Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Alignment of the stellar spin with the orbits of a three-planet system

The Sun’s equator and the planets’ orbital planes are nearly aligned, which is presumably a consequence of their formation from a single spinning gaseous disk. For exoplanetary systems this well-aligned configuration is not guaranteed: dynamical interactions may tilt planetary orbits, or stars may be misaligned with the protoplanetary disk through chaotic accretion1 , magnetic interactions[superscript 2] or torques from neighbouring stars. Indeed, isolated ‘hot Jupiters’ are often misaligned and even orbiting retrograde[superscript 3, 4]. Here we report an analysis of transits of planets over starspots[superscript 5, 6, 7] on the Sun-like star Kepler-30 (ref. 8), and show that the orbits of its three planets are aligned with the stellar equator. Furthermore, the orbits are aligned with one another to within a few degrees. This configuration is similar to that of our Solar System, and contrasts with the isolated hot Jupiters. The orderly alignment seen in the Kepler-30 system suggests that high obliquities are confined to systems that experienced disruptive dynamical interactions. Should this be corroborated by observations of other coplanar multi-planet systems, then star–disk misalignments would be ruled out as the explanation for the high obliquities of hot Jupiters, and dynamical interactions would be implicated as the origin of hot Jupiters.United States. National Aeronautics and Space Administration (Science MissionDirectorate

Structural and functional characterization of Pseudomonas aeruginosa CupB chaperones

Pseudomonas aeruginosa, an important human pathogen, is estimated to be responsible for,10% of nosocomial infections worldwide. The pathogenesis of P. aeruginosa starts from its colonization in the damaged tissue or medical devices (e. g. catheters, prothesis and implanted heart valve etc.) facilitated by several extracellular adhesive factors including fimbrial pili. Several clusters containing fimbrial genes have been previously identified on the P. aeruginosa chromosome and named cup [1]. The assembly of the CupB pili is thought to be coordinated by two chaperones, CupB2 and CupB4. However, due to the lack of structural and biochemical data, their chaperone activities remain speculative. In this study, we report the 2.5 A crystal structure of P. aeruginosa CupB2. Based on the structure, we further tested the binding specificity of CupB2 and CupB4 towards CupB1 (the presumed major pilus subunit) and CupB6 (the putative adhesin) using limited trypsin digestion and strep-tactin pull-down assay. The structural and biochemical data suggest that CupB2 and CupB4 might play different, but not redundant, roles in CupB secretion. CupB2 is likely to be the chaperone of CupB1, and CupB4 could be the chaperone of CupB4:CupB5:CupB6, in which the interaction of CupB4 and CupB6 might be mediated via CupB5

Population-Based Precision Cancer Screening: A Symposium on Evidence, Epidemiology, and Next Steps

Precision medicine, an emerging approach for disease treatment that takes into account individual variability in genes, environment, and lifestyle, is under consideration for preventive interventions, including cancer screening. On September 29, 2015, the National Cancer Institute sponsored a symposium entitled “Precision Cancer Screening in the General Population: Evidence, Epidemiology, and Next Steps”. The goal was two-fold: to share current information on the evidence, practices, and challenges surrounding precision screening for breast, cervical, colorectal, lung, and prostate cancers, and to allow for in-depth discussion among experts in relevant fields regarding how epidemiology and other population sciences can be used to generate evidence to inform precision screening strategies. Attendees concluded that the strength of evidence for efficacy and effectiveness of precision strategies varies by cancer site, that no one research strategy or methodology would be able or appropriate to address the many knowledge gaps in precision screening, and that issues surrounding implementation must be researched as well. Additional discussion needs to occur to identify the high priority research areas in precision cancer screening for pertinent organs and to gather the necessary evidence to determine whether further implementation of precision cancer screening strategies in the general population would be feasible and beneficial

SPECULOOS exoplanet search and its prototype on TRAPPIST

One of the most significant goals of modern science is establishing whether life exists around other suns. The most direct path towards its achievement is the detection and atmospheric characterization of terrestrial exoplanets with potentially habitable surface conditions. The nearest ultracool dwarfs (UCDs), i.e. very-low-mass stars and brown dwarfs with effective temperatures lower than 2700 K, represent a unique opportunity to reach this goal within the next decade. The potential of the transit method for detecting potentially habitable Earth-sized planets around these objects is drastically increased compared to Earth-Sun analogs. Furthermore, only a terrestrial planet transiting a nearby UCD would be amenable for a thorough atmospheric characterization, including the search for possible biosignatures, with near-future facilities such as the James Webb Space Telescope. In this chapter, we first describe the physical properties of UCDs as well as the unique potential they offer for the detection of potentially habitable Earth-sized planets suitable for atmospheric characterization. Then, we present the SPECULOOS ground-based transit survey, that will search for Earth-sized planets transiting the nearest UCDs, as well as its prototype survey on the TRAPPIST telescopes. We conclude by discussing the prospects offered by the recent detection by this prototype survey of a system of seven temperate Earth-sized planets transiting a nearby UCD, TRAPPIST-1.Comment: Submitted as a chapter in the "Handbook of Exoplanets" (editors: H. Deeg & J.A. Belmonte; Section Editor: N. Narita). 16 pages, 4 figure

Structural and biochemical characterization of the exopolysaccharide deacetylase Agd3 required for Aspergillus fumigatus biofilm formation

The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Deletion of a gene encoding a putative deacetylase, Agd3, leads to defects in GAG deacetylation, biofilm formation, and virulence. Here, we show that Agd3 deacetylates GAG in a metal-dependent manner, and is the founding member of carbohydrate esterase family CE18. The active site is formed by four catalytic motifs that are essential for activity. The structure of Agd3 includes an elongated substrate-binding cleft formed by a carbohydrate binding module (CBM) that is the founding member of CBM family 87. Agd3 homologues are encoded in previously unidentified putative bacterial exopolysaccharide biosynthetic operons and in other fungal genomes. The exopolysaccharide galactosaminogalactan (GAG) is an important virulence factor of the fungal pathogen Aspergillus fumigatus. Here, the authors study an A. fumigatus enzyme that deacetylates GAG in a metal-dependent manner and constitutes a founding member of a new carbohydrate esterase family.Bio-organic Synthesi

New frontiers of managerial training: the LiVES project

The evolution of the Internet allowed the Web to become, among the different media, the most global, inter-active and dynamic medium to share information. Therefore, in the last decades, e-Learning has been widely used not only in the academic community, but also in the business sector. Within this context, thanks to their own competences, people can develop specific characteristics which may provide a competitive advantage for their organizations. The development and use of new technologies for the creation of three-dimensional (3D) Virtual Worlds set new challenges and enlarge the very idea of ‘learning environment’. This paper aims at inves-tigating the characteristics of training activities directed at the managerial class, in such a way as to increase their efficacy; it also analyses how the use of specific innovative technologies may be an effective solution.The evolution of the Internet allowed the Web to become, among the different media, the most global, inter-active and dynamic medium to share information. Therefore, in the last decades, e-Learning has been widely used not only in the academic community, but also in the business sector. Within this context, thanks to their own competences, people can develop specific characteristics which may provide a competitive advantage for their organizations. The development and use of new technologies for the creation of three-dimensional (3D) Virtual Worlds set new challenges and enlarge the very idea of ‘learning environment’. This paper aims at inves-tigating the characteristics of training activities directed at the managerial class, in such a way as to increase their efficacy; it also analyses how the use of specific innovative technologies may be an effective solution.Monograph's chapter

Distinguishing Asthma Phenotypes Using Machine Learning Approaches.

Asthma is not a single disease, but an umbrella term for a number of distinct diseases, each of which are caused by a distinct underlying pathophysiological mechanism. These discrete disease entities are often labelled as asthma endotypes. The discovery of different asthma subtypes has moved from subjective approaches in which putative phenotypes are assigned by experts to data-driven ones which incorporate machine learning. This review focuses on the methodological developments of one such machine learning technique-latent class analysis-and how it has contributed to distinguishing asthma and wheezing subtypes in childhood. It also gives a clinical perspective, presenting the findings of studies from the past 5 years that used this approach. The identification of true asthma endotypes may be a crucial step towards understanding their distinct pathophysiological mechanisms, which could ultimately lead to more precise prevention strategies, identification of novel therapeutic targets and the development of effective personalized therapies

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies