Population Effect Model Identifies Gene Expression Predictors of Survival Outcomes in Lung Adenocarcinoma for Both Caucasian and Asian Patients

Background: We analyzed and integrated transcriptome data from two large studies of lung adenocarcinomas on distinct populations. Our goal was to investigate the variable gene expression alterations between paired tumor-normal tissues and prospectively identify those alterations that can reliably predict lung disease related outcomes across populations. Methods: We developed a mixed model that combined the paired tumor-normal RNA-seq from two populations. Alterations in gene expression common to both populations were detected and validated in two independent DNA microarray datasets. A 10-gene prognosis signature was developed through a l1 penalized regression approach and its prognostic value was evaluated in a third independent microarray cohort. Results: Deregulation of apoptosis pathways and increased expression of cell cycle pathways were identified in tumors of both Caucasian and Asian lung adenocarcinoma patients. We demonstrate that a 10-gene biomarker panel can predict prognosis of lung adenocarcinoma in both Caucasians and Asians. Compared to low risk groups, high risk groups showed significantly shorter overall survival time (Caucasian patients data: HR = 3.63, p-value = 0.007; Asian patients data: HR = 3.25, p-value = 0.001). Conclusions: This study uses a statistical framework to detect DEGs between paired tumor and normal tissues that considers variances among patients and ethnicities, which will aid in understanding the common genes and signalling pathways with the largest effect sizes in ethnically diverse cohorts. We propose multifunctional markers for distinguishing tumor from normal tissue and prognosis for both populations studied

Population Effect Model Identifies Gene Expression Predictors of Survival Outcomes in Lung Adenocarcinoma for Both Caucasian and Asian Patients

Background: We analyzed and integrated transcriptome data from two large studies of lung adenocarcinomas on distinct populations. Our goal was to investigate the variable gene expression alterations between paired tumor-normal tissues and prospectively identify those alterations that can reliably predict lung disease related outcomes across populations. Methods: We developed a mixed model that combined the paired tumor-normal RNA-seq from two populations. Alterations in gene expression common to both populations were detected and validated in two independent DNA microarray datasets. A 10-gene prognosis signature was developed through a l1 penalized regression approach and its prognostic value was evaluated in a third independent microarray cohort. Results: Deregulation of apoptosis pathways and increased expression of cell cycle pathways were identified in tumors of both Caucasian and Asian lung adenocarcinoma patients. We demonstrate that a 10-gene biomarker panel can predict prognosis of lung adenocarcinoma in both Caucasians and Asians. Compared to low risk groups, high risk groups showed significantly shorter overall survival time (Caucasian patients data: HR = 3.63, p-value = 0.007; Asian patients data: HR = 3.25, p-value = 0.001). Conclusions: This study uses a statistical framework to detect DEGs between paired tumor and normal tissues that considers variances among patients and ethnicities, which will aid in understanding the common genes and signalling pathways with the largest effect sizes in ethnically diverse cohorts. We propose multifunctional markers for distinguishing tumor from normal tissue and prognosis for both populations studied

Transcriptomic Analyses of Sexual Dimorphism of the Zebrafish Liver and the Effect of Sex Hormones

10.1371/journal.pone.0053562PLoS ONE81

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer

Strong particle production and condensational growth in the upper troposphere sustained by biogenic VOCs from the canopy of the Amazon Basin

Nucleation and condensation associated with biogenic volatile organic compounds (BVOCs) are important aerosol formation pathways, yet their contribution to the upper-tropospheric aerosols remains inconclusive, hindering the understanding of aerosol climate effects. Here, we develop new schemes describing these organic aerosol formation processes in the WRF-Chem model and investigate their impact on the abundance of cloud condensation nuclei (CCN) in the upper troposphere (UT) over the Amazon Basin. We find that the new schemes significantly increase the simulated CCN number concentrations in the UT (e.g., up to -1/4 400 cm-3 at 0.52 % supersaturation) and greatly improve the agreement with the aircraft observations. Organic condensation enhances the simulated CCN concentration by 90 % through promoting particle growth, while organic nucleation, by replenishing new particles, contributes an additional 14 %. Deep convection determines the rate of these organic aerosol formation processes in the UT through controlling the upward transport of biogenic precursors (i.e., BVOCs). This finding emphasizes the importance of the biosphere-atmosphere coupling in regulating upper-tropospheric aerosol concentrations over the tropical forest and calls for attention to its potential role in anthropogenic climate change

Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer

Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap

Frequent rainfall-induced new particle formation within the canopy in the Amazon rainforest

Atmospheric aerosol particles are essential for forming clouds and precipitation, thereby influencing Earth’s energy budget, water cycle and climate on regional and global scales. However, the origin of aerosol particles over the Amazon rainforest during the wet season is poorly understood. Earlier studies showed new particle formation in the outflow of deep convective clouds and suggested a downward flux of aerosol particles during precipitation events. Here we use comprehensive aerosol, trace gas and meteorological data from the Amazon Tall Tower Observatory to show that rainfall regularly induces bursts of nanoparticles in the nucleation size range. This can be attributed to rain-related scavenging of larger particles and a corresponding reduction of the condensation sink, along with an ozone injection into the forest canopy, which could increase the oxidation of biogenic volatile organic compounds, especially terpenes, and enhance new particle formation. During and after rainfall, the nucleation particle concentrations directly above the canopy are greater than those higher up. This gradient persists throughout the wet season for the nucleation size range, indicating continuous particle formation within the canopy, a net upward flux of newly formed particles and a paradigm shift in understanding aerosol–cloud–precipitation interactions in the Amazon. Particle bursts provide a plausible explanation for the formation of cloud condensation nuclei, leading to the local formation of green-ocean clouds and precipitation. Our findings suggest that an interplay of a rain-related reduction in the condensation sink, primary emissions of gases, mainly terpenes, and particles from the forest canopy, and convective cloud processing determines the population of cloud condensation nuclei in pristine rainforest air

Moss kill dates and modeled summer temperature track episodic snowline lowering and ice cap expansion in Arctic Canada through the Common Era

Most extant ice caps mantling low-relief Arctic Canada landscapes remained cold based throughout the late Holocene, preserving in situ bryophytes killed as ice expanded across vegetated landscapes. After reaching peak late Holocene dimensions &sim;1900&thinsp;CE, ice caps receded as Arctic summers warmed, exposing entombed vegetation. The calibrated radiocarbon ages of entombed moss collected near ice cap margins (kill dates) define when ice advanced across the site, killing the moss, and remained over the site until the year of their collection. In an earlier study, we reported 94 last millennium radiocarbon dates on in situ dead moss collected at ice cap margins across Baffin Island, Arctic Canada. Tight clustering of those ages indicated an abrupt onset of the Little Ice Age at &sim;1240&thinsp;CE and further expansion at &sim;1480&thinsp;CE coincident with episodes of major explosive volcanism. Here we test the confidence in kill dates as reliable predictors of expanding ice caps by resampling two previously densely sampled ice complexes &sim;15&nbsp;years later after &sim;250&thinsp;m of ice recession. The probability density functions (PDFs) of the more recent series of ages match PDFs of the earlier series but with a larger fraction of early Common Era ages. Post 2005&thinsp;CE ice recession has exposed relict ice caps that grew during earlier Common Era advances and were preserved beneath later ice cap growth. We compare the 106 kill dates from the two ice complexes with 80 kill dates from 62 other ice caps within 250&thinsp;km of the two densely sampled ice complexes. The PDFs of kill dates from the 62 other ice caps cluster in the same time windows as those from the two ice complexes alone, with the PDF of all 186 kill dates documenting episodes of widespread ice expansion restricted almost exclusively to 250&ndash;450&thinsp;CE, 850&ndash;1000&thinsp;CE, and a dense early Little Ice Age cluster with peaks at &sim;1240 and &sim;1480&thinsp;CE. Ice continued to expand after 1480&thinsp;CE, reaching maximum dimensions at &sim;1880&thinsp;CE that are still visible as zones of sparse vegetation cover in remotely sensed imagery. Intervals of widespread ice cap expansion coincide with persistent decreases in mean summer surface air temperature for the region in a Community Earth System Model (CESM) fully coupled Common Era simulation, suggesting the primary forcings of the observed snowline lowering were both modest declines in summer insolation and cooling resulting from explosive volcanism, most likely intensified by positive feedbacks from increased snow cover and sea ice and reduced northward heat transport by the oceans. The clusters of ice cap expansion defined by moss kill dates are mirrored in an annually resolved Common Era record of ice cap dimensions in Iceland, suggesting this is a circum-North-Atlantic&ndash;Arctic climate signal for the Common Era. During the coldest century of the Common Era, 1780&ndash;1880&thinsp;CE, ice caps mantled &gt;11&thinsp;000&thinsp;km2 of north-central Baffin Island, whereas &lt;100&thinsp;km2 is glaciated at present. The peak Little Ice Age state approached conditions expected during the inception phase of an ice age and was only reversed after 1880&thinsp;CE by anthropogenic alterations of the planetary energy balance. &nbsp;</p

Abrupt onset of the Little Ice Age triggered by volcanism and sustained by sea-ice/ocean feedbacks

[1] Northern Hemisphere summer temperatures over the past 8000 years have been paced by the slow decrease in summer insolation resulting from the precession of the equinoxes. However, the causes of superposed century-scale cold summer anomalies, of which the Little Ice Age (LIA) is the most extreme, remain debated, largely because the natural forcings are either weak or, in the case of volcanism, short lived. Here we present precisely dated records of ice-cap growth from Arctic Canada and Iceland showing that LIA summer cold and ice growth began abruptly between 1275 and 1300 AD, followed by a substantial intensification 1430– 1455 AD. Intervals of sudden ice growth coincide with two of the most volcanically perturbed half centuries of the past mil-lennium. A transient climate model simulation shows that explosive volcanism produces abrupt summer cooling at these times, and that cold summers can be maintained by sea-ice/ ocean feedbacks long after volcanic aerosols are removed. Our results suggest that the onset of the LIA can be linked to an unusual 50-year-long episode with four large sulfur-rich explosive eruptions, each with global sulfate loading&gt;60 Tg. The persistence of cold summers is best explained by conse-quent sea-ice/ocean feedbacks during a hemispheric summer insolation minimum; large changes in solar irradiance are not required. Citation: Miller, G. H., et al. (2012), Abrupt onset of the Little Ice Age triggered by volcanism and sustained by sea-ice/ocea

Molecular Characterization of Transcriptional Regulation of rovA by PhoP and RovA in Yersinia pestis

BACKGROUND: Yersinia pestis is the causative agent of plague. The two transcriptional regulators, PhoP and RovA, are required for the virulence of Y. pestis through the regulation of various virulence-associated loci. They are the global regulators controlling two distinct large complexes of cellular pathways. METHODOLOGY/PRINCIPAL FINDINGS: Based on the LacZ fusion, primer extension, gel mobility shift, and DNase I footprinting assays, RovA is shown to recognize both of the two promoters of its gene in Y. pestis. The autoregulation of RovA appears to be a conserved mechanism shared by Y. pestis and its closely related progenitor, Y. pseudotuberculosis. In Y. pestis, the PhoP regulator responds to low magnesium signals and then negatively controls only one of the two promoters of rovA through PhoP-promoter DNA association. CONCLUSIONS/SIGNIFICANCE: RovA is a direct transcriptional activator for its own gene in Y. pestis, while PhoP recognizes the promoter region of rovA to repress its transcription. The direct regulatory association between PhoP and RovA bridges the PhoP and RovA regulons in Y. pestis