Helical Chirality: a Link between Local Interactions and Global Topology in DNA

DNA supercoiling plays a major role in many cellular functions. The global DNA conformation is however intimately linked to local DNA-DNA interactions influencing both the physical properties and the biological functions of the supercoiled molecule. Juxtaposition of DNA double helices in ubiquitous crossover arrangements participates in multiple functions such as recombination, gene regulation and DNA packaging. However, little is currently known about how the structure and stability of direct DNA-DNA interactions influence the topological state of DNA. Here, a crystallographic analysis shows that due to the intrinsic helical chirality of DNA, crossovers of opposite handedness exhibit markedly different geometries. While right-handed crossovers are self-fitted by sequence-specific groove-backbone interaction and bridging Mg2+ sites, left-handed crossovers are juxtaposed by groove-groove interaction. Our previous calculations have shown that the different geometries result in differential stabilisation in solution, in the presence of divalent cations. The present study reveals that the various topological states of the cell are associated with different inter-segmental interactions. While the unstable left-handed crossovers are exclusively formed in negatively supercoiled DNA, stable right-handed crossovers constitute the local signature of an unusual topological state in the cell, such as the positively supercoiled or relaxed DNA. These findings not only provide a simple mechanism for locally sensing the DNA topology but also lead to the prediction that, due to their different tertiary intra-molecular interactions, supercoiled molecules of opposite signs must display markedly different physical properties. Sticky inter-segmental interactions in positively supercoiled or relaxed DNA are expected to greatly slow down the slithering dynamics of DNA. We therefore suggest that the intrinsic helical chirality of DNA may have oriented the early evolutionary choices for DNA topology

Structural Analysis of the UBA Domain of X-linked Inhibitor of Apoptosis Protein Reveals Different Surfaces for Ubiquitin-Binding and Self-Association

BACKGROUND: Inhibitor of apoptosis proteins (IAPs) belong to a pivotal antiapoptotic protein family that plays a crucial role in tumorigenesis, cancer progression, chemoresistance and poor patient-survival. X-linked inhibitor of apoptosis protein (XIAP) is a prominent member of IAPs attracting intense research because it has been demonstrated to be a physiological inhibitor of caspases and apoptosis. Recently, an evolutionarily conserved ubiquitin-associated (UBA) domain was identified in XIAP and a number of RING domain-bearing IAPs. This has placed the IAPs in the group of ubiquitin binding proteins. Here, we explore the three-dimensional structure of the XIAP UBA domain (XIAP-UBA) and how it interacts with mono-ubiquitin and diubiquitin conjugates. PRINCIPAL FINDINGS: The solution structure of the XIAP-UBA domain was determined by NMR spectroscopy. XIAP-UBA adopts a typical UBA domain fold of three tightly packed alpha-helices but with an additional N-terminal 3(10) helix. The XIAP-UBA binds mono-ubiquitin as well as Lys48-linked and linear-linked diubiquitins at low-micromolar affinities. NMR analysis of the XIAP-UBA-ubiquitin interaction reveals that it involves the classical hydrophobic patches surrounding Ile44 of ubiquitin and the conserved MGF/LV motif surfaces on XIAP-UBA. Furthermore, dimerization of XIAP-UBA was observed. Mapping of the self-association surface of XIAP-UBA reveals that the dimerization interface is formed by residues in the N-terminal 3(10) helix, helix alpha1 and helix alpha2, separate from the ubiquitin-binding surface. CONCLUSION: Our results provide the first structural information of XIAP-UBA and map its interaction with mono-ubiquitin, Lys48-linked and linear-linked diubiquitins. The notion that XIAP-UBA uses different surfaces for ubiquitin-binding and self-association provides a plausible model to explain the reported selectivity of XIAP in binding polyubiquitin chains with different linkages.published_or_final_versio

Dark Matter in the Milky Way's Dwarf Spheroidal Satellites

The Milky Way's dwarf spheroidal satellites include the nearest, smallest and least luminous galaxies known. They also exhibit the largest discrepancies between dynamical and luminous masses. This article reviews the development of empirical constraints on the structure and kinematics of dSph stellar populations and discusses how this phenomenology translates into constraints on the amount and distribution of dark matter within dSphs. Some implications for cosmology and the particle nature of dark matter are discussed, and some topics/questions for future study are identified.Comment: A version with full-resolution figures is available at http://www.cfa.harvard.edu/~mwalker/mwdsph_review.pdf; 70 pages, 22 figures; invited review article to be published in Vol. 5 of the book "Planets, Stars, and Stellar Systems", published by Springe

Forest biodiversity, ecosystem functioning and the provision of ecosystem services

Forests are critical habitats for biodiversity and they are also essential for the provision of a wide range of ecosystem services that are important to human well-being. There is increasing evidence that biodiversity contributes to forest ecosystem functioning and the provision of ecosystem services. Here we provide a review of forest ecosystem services including biomass production, habitat provisioning services, pollination, seed dispersal, resistance to wind storms, fire regulation and mitigation, pest regulation of native and invading insects, carbon sequestration, and cultural ecosystem services, in relation to forest type, structure and diversity. We also consider relationships between forest biodiversity and multifunctionality, and trade-offs among ecosystem services. We compare the concepts of ecosystem processes, functions and services to clarify their definitions. Our review of published studies indicates a lack of empirical studies that establish quantitative and causal relationships between forest biodiversity and many important ecosystem services. The literature is highly skewed; studies on provisioning of nutrition and energy, and on cultural services, delivered by mixed-species forests are under-represented. Planted forests offer ample opportunity for optimising their composition and diversity because replanting after harvesting is a recurring process. Planting mixed-species forests should be given more consideration as they are likely to provide a wider range of ecosystem services within the forest and for adjacent land uses. This review also serves as the introduction to this special issue of Biodiversity and Conservation on various aspects of forest biodiversity and ecosystem services

Long-term efficacy and safety of dasatinib in patients with chronic myeloid leukemia in accelerated phase who are resistant to or intolerant of imatinib

Treatment with a frontline BCR-ABL1 tyrosine kinase inhibitor (TKI; e.g., imatinib, dasatinib, and nilotinib) allows patients with chronic myeloid leukemia (CML) in chronic phase (CP) to achieve a near normal life expectancy1, whereas treatment for CML in accelerated phase (AP) is more problematic. While reports describe outcomes for patients with CML-AP at initial diagnosis2,3, outcomes have been historically worse once CP disease has progressed to AP. Approximately 50% of patients with CML-AP who receive imatinib as initial treatment develop imatinib resistance4 and experience disease progression5. Second-generation TKIs are indicated for patients with CML-CP or advanced CML resistant to/intolerant of prior therapy (including imatinib)6. After initial approval of dasatinib twice a day (BID) for the treatment of patients with CML resistant to/intolerant of imatinib in all stages, this phase 3 CA180-035 study (NCT00123487) was developed to investigate once (QD) or twice (BID) a day dasatinib treatment in patients with CML-AP, CML in blast phase, or Ph+ acute lymphoblastic leukemia resistant to/intolerant of imatinib

Sequentiality of Daily Life Physiology: An Automatized Segmentation Approach

International audience: Based on the hypotheses that (1) a physiological organization exists inside each activity of daily life and (2) the pattern of evolution of physiological variables is characteristic of each activity, pattern changes should be detected on daily life physiological recordings. The present study aims at investigating whether a simple segmentation method can be set up to detect pattern changes on physiological recordings carried out during daily life. Heart and breathing rates and skin temperature have been non-invasively recorded in volunteers following scenarios made of "daily life" steps (13 records). An observer, undergoing the scenario, wrote down annotations during the recording time. Two segmentation procedures have been compared to the annotations, a visual inspection of the signals and an automatic program based on a trends detection algorithm applied to one physiological signal (skin temperature). The annotations resulted in a total number of 213 segments defined on the 13 records, the best visual inspection detected less segments (120) than the automatic program (194). If evaluated in terms of the number of correspondences between the times marks given by annotations and those resulting from both physiologically based segmentations, the automatic program was better than the visual inspection. The mean time lags between annotation and program time marks remain <60 s (the precision of annotation times marks). We conclude that physiological variables time series recorded in common life conditions exhibit different successive patterns that can be detected by a simple trends detection algorithm. Theses sequences are coherent with the corresponding annotated activity

Multiple image deblurring with high dynamic-range Poisson data

An interesting problem arising in astronomical imaging is the reconstruction of an image with high dynamic range, for example a set of bright point sources superimposed to smooth structures. A few methods have been proposed for dealing with this problem and their performance is not always satisfactory. In this paper we propose a solution based on the representation, already proposed elsewhere, of the image as the sum of a pointwise component and a smooth one, with different regularization for the two components. Our approach is in the framework of Poisson data and to this purpose we need efficient deconvolution methods. Therefore, first we briefly describe the application of the Scaled Gradient Projection (SGP) method to the case of different regularization schemes and subsequently we propose how to apply these methods to the case of multiple image deconvolution of high-dynamic range images, with specific reference to the Fizeau interferometer LBTI of the Large Binocular Telescope (LBT). The efficacy of the proposed methods is illustrated both on simulated images and on real images, observed with LBTI, of the Jovian moon Io. The software is available at http://www.oasis.unimore.it/site/home/software.html

Automated unrestricted multigene recombineering for multiprotein complex production.

International audienceStructural and functional studies of many multiprotein complexes depend on recombinant-protein overexpression. Rapid revision of expression experiments and diversification of the complexes are often crucial for success of these projects; therefore, automation is increasingly indispensable. We introduce Acembl, a versatile and automatable system for protein-complex expression in Escherichia coli that uses recombineering to facilitate multigene assembly and diversification. We demonstrated protein-complex expression using Acembl, including production of the complete prokaryotic holotranslocon