874 research outputs found
Linking dwarf galaxies to halo building blocks with the most metal-poor star in Sculptor
Current cosmological models indicate that the Milky Way's stellar halo was
assembled from many smaller systems. Based on the apparent absence of the most
metal-poor stars in present-day dwarf galaxies, recent studies claimed that the
true Galactic building blocks must have been vastly different from the
surviving dwarfs. The discovery of an extremely iron-poor star (S1020549) in
the Sculptor dwarf galaxy based on a medium-resolution spectrum cast some doubt
on this conclusion. However, verification of the iron-deficiency and
measurements of additional elements, such as the alpha-element Mg, are
mandatory for demonstrating that the same type of stars produced the metals
found in dwarf galaxies and the Galactic halo. Only then can dwarf galaxy stars
be conclusively linked to early stellar halo assembly. Here we report
high-resolution spectroscopic abundances for 11 elements in S1020549,
confirming the iron abundance of less than 1/4000th that of the Sun, and
showing that the overall abundance pattern mirrors that seen in low-metallicity
halo stars, including the alpha-elements. Such chemical similarity indicates
that the systems destroyed to form the halo billions of years ago were not
fundamentally different from the progenitors of present-day dwarfs, and
suggests that the early chemical enrichment of all galaxies may be nearly
identical.Comment: 16 pages, including 2 figures. Accepted for publication in Nature. It
is embargoed for discussion in the press until formal publication in Natur
Type IIn supernovae at z ~ 2 from archival data
Supernovae have been confirmed to redshift z ~ 1.7 for type Ia (thermonuclear
detonation of a white dwarf) and to z ~ 0.7 for type II (collapse of the core
of the star). The subclass type IIn supernovae are luminous core-collapse
explosions of massive stars and, unlike other types, are very bright in the
ultraviolet, which should enable them to be found optically at redshifts z ~ 2
and higher. In addition, the interaction of the ejecta with circumstellar
material creates strong, long-lived emission lines that allow spectroscopic
confirmation of many events of this type at z ~ 2 for 3 - 5 years after
explosion. Here we report three spectroscopically confirmed type IIn
supernovae, at redshifts z = 0.808, 2.013 and 2.357, detected in archival data
using a method designed to exploit these properties at z ~ 2. Type IIn
supernovae directly probe the formation of massive stars at high redshift. The
number found to date is consistent with the expectations of a locally measured
stellar initial mass function, but not with an evolving initial mass function
proposed to explain independent observations at low and high redshift.Comment: 8 pages, 2 figures, includes supplementary informatio
Double Opposing-Rhomboid Flaps for Closure of a Circular Facial Defect in a Special Position
Various techniques are used to repair circular defects in special positions on the face. Simple closure will yield unsatisfactory results because of skin tension. As an ideal method of reconstruction, various flaps are used to provide a versatile and safe alternative. The authors applied double opposing-rhomboid flaps, which provided for closure of a circular skin defect without alteration to the original shapes of the vital structures and resulted in an imperceptible scar. With careful designing, 21 patients with circular defects caused by skin tumor excisions to special facial positions have attained effective functional and aesthetic results using this method since 2004
Crystal Structure of the PIM2 Kinase in Complex with an Organoruthenium Inhibitor
BACKGROUND: The serine/threonine kinase PIM2 is highly expressed in human leukemia and lymphomas and has been shown to positively regulate survival and proliferation of tumor cells. Its diverse ATP site makes PIM2 a promising target for the development of anticancer agents. To date our knowledge of catalytic domain structures of the PIM kinase family is limited to PIM1 which has been extensively studied and which shares about 50% sequence identity with PIM2. PRINCIPAL FINDINGS: Here we determined the crystal structure of PIM2 in complex with an organoruthenium complex (inhibition in sub-nanomolar level). Due to its extraordinary shape complementarity this stable organometallic compound is a highly potent inhibitor of PIM kinases. SIGNIFICANCE: The structure of PIM2 revealed several differences to PIM1 which may be explored further to generate isoform selective inhibitors. It has also demonstrated how an organometallic inhibitor can be adapted to the binding site of protein kinases to generate highly potent inhibitors. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1
Truncated and Helix-Constrained Peptides with High Affinity and Specificity for the cFos Coiled-Coil of AP-1
Protein-based therapeutics feature large interacting surfaces. Protein folding endows structural stability to localised surface epitopes, imparting high affinity and target specificity upon interactions with binding partners. However, short synthetic peptides with sequences corresponding to such protein epitopes are unstructured in water and promiscuously bind to proteins with low affinity and specificity. Here we combine structural stability and target specificity of proteins, with low cost and rapid synthesis of small molecules, towards meeting the significant challenge of binding coiled coil proteins in transcriptional regulation. By iteratively truncating a Jun-based peptide from 37 to 22 residues, strategically incorporating i-->i+4 helix-inducing constraints, and positioning unnatural amino acids, we have produced short, water-stable, alpha-helical peptides that bind cFos. A three-dimensional NMR-derived structure for one peptide (24) confirmed a highly stable alpha-helix which was resistant to proteolytic degradation in serum. These short structured peptides are entropically pre-organized for binding with high affinity and specificity to cFos, a key component of the oncogenic transcriptional regulator Activator Protein-1 (AP-1). They competitively antagonized the cJunβcFos coiled-coil interaction. Truncating a Jun-based peptide from 37 to 22 residues decreased the binding enthalpy for cJun by ~9 kcal/mol, but this was compensated by increased conformational entropy (TDS β€ 7.5 kcal/mol). This study demonstrates that rational design of short peptides constrained by alpha-helical cyclic pentapeptide modules is able to retain parental high helicity, as well as high affinity and specificity for cFos. These are important steps towards small antagonists of the cJun-cFos interaction that mediates gene transcription in cancer and inflammatory diseases
The stellar halo of the Galaxy
Stellar halos may hold some of the best preserved fossils of the formation
history of galaxies. They are a natural product of the merging processes that
probably take place during the assembly of a galaxy, and hence may well be the
most ubiquitous component of galaxies, independently of their Hubble type. This
review focuses on our current understanding of the spatial structure, the
kinematics and chemistry of halo stars in the Milky Way. In recent years, we
have experienced a change in paradigm thanks to the discovery of large amounts
of substructure, especially in the outer halo. I discuss the implications of
the currently available observational constraints and fold them into several
possible formation scenarios. Unraveling the formation of the Galactic halo
will be possible in the near future through a combination of large wide field
photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes.
Full-resolution version available at
http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd
Expression of Distal-less, dachshund, and optomotor blind in Neanthes arenaceodentata (Annelida, Nereididae) does not support homology of appendage-forming mechanisms across the Bilateria
The similarity in the genetic regulation of
arthropod and vertebrate appendage formation has been
interpreted as the product of a plesiomorphic gene
network that was primitively involved in bilaterian
appendage development and co-opted to build appendages
(in modern phyla) that are not historically related
as structures. Data from lophotrochozoans are needed to
clarify the pervasiveness of plesiomorphic appendage forming
mechanisms. We assayed the expression of three
arthropod and vertebrate limb gene orthologs, Distal-less
(Dll), dachshund (dac), and optomotor blind (omb), in
direct-developing juveniles of the polychaete Neanthes
arenaceodentata. Parapodial Dll expression marks premorphogenetic
notopodia and neuropodia, becoming restricted
to the bases of notopodial cirri and to ventral
portions of neuropodia. In outgrowing cephalic appendages,
Dll activity is primarily restricted to proximal
domains. Dll expression is also prominent in the brain. dac
expression occurs in the brain, nerve cord ganglia, a pair
of pharyngeal ganglia, presumed interneurons linking a
pair of segmental nerves, and in newly differentiating
mesoderm. Domains of omb expression include the brain,
nerve cord ganglia, one pair of anterior cirri, presumed
precursors of dorsal musculature, and the same pharyngeal
ganglia and presumed interneurons that express dac.
Contrary to their roles in outgrowing arthropod and
vertebrate appendages, Dll, dac, and omb lack comparable
expression in Neanthes appendages, implying independent
evolution of annelid appendage development. We infer
that parapodia and arthropodia are not structurally or
mechanistically homologous (but their primordia might
be), that Dllβs ancestral bilaterian function was in sensory
and central nervous system differentiation, and that
locomotory appendages possibly evolved from sensory
outgrowths
Clumps and streams in the local dark matter distribution
In cold dark matter cosmological models, structures form and grow by merging
of smaller units. Numerical simulations have shown that such merging is
incomplete; the inner cores of halos survive and orbit as "subhalos" within
their hosts. Here we report a simulation that resolves such substructure even
in the very inner regions of the Galactic halo. We find hundreds of very
concentrated dark matter clumps surviving near the solar circle, as well as
numerous cold streams. The simulation reveals the fractal nature of dark matter
clustering: Isolated halos and subhalos contain the same relative amount of
substructure and both have cuspy inner density profiles. The inner mass and
phase-space densities of subhalos match those of recently discovered faint,
dark matter-dominated dwarf satellite galaxies and the overall amount of
substructure can explain the anomalous flux ratios seen in strong gravitational
lenses. Subhalos boost gamma-ray production from dark matter annihilation, by
factors of 4-15, relative to smooth galactic models. Local cosmic ray
production is also enhanced, typically by a factor 1.4, but by more than a
factor of ten in one percent of locations lying sufficiently close to a large
subhalo. These estimates assume that gravitational effects of baryons on dark
matter substructure are small.Comment: 14 pages, 5 figures, to appear in Nature, includes supplementary
information. Full version of Figure 1 available at
http://www.ucolick.org/~diemand/vl2/fig1.pn
The SOCS-Box of HIV-1 Vif Interacts with ElonginBC by Induced-Folding to Recruit Its Cul5-Containing Ubiquitin Ligase Complex
The HIV-1 viral infectivity factor (Vif) protein recruits an E3 ubiquitin ligase complex, comprising the cellular proteins elongin B and C (EloBC), cullin 5 (Cul5) and RING-box 2 (Rbx2), to the anti-viral proteins APOBEC3G (A3G) and APOBEC3F (A3F) and induces their polyubiquitination and proteasomal degradation. In this study, we used purified proteins and direct in vitro binding assays, isothermal titration calorimetry and NMR spectroscopy to describe the molecular mechanism for assembly of the Vif-EloBC ternary complex. We demonstrate that Vif binds to EloBC in two locations, and that both interactions induce structural changes in the SOCS box of Vif as well as EloBC. In particular, in addition to the previously established binding of Vif's BC box to EloC, we report a novel interaction between the conserved Pro-Pro-Leu-Pro motif of Vif and the C-terminal domain of EloB. Using cell-based assays, we further show that this interaction is necessary for the formation of a functional ligase complex, thus establishing a role of this motif. We conclude that HIV-1 Vif engages EloBC via an induced-folding mechanism that does not require additional co-factors, and speculate that these features distinguish Vif from other EloBC specificity factors such as cellular SOCS proteins, and may enhance the prospects of obtaining therapeutic inhibitors of Vif function
RNA localization in neurite morphogenesis and synaptic regulation: current evidence and novel approaches
It is now generally accepted that RNA localization in the central nervous system conveys important roles both during development and in the adult brain. Of special interest is protein synthesis located at the synapse, as this potentially confers selective synaptic modification and has been implicated in the establishment of memories. However, the underlying molecular events are largely unknown. In this review, we will first discuss novel findings that highlight the role of RNA localization in neurons. We will focus on the role of RNA localization in neurotrophin signaling, axon outgrowth, dendrite and dendritic spine morphogenesis as well as in synaptic plasticity. Second, we will briefly present recent work on the role of microRNAs in translational control in dendrites and its implications for learning and memory. Finally, we discuss recent approaches to visualize RNAs in living cells and their employment for studying RNA trafficking in neurons
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