Pedigree analysis of Czech Holstein calves with schistosoma reflexum

<p>Abstract</p> <p>Background</p> <p>Schistosoma reflexum (SR) is congenital syndrome briefly characterized by visceral eventration, severe dorsoflexion and ankylosis of the spine and arthrogryposis. A genetic etiology has been proposed, but conclusive evidence has not yet been provided.</p> <p>Methods</p> <p>Pedigree analysis was carried out in 29 cases of SR in Czech Holsteins and Holstein crosses. Genetic relationship was evaluated and inbreeding coefficients calculated. Pedigrees of 15 Czech Holsteins fathering non-SR affected calves were used for comparison.</p> <p>Results</p> <p>Twenty-one cases occurred in one pedigree founded by three sires while three SR calves occurred in another pedigree with a common grandfather. The sex ratio between affected males and females was 11:6. Affected calves shared common ancestors different from those shared by the unaffected calves. The inbreeding coefficient in the SR affected calves was not increased compared to unaffected calves.</p> <p>Conclusions</p> <p>The findings are consistent with SR being inherited autosomal recessively. Further studies are however needed to confirm this and therefore a breeding trial is recommended where a suspected heterozygous sire is mated to closely related females.</p

Identification of Novel High-Frequency DNA Methylation Changes in Breast Cancer

Recent data have revealed that epigenetic alterations, including DNA methylation and chromatin structure changes, are among the earliest molecular abnormalities to occur during tumorigenesis. The inherent thermodynamic stability of cytosine methylation and the apparent high specificity of the alterations for disease may accelerate the development of powerful molecular diagnostics for cancer. We report a genome-wide analysis of DNA methylation alterations in breast cancer. The approach efficiently identified a large collection of novel differentially DNA methylated loci (∼200), a subset of which was independently validated across a panel of over 230 clinical samples. The differential cytosine methylation events were independent of patient age, tumor stage, estrogen receptor status or family history of breast cancer. The power of the global approach for discovery is underscored by the identification of a single differentially methylated locus, associated with the GHSR gene, capable of distinguishing infiltrating ductal breast carcinoma from normal and benign breast tissues with a sensitivity and specificity of 90% and 96%, respectively. Notably, the frequency of these molecular abnormalities in breast tumors substantially exceeds the frequency of any other single genetic or epigenetic change reported to date. The discovery of over 50 novel DNA methylation-based biomarkers of breast cancer may provide new routes for development of DNA methylation-based diagnostics and prognostics, as well as reveal epigenetically regulated mechanism involved in breast tumorigenesis

Chemical Plausibility of Cu(lll) with Biological Ligation in pMMO

The mechanisms of dioxygen activation and methane C−H oxidation in particulate methane monooxygenase (pMMO) are currently unknown. Recent studies support a binuclear copper site as the catalytic center. We report the low-temperature assembly of a high-valent dicopper(III) bis(μ-oxide) complex bearing marked structural fidelity to the proposed active site of pMMO. This unprecedented dioxygen-bonded Cu(III) species with exclusive biological ligation directly informs on the chemical plausibility and thermodynamic stability of the bis(μ-oxide) structure in such dicopper sites and foretells unusual optical signatures of an oxygenation product in pMMO. Though the ultimate pMMO active oxidant is still debated, C–H oxidation of exogenous substrates is observed with the reported Cu(III) complexes. The assembly of a high valent species both narrows the search for relevant pMMO intermediates and provides evidence to substantiate the role of Cu(III) in biological redox processes

Chemical Plausibility of Cu(III) with Biological Ligation in pMMO

The mechanisms of dioxygen activation and methane C−H oxidation in particulate methane monooxygenase (pMMO) are currently unknown. Recent studies support a binuclear copper site as the catalytic center. We report the low-temperature assembly of a high-valent dicopper­(III) bis­(μ-oxide) complex bearing marked structural fidelity to the proposed active site of pMMO. This unprecedented dioxygen-bonded Cu­(III) species with exclusive biological ligation directly informs on the chemical plausibility and thermodynamic stability of the bis­(μ-oxide) structure in such dicopper sites and foretells unusual optical signatures of an oxygenation product in pMMO. Though the ultimate pMMO active oxidant is still debated, C–H oxidation of exogenous substrates is observed with the reported Cu­(III) complexes. The assembly of a high valent species both narrows the search for relevant pMMO intermediates and provides evidence to substantiate the role of Cu­(III) in biological redox processes

Primary Amine Stabilization of a Dicopper(III) Bis(μ-oxo) Species: Modeling the Ligation in pMMO

Here we report the formation of the first examples of dicopper­(III) bis­(μ-oxo) complexes ligated by the primary amines, propylenediamine, and <i>N</i>,<i>N</i>,-dimethyl propylenediamine. Stabilization of these new compounds is effected at −125 °C by “core capture” introduction of exogenous ligand to a preformed dicopper­(III) bis­(μ-oxo) complex supported by the peralkylated tetramethyl propylenediamine. Primary amine ligation in these compounds matches the single primary amine coordination of the putative active site of particulate methane monooxygenase (pMMO) and polysaccharide monooxygenase. Reactivity studies presented here show primary amine ligated cores are competent oxidants, capable of activating C–H bonds by an H-atom abstraction mechanism. Trends in spectroscopy, structure, and reactivity provide hints to the potential role of primary amine ligation in pMMO: increased substrate accessibility to the redox active orbitals of the Cu₂O₂ core and greater stabilization of the oxidant without attenuation of oxidizing power

Direct Copper(III) Formation from O₂ and Copper(I) with Histamine Ligation

Histamine chelation of copper­(I) by a terminal histidine residue in copper hydroxylating enzymes activates dioxygen to form unknown oxidants, generally assumed as copper­(II) species. The direct formation of copper­(III)-containing products from the oxygenation of histamine-ligated copper­(I) complexes is demonstrated here, indicating that copper­(III) is a viable oxidation state in such products from both kinetic and thermodynamic perspectives. At low temperatures, both trinuclear Cu­(II)₂Cu­(III)­O₂ and dinuclear Cu­(III)₂O₂ predominate, with the distribution dependent on the histamine ligand structure and oxygenation conditions. Kinetics studies suggest the bifurcation point to these two products is an unobserved peroxide-level dimer intermediate. The hydrogen atom reactivity difference between the trinuclear and binuclear complexes at parity of histamine ligand is striking. This behavior is best attributed to the accessibility of the bridging oxide ligands to exogenous substrates rather than a difference in oxidizing abilities of the clusters