Stellar Kinematics in the Complicated Inner Spheroid of M31: Discovery of Substructure Along the Southeastern Minor Axis and its Relationship to the Giant Southern Stream

We present the discovery of a kinematically-cold stellar population along the SE minor axis of the Andromeda galaxy (M31) that is likely the forward continuation of M31's giant southern stream. This discovery was made in the course of an on-going spectroscopic survey of red giant branch (RGB) stars in M31 using the DEIMOS instrument on the Keck II 10-m telescope. Stellar kinematics are investigated in eight fields located 9-30 kpc from M31's center (in projection). A likelihood method based on photometric and spectroscopic diagnostics is used to isolate confirmed M31 RGB stars from foreground Milky Way dwarf stars: for the first time, this is done without using radial velocity as a selection criterion, allowing an unbiased study of M31's stellar kinematics. The radial velocity distribution of the 1013 M31 RGB stars shows evidence for the presence of two components. The broad (hot) component has a velocity dispersion of 129 km/s and presumably represents M31's virialized spheroid. A significant fraction (19%) of the population is in a narrow (cold) component centered near M31's systemic velocity with a velocity dispersion that decreases with increasing radial distance, from 55.5 km/s at R_proj=12 kpc to 10.6 km/s at R_proj=18 kpc. The spatial and velocity distribution of the cold component matches that of the "Southeast shelf" predicted by the Fardal et al. (2007) orbital model of the progenitor of the giant southern stream. The metallicity distribution of the cold component matches that of the giant southern stream, but is about 0.2 dex more metal rich on average than that of the hot spheroidal component. We discuss the implications of our discovery on the interpretation of the intermediate-age spheroid population found in this region in recent ultra-deep HST imaging studies.Comment: 23 pages, 16 figures, 2 tables, accepted for publication in the Astrophysical Journal. Changes from previous version: expanded discussion in sections 4.2 and 7.2, removal of section 7.1.4 and associated figure (discussion moved to section 7.1.2

The SPLASH Survey: A Spectroscopic Portrait of Andromeda's Giant Southern Stream

The giant southern stream (GSS) is the most prominent tidal debris feature in M31's stellar halo. The GSS is composed of a relatively metal-rich, high surface-brightness "core" and a lower metallicity, lower surface brightness "envelope." We present Keck/DEIMOS spectroscopy of red giant stars in six fields in the vicinity of M31's GSS and one field on Stream C, an arc-like feature on M31's SE minor axis at R=60 kpc. Several GSS-related findings and measurements are presented here. We present the innermost kinematical detection of the GSS core to date (R=17 kpc). This field also contains the continuation of a second kinematically cold component originally seen in a GSS core field at R=21 kpc. The velocity gradients of the GSS and the second component in the combined data set are parallel over a radial range of 7 kpc, suggesting a possible bifurcation in the line-of-sight velocities of GSS stars. We also present the first kinematical detection of substructure in the GSS envelope. Using kinematically identified samples, we show that the envelope debris has a ~0.7 dex lower mean photometric metallicity and possibly higher intrinsic velocity dispersion than the GSS core. The GSS is also identified in the field of the M31 dSph satellite And I; the GSS in this field has a metallicity distribution identical to that of the GSS core. We confirm the presence of two kinematically cold components in Stream C, and measure intrinsic velocity dispersions of ~10 and ~4 km/s. This compilation of the kinematical (mean velocity, intrinsic velocity dispersion) and chemical properties of stars in the GSS core and envelope, coupled with published surface brightness measurements and wide-area star-count maps, will improve constraints on the orbit and internal structure of the dwarf satellite progenitor.Comment: Accepted for publication in Ap

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL[superscript T315I] gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL[superscript T315I]. To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL[superscript T315I] CML cells on c-Myc through nonobvious off targets

The co-evolution of policy mixes and socio-technical systems: towards a conceptual framework of policy mix feedback in sustainability transitions

Understanding how policymaking processes can influence the rate and direction of socio-technical change towards sustainability is an important, yet underexplored research agenda in the field of sustainability transitions. Some studies have sought to explain how individual policy instruments can influence transitions, and the politics surrounding this process. We argue that such individual policy instruments can cause wider feedback mechanisms that influence not only their own future development, but also other instruments in the same area. Consequently, by extending the scope of analysis to that of a policy mix allows us to account for multiple policy effects on socio-technical change and resultant feedback mechanisms influencing the policy processes that underpin further policy mix change. This paper takes a first step in this regard by combining policy studies and innovation studies literatures to conceptualise the co-evolutionary dynamics of policy mixes and socio-technical systems. We focus on policy processes to help explain how policy mixes influence socio-technical change, and how changes in the socio-technical system also shape the evolution of the policy mix. To do so we draw on insights from the policy feedback literature, and propose a novel conceptual framework. The framework highlights that policy mixes aiming to foster sustainability transitions need to be designed to create incentives for beneficiaries to mobilise further support, while overcoming a number of prevailing challenges which may undermine political support over time. In the paper, we illustrate the framework using the example of the zero carbon homes policy mix in the UK. We conclude with deriving research and policy implications for analysing and designing dynamic policy mixes for sustainability transitions

Policy mixes for sustainability transitions: an extended concept and framework for analysis

Reaching a better understanding of the policies and politics of transitions presents a main agenda item in the emerging field of sustainability transitions. One important requirement for these transitions, such as the move towards a decarbonized energy system, is the redirection and acceleration of technological change, for which policies play a key role. In this regard, several studies have argued for the need to combine different policy instruments in so-called policy mixes. However, existing policy mix studies often fall short of reflecting the complexity and dynamics of actual policy mixes, the underlying politics and the evaluation of their impacts. In this paper we take a first step towards an extended, interdisciplinary policy mix concept based on a review of the bodies of literature on innovation studies, environmental economics and policy analysis. The concept introduces a clear terminology and consists of the three building blocks elements, policy processes and characteristics, which can be delineated by several dimensions. Based on this, we discuss its application as analytical framework for empirical studies analyzing the impact of the policy mix on technological change. Throughout the paper we illustrate the proposed concept by using the example of the policy mix for fostering the transition of the German energy system to renewable power generation technologies. Finally, we derive policy implications and suggest avenues for future research

A framework for human microbiome research

A variety of microbial communities and their genes (the microbiome) exist throughout the human body, with fundamental roles in human health and disease. The National Institutes of Health (NIH)-funded Human Microbiome Project Consortium has established a population-scale framework to develop metagenomic protocols, resulting in a broad range of quality-controlled resources and data including standardized methods for creating, processing and interpreting distinct types of high-throughput metagenomic data available to the scientific community. Here we present resources from a population of 242 healthy adults sampled at 15 or 18 body sites up to three times, which have generated 5,177 microbial taxonomic profiles from 16S ribosomal RNA genes and over 3.5 terabases of metagenomic sequence so far. In parallel, approximately 800 reference strains isolated from the human body have been sequenced. Collectively, these data represent the largest resource describing the abundance and variety of the human microbiome, while providing a framework for current and future studies

Structure, function and diversity of the healthy human microbiome

Author Posting. © The Authors, 2012. This article is posted here by permission of Nature Publishing Group. The definitive version was published in Nature 486 (2012): 207-214, doi:10.1038/nature11234.Studies of the human microbiome have revealed that even healthy individuals differ remarkably in the microbes that occupy habitats such as the gut, skin and vagina. Much of this diversity remains unexplained, although diet, environment, host genetics and early microbial exposure have all been implicated. Accordingly, to characterize the ecology of human-associated microbial communities, the Human Microbiome Project has analysed the largest cohort and set of distinct, clinically relevant body habitats so far. We found the diversity and abundance of each habitat’s signature microbes to vary widely even among healthy subjects, with strong niche specialization both within and among individuals. The project encountered an estimated 81–99% of the genera, enzyme families and community configurations occupied by the healthy Western microbiome. Metagenomic carriage of metabolic pathways was stable among individuals despite variation in community structure, and ethnic/racial background proved to be one of the strongest associations of both pathways and microbes with clinical metadata. These results thus delineate the range of structural and functional configurations normal in the microbial communities of a healthy population, enabling future characterization of the epidemiology, ecology and translational applications of the human microbiome.This research was supported in part by National Institutes of Health grants U54HG004969 to B.W.B.; U54HG003273 to R.A.G.; U54HG004973 to R.A.G., S.K.H. and J.F.P.; U54HG003067 to E.S.Lander; U54AI084844 to K.E.N.; N01AI30071 to R.L.Strausberg; U54HG004968 to G.M.W.; U01HG004866 to O.R.W.; U54HG003079 to R.K.W.; R01HG005969 to C.H.; R01HG004872 to R.K.; R01HG004885 to M.P.; R01HG005975 to P.D.S.; R01HG004908 to Y.Y.; R01HG004900 to M.K.Cho and P. Sankar; R01HG005171 to D.E.H.; R01HG004853 to A.L.M.; R01HG004856 to R.R.; R01HG004877 to R.R.S. and R.F.; R01HG005172 to P. Spicer.; R01HG004857 to M.P.; R01HG004906 to T.M.S.; R21HG005811 to E.A.V.; M.J.B. was supported by UH2AR057506; G.A.B. was supported by UH2AI083263 and UH3AI083263 (G.A.B., C. N. Cornelissen, L. K. Eaves and J. F. Strauss); S.M.H. was supported by UH3DK083993 (V. B. Young, E. B. Chang, F. Meyer, T. M. S., M. L. Sogin, J. M. Tiedje); K.P.R. was supported by UH2DK083990 (J. V.); J.A.S. and H.H.K. were supported by UH2AR057504 and UH3AR057504 (J.A.S.); DP2OD001500 to K.M.A.; N01HG62088 to the Coriell Institute for Medical Research; U01DE016937 to F.E.D.; S.K.H. was supported by RC1DE0202098 and R01DE021574 (S.K.H. and H. Li); J.I. was supported by R21CA139193 (J.I. and D. S. Michaud); K.P.L. was supported by P30DE020751 (D. J. Smith); Army Research Office grant W911NF-11-1-0473 to C.H.; National Science Foundation grants NSF DBI-1053486 to C.H. and NSF IIS-0812111 to M.P.; The Office of Science of the US Department of Energy under Contract No. DE-AC02-05CH11231 for P.S. C.; LANL Laboratory-Directed Research and Development grant 20100034DR and the US Defense Threat Reduction Agency grants B104153I and B084531I to P.S.C.; Research Foundation - Flanders (FWO) grant to K.F. and J.Raes; R.K. is an HHMI Early Career Scientist; Gordon&BettyMoore Foundation funding and institutional funding fromthe J. David Gladstone Institutes to K.S.P.; A.M.S. was supported by fellowships provided by the Rackham Graduate School and the NIH Molecular Mechanisms in Microbial Pathogenesis Training Grant T32AI007528; a Crohn’s and Colitis Foundation of Canada Grant in Aid of Research to E.A.V.; 2010 IBM Faculty Award to K.C.W.; analysis of the HMPdata was performed using National Energy Research Scientific Computing resources, the BluBioU Computational Resource at Rice University

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe