A role for glycosaminoglycans in the development of collagen fibrils

AbstractExtensive data on the glycosaminoglycan (GAG) composition and the collagen fibril diameter distribution have been collected for a diverse range of connective tissues. It is shown that tissues with the smallest diameter collagen fibrils (mass-average diameter < 60 nm) have high concentrations of hyaluronic acid and that tissues with the largest diameter collagen fibrils (mass-average diameter ∼200 nm) have high concentrations of dermatan sulphate. It is suggested that the lateral growth of fibrils beyond a diameter of about 60 nm is inhibited by the presence of an excess of hyaluronic acid but that this inhibitory effect may be removed by an increasing concentration of chondroitin sulphate and/or dermatan sulphate. It is also postulated that high concentrations of chondroitin sulphate will inhibit fibril growth beyond a mass-average diameter of ∼150 nm. Such an inhibition may in turn be removed by an increasing concentration of dermatan sulphate such that it becomes the dominant GAG present in the tissue

Consequences of Two Different Amino-Acid Substitutions at the Same Codon in KRT14 Indicate Definitive Roles of Structural Distortion in Epidermolysis Bullosa Simplex Pathogenesis

Numerous inherited diseases develop due to missense mutations, leading to an amino-acid substitution. Whether an amino-acid change is pathogenic depends on the level of deleterious effects caused by the amino-acid alteration. We show an example of different structural and phenotypic consequences caused by two individual amino-acid changes at the same position. Epidermolysis bullosa simplex (EBS) is a genodermatosis resulting from KRT5 or KRT14 mutations. Mutation analysis of an EBS family revealed that affected individuals were heterozygous for a, to our knowledge, previously unreported mutation of c.1237G>C (p.Ala413Pro) in KRT14. Interestingly, 2 of 100 unrelated normal controls were heterozygous, and 1 of the 100 was homozygous for a different mutation in this position, c.1237G>A (p.Ala413Thr). In silico modeling of the protein demonstrated deleterious structural effects from proline substitution but not from threonine substitution. In vitro transfection studies revealed a significantly larger number of keratin-clumped cells in HaCaT cells transfected with mutant KRT14 complementary DNA (cDNA) harboring p.Ala413Pro than those transfected with wild-type KRT14 cDNA or mutant KRT14 cDNA harboring p.Ala413Thr. These results show that changes in two distinct amino acids at a locus are destined to elicit different phenotypes due to the degree of structural distortion resulting from the amino-acid alterations

New consensus nomenclature for mammalian keratins

Keratins are intermediate filament–forming proteins that provide mechanical support and fulfill a variety of additional functions in epithelial cells. In 1982, a nomenclature was devised to name the keratin proteins that were known at that point. The systematic sequencing of the human genome in recent years uncovered the existence of several novel keratin genes and their encoded proteins. Their naming could not be adequately handled in the context of the original system. We propose a new consensus nomenclature for keratin genes and proteins that relies upon and extends the 1982 system and adheres to the guidelines issued by the Human and Mouse Genome Nomenclature Committees. This revised nomenclature accommodates functional genes and pseudogenes, and although designed specifically for the full complement of human keratins, it offers the flexibility needed to incorporate additional keratins from other mammalian species

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

EuFe2_2As2_2 under high pressure: an antiferromagnetic bulk superconductor

We report the ac magnetic susceptibility $\chi_{ac}$ and resistivity $\rho$ measurements of EuFe$_2$As$_2$ under high pressure $P$. By observing nearly 100% superconducting shielding and zero resistivity at $P$ = 28 kbar, we establish that $P$-induced superconductivity occurs at $T_c \sim$~30 K in EuFe$_2$As$_2$. $\rho$ shows an anomalous nearly linear temperature dependence from room temperature down to $T_c$ at the same $P$. $\chi_{ac}$ indicates that an antiferromagnetic order of Eu$^{2+}$ moments with $T_N \sim$~20 K persists in the superconducting phase. The temperature dependence of the upper critical field is also determined.Comment: To appear in J. Phys. Soc. Jpn., Vol. 78 No.

Measurement of the electron energy spectrum and its moments in inclusive B -> Xe nu decays

We report a measurement of the inclusive electron energy spectrum for semileptonic decays of B mesons in a data sample of 52 million Y(4S)-->B(B) over bar decays collected with the BABAR detector at the PEP-II asymmetric-energy B-meson factory at SLAC. We determine the branching fraction, first, second, and third moments of the spectrum for lower cutoffs on the electron energy between 0.6 and 1.5 GeV. We measure the partial branching fraction to be B(B-->Xenu,E-e>0.6 GeV)=[10.36+/-0.06(stat.)+/-0.23(sys.)]%

Human and <i>Xenopus<i> Cingulin Share a Modular Organization of the Coiled-Coil Rod Domain: Predictions for Intra- and Intermolecular Assembly

The complete nucleotide and derived amino acid sequences of Homo sapiens cingulin cDNA (5143 bp) were determined by sequencing two distinct EST clones that showed significant sequence homology to Xenopus laevis cingulin. Protein sequence analysis indicates that the molecule contains two chains and has a tripartite structure with N-terminal (head) domains, a coiled-coil rod domain (length, 120 nm), and short C-terminal (tail) domains. Human and Xenopus cingulin heads are only 33% identical, yet a human cingulin N-terminal fragment still interacts with canine ZO-1 and ZO-2 in vitro. The rod domain contains two A and two B subdomains, though it lacks the third B subdomain present in Xenopus cingulin. The heptad substructures of Xenopus and human cingulins were further characterized by computer analysis and indicated that the two-stranded coiled-coil structure contained chains that were parallel and in axial register. Fast Fourier transform analysis and a scoring technique designed to recognize potential interactions between different supramolecular arrangements suggests that cingulin dimers may further assemble through antiparallel interactions between the last ∼100 amino acids of the coiled-coil region. Cingulin mRNA (∼5.2 kb) was detected by Northern blotting in epithelial tissues. A human cingulin EST was mapped to chromosome 1q21 using the UniGene database

Human and <i>Xenopus<i> Cingulin Share a Modular Organization of the Coiled-Coil Rod Domain: Predictions for Intra- and Intermolecular Assembly

The complete nucleotide and derived amino acid sequences of Homo sapiens cingulin cDNA (5143 bp) were determined by sequencing two distinct EST clones that showed significant sequence homology to Xenopus laevis cingulin. Protein sequence analysis indicates that the molecule contains two chains and has a tripartite structure with N-terminal (head) domains, a coiled-coil rod domain (length, 120 nm), and short C-terminal (tail) domains. Human and Xenopus cingulin heads are only 33% identical, yet a human cingulin N-terminal fragment still interacts with canine ZO-1 and ZO-2 in vitro. The rod domain contains two A and two B subdomains, though it lacks the third B subdomain present in Xenopus cingulin. The heptad substructures of Xenopus and human cingulins were further characterized by computer analysis and indicated that the two-stranded coiled-coil structure contained chains that were parallel and in axial register. Fast Fourier transform analysis and a scoring technique designed to recognize potential interactions between different supramolecular arrangements suggests that cingulin dimers may further assemble through antiparallel interactions between the last ∼100 amino acids of the coiled-coil region. Cingulin mRNA (∼5.2 kb) was detected by Northern blotting in epithelial tissues. A human cingulin EST was mapped to chromosome 1q21 using the UniGene database