RGBM: regularized gradient boosting machines for identification of the transcriptional regulators of discrete glioma subtypes

We propose a generic framework for gene regulatory network (GRN) inference approached as a feature selection problem. GRNs obtained using Machine Learning techniques are often dense, whereas real GRNs are rather sparse. We use a Tikonov regularization inspired optimal L-curve criterion that utilizes the edge weight distribution for a given target gene to determine the optimal set of TFs associated with it. Our proposed framework allows to incorporate a mechanistic active biding network based on cis-regulatory motif analysis. We evaluate our regularization framework in conjunction with two non-linear ML techniques, namely gradient boosting machines (GBM) and random-forests (GENIE), resulting in a regularized feature selection based method specifically called RGBM and RGENIE respectively. RGBM has been used to identify the main transcription factors that are causally involved as master regulators of the gene expression signature activated in the FGFR3-TACC3-positive glioblastoma. Here, we illustrate that RGBM identifies the main regulators of the molecular subtypes of brain tumors. Our analysis reveals the identity and corresponding biological activities of the master regulators characterizing the difference between G-CIMP-high and G-CIMP-low subtypes and between PA-like and LGm6-GBM, thus providing a clue to the yet undetermined nature of the transcriptional events among these subtypes

Galaxy pre-processing in substructures around z∼\sim0.4 galaxy clusters

We present a detailed analysis of galaxy colours in two galaxy clusters at \mbox{z $\sim$ 0.4}, \mbox{MACS J0416.1-2403} and \mbox{MACS J1206.2-0847}, drawn from the CLASH-VLT survey, to investigate the role of pre-processing in the quenching of star formation. We estimate the fractions of red and blue galaxies within the main cluster and the detected substructures and study the trends of the colour fractions as a function of the projected distance from the cluster and substructure centres. Our results show that the colours of cluster and substructure members have consistent spatial distributions. In particular, the colour fractions of galaxies inside substructures follow the same spatial trends observed in the main clusters. Additionally, we find that at large cluster-centric distances \mbox{($r \geq r_{200}$)} the fraction of blue galaxies in both the main clusters and in the substructures is always lower than the average fraction of UVJ-selected star-forming galaxies in the field as measured in the COSMOS/UltraVista data set. We finally estimate environmental quenching efficiencies in the clusters and in the substructures and find that at large distances from the cluster centres, the quenching efficiency of substructures becomes comparable to the quenching efficiency of clusters. Our results suggest that pre-processing plays a significant role in the formation and evolution of passive galaxies in clusters at low redshifts.Comment: Accepted for publication in MNRAS. 28 pages, 14 figures, 20 table

The importance of major mergers in the build up of stellar mass in brightest cluster galaxies at z=1

Recent independent results from numerical simulations and observations have shown that brightest cluster galaxies (BCGs) have increased their stellar mass by a factor of almost two between z~0.9 and z~0.2. The numerical simulations further suggest that more than half this mass is accreted through major mergers. Using a sample of 18 distant galaxy clusters with over 600 spectroscopically confirmed cluster members between them, we search for observational evidence that major mergers do play a significant role. We find a major merger rate of 0.38 +/- 0.14 mergers per Gyr at z~1. While the uncertainties, which stem from the small size of our sample, are relatively large, our rate is consistent with the results that are derived from numerical simulations. If we assume that this rate continues to the present day and that half of the mass of the companion is accreted onto the BCG during these mergers, then we find that this rate can explain the growth in the stellar mass of the BCGs that is observed and predicted by simulations. Major mergers therefore appear to be playing an important role, perhaps even the dominant one, in the build up of stellar mass in these extraordinary galaxies.Comment: 15 pages, 6 figures, accepted for publication in MNRAS. Reduced data will be made available through the ESO archiv

JAK/Stat5-mediated subtype-specific lymphocyte antigen 6 complex, locus G6D (LY6G6D) expression drives mismatch repair proficient colorectal cancer

Background: Human microsatellite-stable (MSS) colorectal cancers (CRCs) are immunologically "cold" tumour subtypes characterized by reduced immune cytotoxicity. The molecular linkages between immune-resistance and human MSS CRC is not clear. Methods: We used transcriptome profiling, in silico analysis, immunohistochemistry, western blot, RT-qPCR and immunofluorescence staining to characterize novel CRC immune biomarkers. The effects of selective antagonists were tested by in vitro assays of long term viability and analysis of kinase active forms using anti-phospho antibodies. Results: We identified the lymphocyte antigen 6 complex, locus G6D (LY6G6D) as significantly overexpressed (around 15-fold) in CRC when compared with its relatively low expression in other human solid tumours. LY6G6D up-regulation was predominant in MSS CRCs characterized by an enrichment of immune suppressive regulatory T-cells and a limited repertoire of PD-1/PD-L1 immune checkpoint receptors. Coexpression of LY6G6D and CD15 increases the risk of metastatic relapse in response to therapy. Both JAK-STAT5 and RAS-MEK-ERK cascades act in concert as key regulators of LY6G6D and Fucosyltransferase 4 (FUT4), which direct CD15-mediated immune-resistance. Momelotinib, an inhibitor of JAK1/JAK2, consistently abrogated the STAT5/LY6G6D axis in vitro, sensitizing MSS cancer cells with an intact JAK-STAT signaling, to efficiently respond to trametinib, a MEK inhibitor used in clinical setting. Notably, colon cancer cells can evade JAK2/JAK1-targeted therapy by a reversible shift of the RAS-MEK-ERK pathway activity, which explains the treatment failure of JAK1/2 inhibitors in refractory CRC. Conclusions: Combined targeting of STAT5 and MAPK pathways has superior therapeutic effects on immune resistance. In addition, the new identified LY6G6D antigen is a promising molecular target for human MSS CRC

Loss of Primary Cilia Potentiates BRAF/MAPK Pathway Activation in Rhabdoid Colorectal Carcinoma: A Series of 21 Cases Showing Ciliary Rootlet CoiledCoil (CROCC) Alterations

A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target

The GOGREEN survey : Internal dynamics of clusters of galaxies at redshift 0.9-1.4

Context. The study of galaxy cluster mass profiles (M(r)) provides constraints on the nature of dark matter and on physical processes affecting the mass distribution. The study of galaxy cluster velocity anisotropy profiles (beta (r)) informs the orbits of galaxies in clusters, which are related to their evolution. The combination of mass profiles and velocity anisotropy profiles allows us to determine the pseudo phase-space density profiles (Q(r)); numerical simulations predict that these profiles follow a simple power law in cluster-centric distance.Aims. We determine the mass, velocity anisotropy, and pseudo phase-space density profiles of clusters of galaxies at the highest redshifts investigated in detail to date.Methods. We exploited the combination of the GOGREEN and GCLASS spectroscopic data-sets for 14 clusters with mass M-200 >= 10(14) M-circle dot at redshifts 0.9 = 10(9.5) M-circle dot. We used the MAMPOSSt method to constrain several M(r) and beta (r) models, and we then inverted the Jeans equation to determine the ensemble cluster beta (r) in a non-parametric way. Finally, we combined the results of the M(r) and beta (r) analysis to determine Q(r) for the ensemble cluster.Results. The concentration c(200) of the ensemble cluster mass profile is in excellent agreement with predictions from Lambda cold dark matter (Lambda CDM) cosmological numerical simulations, and with previous determinations for clusters of similar mass and at similar redshifts, obtained from gravitational lensing and X-ray data. We see no significant difference between the total mass density and either the galaxy number density distributions or the stellar mass distribution. Star-forming galaxies are spatially significantly less concentrated than quiescent galaxies. The orbits of cluster galaxies are isotropic near the center and more radial outside. Star-forming galaxies and galaxies of low stellar mass tend to move on more radially elongated orbits than quiescent galaxies and galaxies of high stellar mass. The profile Q(r), determined using either the total mass or the number density profile, is very close to the power-law behavior predicted by numerical simulations.Conclusions. The internal dynamics of clusters at the highest redshift probed in detail to date are very similar to those of lower-redshift clusters, and in excellent agreement with predictions of numerical simulations. The clusters in our sample have already reached a high degree of dynamical relaxation.Peer reviewe

The Importance of Major Mergers in the Build Up of Stellar Mass in Brightest Cluster Galaxies at \u3cem\u3ez\u3c/em\u3e = 1

Recent independent results from numerical simulations and observations have shown that brightest cluster galaxies (BCGs) have increased their stellar mass by a factor of almost 2 between z ∼ 0.9 and z ∼ 0.2. The numerical simulations further suggest that more than half this mass is accreted through major mergers. Using a sample of 18 distant galaxy clusters with over 600 spectroscopically confirmed cluster members between them, we search for observational evidence that major mergers do play a significant role. We find a major merger rate of 0.38 ± 0.14 mergers per Gyr at z ∼ 1. While the uncertainties, which stem from the small size of our sample, are relatively large, our rate is consistent with the results that are derived from numerical simulations. If we assume that this rate continues to the present day and that half of the mass of the companion is accreted on to the BCG during these mergers, then we find that this rate can explain the growth in the stellar mass of the BCGs that is observed and predicted by simulations. Major mergers therefore appear to be playing an important role, perhaps even the dominant one, in the build up of stellar mass in these extraordinary galaxies

Gemini Observations of Galaxies in Rich Early Environments (GOGREEN) I : survey description.

We describe a new Large Program in progress on the Gemini North and South telescopes: Gemini Observations of Galaxies in Rich Early Environments (GOGREEN). This is an imaging and deep spectroscopic survey of 21 galaxy systems at 1 10 in halo mass. The scientific objectives include measuring the role of environment in the evolution of low-mass galaxies, and measuring the dynamics and stellar contents of their host haloes. The targets are selected from the SpARCS, SPT, COSMOS, and SXDS surveys, to be the evolutionary counterparts of today's clusters and groups. The new red-sensitive Hamamatsu detectors on GMOS, coupled with the nod-and-shuffle sky subtraction, allow simultaneous wavelength coverage over λ ∼ 0.6–1.05 μm, and this enables a homogeneous and statistically complete redshift survey of galaxies of all types. The spectroscopic sample targets galaxies with AB magnitudes z΄ < 24.25 and [3.6] μm < 22.5, and is therefore statistically complete for stellar masses M* ≳ 1010.3 M⊙, for all galaxy types and over the entire redshift range. Deep, multiwavelength imaging has been acquired over larger fields for most systems, spanning u through K, in addition to deep IRAC imaging at 3.6 μm. The spectroscopy is ∼50 per cent complete as of semester 17A, and we anticipate a final sample of ∼500 new cluster members. Combined with existing spectroscopy on the brighter galaxies from GCLASS, SPT, and other sources, GOGREEN will be a large legacy cluster and field galaxy sample at this redshift that spectroscopically covers a wide range in stellar mass, halo mass, and clustercentric radius

The GOGREEN Survey: Evidence of an excess of quiescent disks in clusters at 1.0<z<1.41.0<z<1.4

We present results on the measured shapes of 832 galaxies in 11 galaxy clusters at 1.0 < z <1.4 from the GOGREEN survey. We measure the axis ratio ($q$), the ratio of the minor to the major axis, of the cluster galaxies from near-infrared Hubble Space Telescope imaging using S\'ersic profile fitting and compare them with a field sample. We find that the median $q$ of both star-forming and quiescent galaxies in clusters increases with stellar mass, similar to the field. Comparing the axis ratio distributions between clusters and the field in four mass bins, the distributions for star-forming galaxies in clusters are consistent with those in the field. Conversely, the distributions for quiescent galaxies in the two environments are distinct, most remarkably in $10.1\leq\log(M/{\rm M}_{\odot})<10.5$ where clusters show a flatter distribution, with an excess at low $q$. Modelling the distribution with oblate and triaxial components, we find that the cluster and field sample difference is consistent with an excess of flattened oblate quiescent galaxies in clusters. The oblate population contribution drops at high masses, resulting in a narrower $q$ distribution in the massive population than at lower masses. Using a simple accretion model, we show that the observed $q$ distributions and quenched fractions are consistent with a scenario where no morphological transformation occurs for the environmentally quenched population in the two intermediate mass bins. Our results suggest that environmental quenching mechanism(s) likely produce a population that has a different morphological mix than those resulting from the dominant quenching mechanism in the field.Comment: Accepted for publication in ApJ. 25 pages, 15 figure