Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.     

Ferromagnetism in one-dimensional monatomic metal chains

Two-dimensional systems, such as ultrathin epitaxial films and superlattices, display magnetic properties distinct from bulk materials. A challenging aim of current research in magnetism is to explore structures of still lower dimensionality. As the dimensionality of a physical system is reduced, magnetic ordering tends to decrease as fluctuations become relatively more important. Spin lattice models predict that an infinite one-dimensional linear chain with short-range magnetic interactions spontaneously breaks up into segments with different orientation of the magnetization, thereby prohibiting long-range ferromagnetic order at a finite temperature. These models, however, do not take into account kinetic barriers to reaching equilibrium or interactions with the substrates that support the one-dimensional nanostructures. Here we demonstrate the existence of both short- and long-range ferromagnetic order for one-dimensional monatomic chains of Co constructed on a Pt substrate. We find evidence that the monatomic chains consist of thermally fluctuating segments of ferromagnetically coupled atoms which, below a threshold temperature, evolve into a ferromagnetic long-range-ordered state owing to the presence of anisotropy barriers. The Co chains are characterized by large localized orbital moments and correspondingly large magnetic anisotropy energies compared to two-dimensional films and bulk Co.     

A modified dipeptide from the algaCystoseira corniculata hauck

Summary A modifiedl-Phe-l-Phe dipeptide has been isolated from the algaCystoseira corniculata.We thank ProfessorK. C. Güven, Botanical Institute, University of Istanbul, for collecting the alga.     

Loss of Siglec-14 reduces the risk of chronic obstructive pulmonary disease exacerbation

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. COPD exacerbation, or episodic worsening of symptoms, often results in hospitalization and increased mortality rates. Airway infections by new bacterial strains, such as nontypeable Haemophilus influenzae (NTHi), are a major cause of COPD exacerbation. NTHi express lipooligosaccharides that contain sialic acids, and may interact with Siglec-14, a sialic acid recognition protein on myeloid cells that serves as an activating signal transduction receptor. A null allele polymorphism in SIGLEC14 may attenuate the inflammatory responses to NTHi by eliminating Siglec-14 expression. We asked if the loss of Siglec-14 attenuates the inflammatory response by myeloid cells against NTHi, and if the SIGLEC14-null polymorphism has any effect on COPD exacerbation. We found that NTHi interacts with Siglec-14 to enhance proinflammatory cytokine production in a tissue culture model. Inhibitors of the Syk tyrosine kinase suppress this response. Loss of Siglec-14, due to SIGLEC14-null allele homozygosity, is associated with a reduced risk of COPD exacerbation in a Japanese patient population. Taken together, Siglec-14 and its downstream signaling pathway facilitate the “infection–inflammation–exacerbation” axis of COPD disease progression, and may represent promising targets for therapeutic intervention.     

Development of a new coated electrode with low nickel content for welding ductile iron and its response to austempering

Coated Electrodes with small amounts of nickel were developed for welding ductile iron (DI) and conversion of the same into austempered ductile iron (ADI) after austempering. Among six electrodes, Trials 3 and 4 were selected for establishing crack-free weld deposits via preheating and post-weld heat treatment. Austenitization was performed at 900℃ for 2 h and austempering at 300 or 350℃ for three different holding times to observe the results of austempering with respect to the microstructure, hardness, and austempering kinetics of the samples. The microstructures of the weld deposits showed needle-like bainitic ferrite with small amounts of retained austenite when treated at 300℃ and feathery bainitic ferrite with large amounts of retainedaustenite when treated at 350℃. The electrode labeled with Trial 3 revealed greater austenite contents than that labeled with Trial 4 when treated with a 2 h holding time regardless of the austempering temperature applied. The transformation rate of the bainitic ferrite of Trial 3 was relatively higher than that of Trial 4 and showed a lower rate constant, leading to a higher diffusion rate of carbon in austenite.     

Patched acts catalytically to suppress the activity of Smoothened

Mutations affecting the transmembrane proteins Patched (Ptc) or Smoothened (Smo) that trigger ligand-independent activity of the Hedgehog (Hh) signalling pathway are associated with human tumours such as basal cell carcinoma (BCC) and medulloblastoma. Despite extensive genetic studies demonstrating the importance of these receptor components in embryonic patterning and cancer, the mechanism by which Ptc regulates Smo is not understood. Here we report that Ptc and Smo are not significantly associated within Hh-responsive cells. Furthermore, we show that free Ptc (unbound by Hh) acts sub-stoichiometrically to suppress Smo activity and thus is critical in specifying the level of pathway activity. Patched is a twelve-transmembrane protein with homology to bacterial proton-driven transmembrane molecular transporters; we demonstrate that the function of Ptc is impaired by alterations of residues that are conserved in and required for function of these bacterial transporters. These results suggest that the Ptc tumour suppressor functions normally as a transmembrane molecular transporter, which acts indirectly to inhibit Smo activity, possibly through changes in distribution or concentration of a small molecule.     

Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins

All cells in nature are covered by a dense and complex array of carbohydrates. Given their prominence on cell surfaces, it is not surprising that these glycans mediate and/or modulate many cellular interactions. Proteins that bind sialic acid, a sugar that is found on the surface of the cell and on secreted proteins in vertebrates, are involved in a broad range of biological processes, including intercellular adhesion, signalling and microbial attachment. Studying the roles of such proteins in vertebrates has improved our understanding of normal physiology, disease and human evolution.     

Bayesian Forecasting for Time Series of Categorical Data

Time series of categorical data is not a widely studied research topic. Particularly, there is no available work on the Bayesian analysis of categorical time series processes. With the objective of filling that gap, in the present paper we consider the problem of Bayesian analysis including Bayesian forecasting for time series of categorical data, which is modelled by Pegram's mixing operator, applicable for both ordinal and nominal data structures. In particular, we consider Pegram's operator‐based autoregressive process for the analysis. Real datasets on infant sleep status are analysed for illustrations. We also illustrate that the Bayesian forecasting is more accurate than the corresponding frequentist's approach when we intend to forecast a large time gap ahead. Copyright © 2016 John Wiley & Sons, Ltd.