Emergence of Bulk CsCl Structure in (CsCl)nCs+ Cluster Ions

The emergence of CsCl bulk structure in (CsCl)nCs+ cluster ions is investigated using a mixed quantum-mechanical/semiempirical theoretical approach. We find that rhombic dodecahedral fragments (with bulk CsCl symmetry) are more stable than rock-salt fragments after the completion of the fifth rhombic dodecahedral atomic shell. From this size (n=184) on, a new set of magic numbers should appear in the experimental mass spectra. We also propose another experimental test for this transition, which explicitely involves the electronic structure of the cluster. Finally, we perform more detailed calculations in the size range n=31--33, where recent experimental investigations have found indications of the presence of rhombic dodecahedral (CsCl)32Cs+ isomers in the cluster beams.Comment: LaTeX file. 6 pages and 4 pictures. Accepted for publication in Phys. Rev.

Structural and Electronic Properties of Small Neutral (MgO)n Clusters

Ab initio Perturbed Ion (PI) calculations are reported for neutral stoichiometric (MgO)n clusters (n<14). An extensive number of isomer structures was identified and studied. For the isomers of (MgO)n (n<8) clusters, a full geometrical relaxation was considered. Correlation corrections were included for all cluster sizes using the Coulomb-Hartree-Fock (CHF) model proposed by Clementi. The results obtained compare favorably to the experimental data and other previous theoretical studies. Inclusion of correlaiotn is crucial in order to achieve a good description of these systems. We find an important number of new isomers which allows us to interpret the experimental magic numbers without the assumption of structures based on (MgO)3 subunits. Finally, as an electronic property, the variations in the cluster ionization potential with the cluster size were studied and related to the structural isomer properties.Comment: 24 pages, LaTeX, 7 figures in GIF format. Accepted for publication in Phys. Rev.

Structural Transitions and Global Minima of Sodium Chloride Clusters

In recent experiments on sodium chloride clusters structural transitions between nanocrystals with different cuboidal shapes were detected. Here we determine reaction pathways between the low energy isomers of one of these clusters, (NaCl)35Cl-. The key process in these structural transitions is a highly cooperative rearrangement in which two parts of the nanocrystal slip past one another on a {110} plane in a direction. In this way the nanocrystals can plastically deform, in contrast to the brittle behaviour of bulk sodium chloride crystals at the same temperatures; the nanocrystals have mechanical properties which are a unique feature of their finite size. We also report and compare the global potential energy minima for (NaCl)NCl- using two empirical potentials, and comment on the effect of polarization.Comment: extended version, 13 pages, 8 figures, revte

Replacement of Sublineages of Avian Influenza (H5N1) by Reassortments, Sub-Saharan Africa

The 3 sublineages initially introduced into Nigeria in 2006 were gradually replaced by different reassortants

A transient homotypic interaction model for the influenza A virus NS1 protein effector domain

Influenza A virus NS1 protein is a multifunctional virulence factor consisting of an RNA binding domain (RBD), a short linker, an effector domain (ED), and a C-terminal 'tail'. Although poorly understood, NS1 multimerization may autoregulate its actions. While RBD dimerization seems functionally conserved, two possible apo ED dimers have been proposed (helix-helix and strand-strand). Here, we analyze all available RBD, ED, and full-length NS1 structures, including four novel crystal structures obtained using EDs from divergent human and avian viruses, as well as two forms of a monomeric ED mutant. The data reveal the helix-helix interface as the only strictly conserved ED homodimeric contact. Furthermore, a mutant NS1 unable to form the helix-helix dimer is compromised in its ability to bind dsRNA efficiently, implying that ED multimerization influences RBD activity. Our bioinformatical work also suggests that the helix-helix interface is variable and transient, thereby allowing two ED monomers to twist relative to one another and possibly separate. In this regard, we found a mAb that recognizes NS1 via a residue completely buried within the ED helix-helix interface, and which may help highlight potential different conformational populations of NS1 (putatively termed 'helix-closed' and 'helix-open') in virus-infected cells. 'Helix-closed' conformations appear to enhance dsRNA binding, and 'helix-open' conformations allow otherwise inaccessible interactions with host factors. Our data support a new model of NS1 regulation in which the RBD remains dimeric throughout infection, while the ED switches between several quaternary states in order to expand its functional space. Such a concept may be applicable to other small multifunctional proteins

Entropic effects on the structure of Lennard-Jones clusters

We examine in detail the causes of the structural transitions that occur for those small Lennard-Jones clusters that have a non-icosahedral global minima. Based on the principles learned from these examples we develop a method to construct structural phase diagrams that show in a coarse-grained manner how the equilibrium structure of large clusters depends on both size and temperature. The method can be augmented to account for anharmonicity and quantum effects. Our results illustrate that the vibrational entropy can play a crucial role in determining the equilibrium structure of a cluster.Comment: 13 pages, 9 figure

Phosphorylation of Serine 248 of C/EBPα Is Dispensable for Myelopoiesis but Its Disruption Leads to a Low Penetrant Myeloid Disorder with Long Latency

BACKGROUND: Transcription factors play a key role in lineage commitment and differentiation of stem cells into distinct mature cells. In hematopoiesis, they regulate lineage-specific gene expression in a stage-specific manner through various physical and functional interactions with regulatory proteins that are simultanously recruited and activated to ensure timely gene expression. The transcription factor CCAAT/enhancer binding protein α (C/EBPα) is such a factor and is essential for the development of granulocytic/monocytic cells. The activity of C/EBPα is regulated on several levels including gene expression, alternative translation, protein interactions and posttranslational modifications, such as phosphorylation. In particular, the phosphorylation of serine 248 of the transactivation domain has been shown to be of crucial importance for granulocytic differentiation of 32Dcl3 cells in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Here, we use mouse genetics to investigate the significance of C/EBPα serine 248 in vivo through the construction and analysis of Cebpa(S248A/S248A) knock-in mice. Surprisingly, 8-week old Cebpa(S248A/S248A) mice display normal steady-state hematopoiesis including unaltered development of mature myeloid cells. However, over time some of the animals develop a hematopoietic disorder with accumulation of multipotent, megakaryocytic and erythroid progenitor cells and a mild impairment of differentiation along the granulocytic-monocytic lineage. Furthermore, BM cells from Cebpa(S248A/S248A) animals display a competitive advantage compared to wild type cells in a transplantation assay. CONCLUSIONS/SIGNIFICANCE: Taken together, our data shows that the substitution of C/EBPα serine 248 to alanine favors the selection of the megakaryocytic/erythroid lineage over the monocytic/granulocytic compartment in old mice and suggests that S248 phosphorylation may be required to maintain proper hematopoietic homeostasis in response to changes in the wiring of cellular signalling networks. More broadly, the marked differences between the phenotype of the S248A variant in vivo and in vitro highlight the need to exert caution when extending in vitro phenotypes to the more appropriate in vivo context

Enterovirus 71 3C Protease Cleaves a Novel Target CstF-64 and Inhibits Cellular Polyadenylation

Identification of novel cellular proteins as substrates to viral proteases would provide a new insight into the mechanism of cell–virus interplay. Eight nuclear proteins as potential targets for enterovirus 71 (EV71) 3C protease (3Cpro) cleavages were identified by 2D electrophoresis and MALDI-TOF analysis. Of these proteins, CstF-64, which is a critical factor for 3′ pre-mRNA processing in a cell nucleus, was selected for further study. A time-course study to monitor the expression levels of CstF-64 in EV71-infected cells also revealed that the reduction of CstF-64 during virus infection was correlated with the production of viral 3Cpro. CstF-64 was cleaved in vitro by 3Cpro but neither by mutant 3Cpro (in which the catalytic site was inactivated) nor by another EV71 protease 2Apro. Serial mutagenesis was performed in CstF-64, revealing that the 3Cpro cleavage sites are located at position 251 in the N-terminal P/G-rich domain and at multiple positions close to the C-terminus of CstF-64 (around position 500). An accumulation of unprocessed pre-mRNA and the depression of mature mRNA were observed in EV71-infected cells. An in vitro assay revealed the inhibition of the 3′-end pre-mRNA processing and polyadenylation in 3Cpro-treated nuclear extract, and this impairment was rescued by adding purified recombinant CstF-64 protein. In summing up the above results, we suggest that 3Cpro cleavage inactivates CstF-64 and impairs the host cell polyadenylation in vitro, as well as in virus-infected cells. This finding is, to our knowledge, the first to demonstrate that a picornavirus protein affects the polyadenylation of host mRNA

Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom

The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to alpha-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves. IMPORTANCE: Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection in the United Kingdom. To determine the causes of this variation, we studied genetic changes in virus isolates from individual hospitalized patients. There were no consistent differences between these viruses and those circulating in the community, but we found multiple evolutionary changes that in combination over time increased the virus's ability to infect human cells. These adaptations may explain the remarkable ability of A(H1N1)pdm09 virus to continue to circulate despite widespread immunity and the apparent increase in severity of influenza over successive waves of infection