaviours, body mass index (BMI), co-morbidities and medical treatments. Mendelian randomisation further supported the link between the BHS and CVD incidence (HR = 1.31 [1.21–1.42]). The BHS contributed to CVD incidence prediction (age-adjusted C-statistic = 0.58), other than through education and health behaviours. Interpretation: The BHS captures features of the embodiment of education, health behaviours, and more proximal unknown factors which all complementarily contribute to all-cause, cancer and CVD morbidity and premature death. © 2020 The Author(s)Peer reviewe

Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case–control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients

Effects of exposure to water disinfection by-products in a swimming pool: A metabolome-wide association study

BACKGROUND: Exposure to disinfection by-products (DBPs) in drinking water and chlorinated swimming pools are associated with adverse health outcomes, but biological mechanisms remain poorly understood. OBJECTIVES: Evaluate short-term changes in metabolic profiles in response to DBP exposure while swimming in a chlorinated pool. MATERIALS AND METHODS: The PISCINA-II study (EXPOsOMICS project) includes 60 volunteers swimming 40min in an indoor pool. Levels of most common DBPs were measured in water and in exhaled breath before and after swimming. Blood samples, collected before and 2h after swimming, were used for metabolic profiling by liquid-chromatography coupled to high-resolution mass-spectrometry. Metabolome-wide association between DBP exposures and each metabolic feature was evaluated using multivariate normal (MVN) models. Sensitivity analyses and compound annotation were conducted. RESULTS: Exposure levels of all DBPs in exhaled breath were higher after the experiment. A total of 6,471 metabolic features were detected and 293 features were associated with at least one DBP in exhaled breath following Bonferroni correction. A total of 333 metabolic features were associated to at least one DBP measured in water or urine. Uptake of DBPs and physical activity were strongly correlated and mutual adjustment reduced the number of statistically significant associations. From the 293 features, 20 could be identified corresponding to 13 metabolites including compounds in the tryptophan metabolism pathway. CONCLUSION: Our study identified numerous molecular changes following a swim in a chlorinated pool. While we could not explicitly evaluate which experiment-related factors induced these associations, molecular characterization highlighted metabolic features associated with exposure changes during swimming