Sequencing human-gibbon breakpoints of synteny reveals mosaic new insertions at rearrangement sites

The gibbon genome exhibits extensive karyotypic diversity with an increased rate of chromosomal rearrangements during evolution. In an effort to understand the mechanistic origin and implications of these rearrangement events, we sequenced 24 synteny breakpoint regions in the white-cheeked gibbon (Nomascus leucogenys, NLE) in the form of high-quality BAC insert sequences (4.2 Mbp). While there is a significant deficit of breakpoints in genes, we identified seven human gene structures involved in signaling pathways (DEPDC4, GNG10), phospholipid metabolism (ENPP5, PLSCR2), beta-oxidation (ECH1), cellular structure and transport (HEATR4), and transcription (ZNF461), that have been disrupted in the NLE gibbon lineage. Notably, only three of these genes show the expected evolutionary signatures of pseudogenization. Sequence analysis of the breakpoints suggested both nonclassical nonhomologous end-joining (NHEJ) and replication-based mechanisms of rearrangement. A substantial number (11/24) of human-NLE gibbon breakpoints showed new insertions of gibbon-specific repeats and mosaic structures formed from disparate sequences including segmental duplications, LINE, SINE, and LTR elements. Analysis of these sites provides a model for a replication-dependent repair mechanism for double-strand breaks (DSBs) at rearrangement sites and insights into the structure and formation of primate segmental duplications at sites of genomic rearrangements during evolution.

Detection of Body Dump Sites and Clandestine Burials: a GIS-Based Landscape Approach

Forensic archaeology has been of inestimable help in the location and excavation of clandestine burials (Hunter 1996a:16-17, 1996b; Killam 2004; Levine et al. 1984). Landscape archaeology techniques have been adapted and widely applied for such purposes. In this article, an adaptation of one of the most common applications of archaeological GIS, that is predictive site location, is applied to the detection of body dump sites and clandestine burial sites, bringing together in the process the fields of landscape archaeology, forensic sciences, and GIS.

Complexation to macromolecules with a large number of sites

This paper presents an approach based on the saddle-point approximation to study the equilibrium interactions between small molecules and macromolecules with a large number of sites. For this case, the application of the Darwin–Fowler method results in very simple expressions for the stoichiometric equilibrium constants and their corresponding free energies in terms of integrals of the binding curve plus a correction term which depends on the first derivatives of the binding curve in the points corresponding to an integer value of the mean occupation number. These expressions are simplified when the number of sites tends to infinity, providing an interpretation of the binding curve in terms of the stoichiometric stability constants. The formalism presented is applied to some simple complexation models, obtaining good values for the free energies involved. When heterogeneous complexation is assumed, simple expressions are obtained to relate the macroscopic description of the binding, given by the stoichiomeric constants, with the microscopic description in terms of the intrinsic stability constants or the affinity spectrum. © 1999 American Institute of Physics.

Controlling the spin of metal atoms adsorbed on oxide surfaces: Ni on regular and defective sites of the MgO(001) surface

We have analyzed the relative energy of nonmagnetic and magnetic low-lying electronic states of Ni atoms adsorbed on regular and defective sites of the MgO(001) surface. To this end cluster and periodic surface models are used within density functional theory. For Ni atoms adsorbed on oxygen vacancies at low coverage, the interaction energy between the metal and the support is much larger than on regular sites. Strong bonding results in a diamagnetic adsorbed species and the energy required to reach the high-spin state increases. Moreover, a correlation appears between the low-spin to high-spin energy difference and the interaction energy hypothesizing that it is possible to prepare the surface to tune the high-spin to low-spin energy difference. Magnetic properties of adsorbed thin films obtained upon increasing coverage are more difficult to interpret. This is because the metallic bond is readily formed and dominates over the effect of the atoms directly bound to the vacancy.

Treatment of rats with a self-selected hyperlipidic diet, increases the lipid content of the main adipose tissue sites in a proportion similar to that of the lipids in the rest of organs and tissues

Adipose tissue (AT) is distributed as large differentiated masses, and smaller depots covering vessels, and organs, as well as interspersed within them. The differences between types and size of cells makes AT one of the most disperse and complex organs. Lipid storage is partly shared by other tissues such as muscle and liver. We intended to obtain an approximate estimation of the size of lipid reserves stored outside the main fat depots. Both male and female rats were made overweight by 4-weeks feeding of a cafeteria diet. Total lipid content was analyzed in brain, liver, gastrocnemius muscle, four white AT sites: subcutaneous, perigonadal, retroperitoneal and mesenteric, two brown AT sites (interscapular and perirenal) and in a pool of the rest of organs and tissues (after discarding gut contents). Organ lipid content was estimated and tabulated for each individual rat. Food intake was measured daily. There was a surprisingly high proportion of lipid not accounted for by the main macroscopic AT sites, even when brain, liver and BAT main sites were discounted. Muscle contained about 8% of body lipids, liver 1-1.4%, four white AT sites lipid 28-63% of body lipid, and the rest of the body (including muscle) 38-44%. There was a good correlation between AT lipid and body lipid, but lipid in"other organs" was highly correlated too with body lipid. Brain lipid was not. Irrespective of dietary intake, accumulation of body fat was uniform both for the main lipid storage and handling organs: large masses of AT (but also liver, muscle), as well as in the"rest" of tissues. These storage sites, in specialized (adipose) or not-specialized (liver, muscle) tissues reacted in parallel against a hyperlipidic diet challenge. We postulate that body lipid stores are handled and regulated coordinately, with a more centralized and overall mechanisms than usually assumed.

Ultra-Deep Pyrosequencing Detects Conserved Genomic Sites and Quantifies Linkage of Drug-Resistant Amino Acid Changes in the Hepatitis B Virus Genome

Selection of amino acid substitutions associated with resistance to nucleos(t)ide-analog (NA) therapy in the hepatitis B virus (HBV) reverse transcriptase (RT) and their combination in a single viral genome complicates treatment of chronic HBV infection and may affect the overlapping surface coding region. In this study, the variability of an overlapping polymerase-surface region, critical for NA resistance, is investigated before treatment and under antiviral therapy, with assessment of NA-resistant amino acid changes simultaneously occurring in the same genome (linkage analysis) and their influence on the surface coding region.

Oxygen vacancies as active sites for water dissociation on rutile TiO2(110)

Through an interplay between scanning tunneling microscopy experiments and density functional theory calculations, we determine unambiguously the active surface site responsible for the dissociation of water molecules adsorbed on rutile TiO2(110). Oxygen vacancies in the surface layer are shown to dissociate H2O through the transfer of one proton to a nearby oxygen atom, forming two hydroxyl groups for every vacancy. The amount of water dissociation is limited by the density of oxygen vacancies present on the clean surface exclusively. The dissociation process sets in as soon as molecular water is able to diffuse to the active site.

SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites

The Class IIa histone deacetylases (HDAC)4 and HDAC5 play a role in neuronal survival and behavioral adaptation in the CNS. Phosphorylation at 2/3 N-terminal sites promote their nuclear export. We investigated whether non-canonical signaling routes to Class IIa HDAC export exist because of their association with the co-repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N-terminal phosphorylation sites (HDAC4(MUT), HDAC5(MUT)) are constitutively nuclear, co-expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 (RD3) is critical for co-shuttling of HDAC5(MUT), consistent with the role for this domain in Class IIa HDAC association. In the context of BDNF signaling, we found that HDAC5(WT), which was more cytoplasmic than HDAC5(MUT), accumulated in the nucleus after BDNF treatment. However, co-expression of SMRT blocked BDNF-induced HDAC5(WT) import in a RD3-dependent manner. In effect, SMRT-mediated HDAC5(WT) export was opposing the BDNF-induced HDAC5 nuclear accumulation observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs exportable by a wider range of signals than those which simply

Building complexity in O2-binding copper complexes : site-selective metalation and intermolecular O2-binding at dicopper and heterometallic complexes derived from an unsymmetric ligand

A novel unsymmetric dinucleating ligand (LN3N4) combining a tridentate and a tetradentate binding sites linked through a m-xylyl spacer was synthesized as ligand scaffold for preparing homo- and dimetallic complexes, where the two metal ions are bound in two different coordination environments. Site-selective binding of different metal ions is demonstrated. LN3N4 is able to discriminate between CuI and a complementary metal (M′ = CuI, ZnII, FeII, CuII, or GaIII) so that pure heterodimetallic complexes with a general formula [CuIM′(LN3N4)]n+ are synthesized. Reaction of the dicopper(I) complex [CuI 2(LN3N4)]2+ with O2 leads to the formation of two different copper-dioxygen (Cu2O2) intermolecular species (O and TP) between two copper atoms located in the same site from different complex molecules. Taking advantage of this feature, reaction of the heterodimetallic complexes [CuM′(LN3N4)]n+ with O2 at low temperature is used as a tool to determine the final position of the CuI center in the system because only one of the two Cu2O2 species is formed