The eukaryotic linear motif resource - 2018 update.

Short linear motifs (SLiMs) are protein binding modules that play major roles in almost all cellular processes. SLiMs are short, often highly degenerate, difficult to characterize and hard to detect. The eukaryotic linear motif (ELM) resource (elm.eu.org) is dedicated to SLiMs, consisting of a manually curated database of over 275 motif classes and over 3000 motif instances, and a pipeline to discover candidate SLiMs in protein sequences. For 15 years, ELM has been one of the major resources for motif research. In this database update, we present the latest additions to the database including 32 new motif classes, and new features including Uniprot and Reactome integration. Finally, to help provide cellular context, we present some biological insights about SLiMs in the cell cycle, as targets for bacterial pathogenicity and their functionality in the human kinome

A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging

The immune system is critical in modulating cancer progression, but knowledge of immune composition, phenotype, and interactions with tumor is limited. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to simultaneously quantify in situ expression of 36 proteins covering identity, function, and immune regulation at sub-cellular resolution in 41 triple-negative breast cancer patients. Multi-step processing, including deep-learning-based segmentation, revealed variability in the composition of tumor-immune populations across individuals, reconciled by overall immune infiltration and enriched co-occurrence of immune subpopulations and checkpoint expression. Spatial enrichment analysis showed immune mixed and compartmentalized tumors, coinciding with expression of PD1, PD-L1, and IDO in a cell-type- and location-specific manner. Ordered immune structures along the tumor-immune border were associated with compartmentalization and linked to survival. These data demonstrate organization in the tumor-immune microenvironment that is structured in cellular composition, spatial arrangement, and regulatory-protein expression and provide a framework to apply multiplexed imaging to immune oncology

A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging

The immune system is critical in modulating cancer progression, but knowledge of immune composition, phenotype, and interactions with tumor is limited. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to simultaneously quantify in situ expression of 36 proteins covering identity, function, and immune regulation at sub-cellular resolution in 41 triple-negative breast cancer patients. Multi-step processing, including deep-learning-based segmentation, revealed variability in the composition of tumor-immune populations across individuals, reconciled by overall immune infiltration and enriched co-occurrence of immune subpopulations and checkpoint expression. Spatial enrichment analysis showed immune mixed and compartmentalized tumors, coinciding with expression of PD1, PD-L1, and IDO in a cell-type- and location-specific manner. Ordered immune structures along the tumor-immune border were associated with compartmentalization and linked to survival. These data demonstrate organization in the tumor-immune microenvironment that is structured in cellular composition, spatial arrangement, and regulatory-protein expression and provide a framework to apply multiplexed imaging to immune oncology

The eukaryotic linear motif resource ELM: 10 years and counting

The eukaryotic linear motif (ELM http://elm.eu.org) resource is a hub for collecting, classifying and curating information about short linear motifs (SLiMs). For >10 years, this resource has provided the scientific community with a freely accessible guide to the biology and function of linear motifs. The current version of ELM contains ∼200 different motif classes with over 2400 experimentally validated instances manually curated from >2000 scientific publications. Furthermore, detailed information about motif-mediated interactions has been annotated and made available in standard exchange formats. Where appropriate, links are provided to resources such as switches.elm.eu.org and KEGG pathways.Fil: Dinkel, Holder. European Molecular Biology Laboratory; AlemaniaFil: Van Roey, Kim. European Molecular Biology Laboratory; AlemaniaFil: Michael, Sushama. European Molecular Biology Laboratory; AlemaniaFil: Davey, Norman E.. University Of California ; Estados UnidosFil: Weatheritt, Robert J.. MRC. Laboratory of Molecular Biology; Estados UnidosFil: Born, Diana. Ruprecht-Karls-Universität; AlemaniaFil: Speck, Tobias. Ruprecht-Karls-Universität; AlemaniaFil: Kruger, Daniel. Ruprecht-Karls-Universität; AlemaniaFil: Grebnev, Gleb. University College Dublin; IrlandaFil: Kuban, Marta. Maria Sklodowska-Curie Memorial Cancer Center. Laboratory of Bioinformatics and Biostatistics; PoloniaFil: Strumillo, Marta. Maria Sklodowska-Curie Memorial Cancer Center. Laboratory of Bioinformatics and Biostatistics; PoloniaFil: Uyar, Bora. European Molecular Biology Laboratory; AlemaniaFil: Budd, Aidan. European Molecular Biology Laboratory; AlemaniaFil: Altenberg, Brigitte. European Molecular Biology Laboratory; AlemaniaFil: Seiler, Markus. European Molecular Biology Laboratory; AlemaniaFil: Chemes, Lucia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquimicas de Buenos Aires; Argentina. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Glavina, Juliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sánchez Miguel, Ignacio Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Diella, Francesca. European Molecular Biology Laboratory; AlemaniaFil: Gibson, Toby J. European Molecular Biology Laboratory; Alemani

Climate dynamics and fluid mechanics: Natural variability and related uncertainties

The purpose of this review-and-research paper is twofold: (i) to review the role played in climate dynamics by fluid-dynamical models; and (ii) to contribute to the understanding and reduction of the uncertainties in future climate-change projections. To illustrate the first point, we focus on the large-scale, wind-driven flow of the mid-latitude oceans which contribute in a crucial way to Earth's climate, and to changes therein. We study the low-frequency variability (LFV) of the wind-driven, double-gyre circulation in mid-latitude ocean basins, via the bifurcation sequence that leads from steady states through periodic solutions and on to the chaotic, irregular flows documented in the observations. This sequence involves local, pitchfork and Hopf bifurcations, as well as global, homoclinic ones. The natural climate variability induced by the LFV of the ocean circulation is but one of the causes of uncertainties in climate projections. Another major cause of such uncertainties could reside in the structural instability in the topological sense, of the equations governing climate dynamics, including but not restricted to those of atmospheric and ocean dynamics. We propose a novel approach to understand, and possibly reduce, these uncertainties, based on the concepts and methods of random dynamical systems theory. As a very first step, we study the effect of noise on the topological classes of the Arnol'd family of circle maps, a paradigmatic model of frequency locking as occurring in the nonlinear interactions between the El Nino-Southern Oscillations (ENSO) and the seasonal cycle. It is shown that the maps' fine-grained resonant landscape is smoothed by the noise, thus permitting their coarse-grained classification. This result is consistent with stabilizing effects of stochastic parametrization obtained in modeling of ENSO phenomenon via some general circulation models.Comment: Invited survey paper for Special Issue on The Euler Equations: 250 Years On, in Physica D: Nonlinear phenomen

ELM—the database of eukaryotic linear motifs

Linear motifs are short, evolutionarily plastic components of regulatory proteins and provide low-affinity interaction interfaces. These compact modules play central roles in mediating every aspect of the regulatory functionality of the cell. They are particularly prominent in mediating cell signaling, controlling protein turnover and directing protein localization. Given their importance, our understanding of motifs is surprisingly limited, largely as a result of the difficulty of discovery, both experimentally and computationally. The Eukaryotic Linear Motif (ELM) resource at http://elm.eu.org provides the biological community with a comprehensive database of known experimentally validated motifs, and an exploratory tool to discover putative linear motifs in user-submitted protein sequences. The current update of the ELM database comprises 1800 annotated motif instances representing 170 distinct functional classes, including approximately 500 novel instances and 24 novel classes. Several older motif class entries have been also revisited, improving annotation and adding novel instances. Furthermore, addition of full-text search capabilities, an enhanced interface and simplified batch download has improved the overall accessibility of the ELM data. The motif discovery portion of the ELM resource has added conservation, and structural attributes have been incorporated to aid users to discriminate biologically relevant motifs from stochastically occurring non-functional instance

Materialist and Post-Materialist Concerns and the Wish for a Strong Leader in 27 Countries

There is evidence that democracies are under threat around the world while the quest for strong leaders is increasing. Although the causes of these developments are complex and multifaceted, here we focus on one factor: the extent to which citizens express materialist and post-materialist concerns. We explore whether objective higher levels of democracy are differentially associated with materialist and post-materialist concerns and, in turn, whether this is related to the wish for a strong leader. Testing this hypothesis across 27 countries (N = 5,741) demonstrated a direct negative effect of democracies' development on the wish for a strong leader. Further, multi-level mediation analysis showed that the relation between the Democracy Index and the wish for a strong leader was mediated by materialist concerns. This pattern of results suggests that lower levels of democracy are associated with enhanced concerns about basic needs and this is linked to greater support for strong leaders.Peer reviewe

Materialist and Post-Materialist Concerns and the Wish for a Strong Leader in 27 Countries

There is evidence that democracies are under threat around the world while the quest for strong leaders is increasing. Although the causes of these developments are complex and multifaceted, here we focus on one factor: the extent to which citizens express materialist and post-materialist concerns. We explore whether objective higher levels of democracy are differentially associated with materialist and post-materialist concerns and, in turn, whether this is related to the wish for a strong leader. Testing this hypothesis across 27 countries (N = 5,741) demonstrated a direct negative effect of democracies' development on the wish for a strong leader. Further, multi-level mediation analysis showed that the relation between the Democracy Index and the wish for a strong leader was mediated by materialist concerns. This pattern of results suggests that lower levels of democracy are associated with enhanced concerns about basic needs and this is linked to greater support for strong leaders.Peer reviewe

ELM: the status of the 2010 eukaryotic linear motif resource

Linear motifs are short segments of multidomain proteins that provide regulatory functions independently of protein tertiary structure. Much of intracellular signalling passes through protein modifications at linear motifs. Many thousands of linear motif instances, most notably phosphorylation sites, have now been reported. Although clearly very abundant, linear motifs are difficult to predict de novo in protein sequences due to the difficulty of obtaining robust statistical assessments. The ELM resource at http://elm.eu.org/ provides an expanding knowledge base, currently covering 146 known motifs, with annotation that includes >1300 experimentally reported instances. ELM is also an exploratory tool for suggesting new candidates of known linear motifs in proteins of interest. Information about protein domains, protein structure and native disorder, cellular and taxonomic contexts is used to reduce or deprecate false positive matches. Results are graphically displayed in a ‘Bar Code’ format, which also displays known instances from homologous proteins through a novel ‘Instance Mapper’ protocol based on PHI-BLAST. ELM server output provides links to the ELM annotation as well as to a number of remote resources. Using the links, researchers can explore the motifs, proteins, complex structures and associated literature to evaluate whether candidate motifs might be worth experimental investigation

Revisiting the Measurement of Anomie

Peer reviewe