Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.     

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.     

Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells.

The cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in cultured cystic fibrosis airway epithelial cells and Cl- channel activation assessed in single cells using a fluorescence microscopic assay and the patch-clamp technique. Expression of CFTR, but not of a mutant form of CFTR (delta F508), corrected the Cl- channel defect. Correction of the phenotypic defect demonstrates a causal relationship between mutations in the CFTR gene and defective Cl- transport which is the hallmark of the disease.     

WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature

Macrophages have a critical role in inflammatory and immune responses through their ability to recognize and engulf apoptotic cells. Here we show that macrophages initiate a cell-death programme in target cells by activating the canonical WNT pathway. We show in mice that macrophage WNT7b is a short-range paracrine signal required for WNT-pathway responses and programmed cell death in the vascular endothelial cells of the temporary hyaloid vessels of the developing eye. These findings indicate that macrophages can use WNT ligands to influence cell-fate decisions--including cell death--in adjacent cells, and raise the possibility that they do so in many different cellular contexts.     

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10

The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin^?/? mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.     

The 4700 aB.P. volcanic signal detected in Vostok BH8 ice core, Antarctica

The detailed electrical conductivity measuremerit （ECM）, trace chemical compositions and microparticles concentration analysis are performed for BH8 ice core from the depth of 126.0m to 130.0m at Vostok Station. At depth 128.7m, a volcanic signal 4726 a B.P. is detected. The volcanic sulphate flux is 95.8 kg·km^-2, sulphate peak concentration 1352.8 ng·g^-1, duration time about 10.1 years, comparable with some well-known volcanic events. The results indicate that it seems to be a relatively large scale, long lasting volcanic signal with farther volcanic origin.     

The Price of Success: Sociologist Harry Alpert,the NSF's First Social Science Policy Architect

Harry Alpert (1912–1977), the US sociologist, is best-known for his directorship of the National Science Foundation's social science programme in the 1950s. This study extends our understanding of Alpert in two main ways: first, by examining the earlier development of his views and career. Beginning with his 1939 biography of Emile Durkheim, we explore the early development of Alpert's views about foundational questions concerning the scientific status of sociology and social science more generally, proper social science methodology, the practical value of social science, the academic institutionalisation of sociology, and the unity-of-science viewpoint. Second, this paper illuminates Alpert's complex involvement with certain tensions in mid-century US social science that were themselves linked to major transformations in national science policy, public patronage, and unequal relations between the social and natural sciences. We show that Alpert's views about the intellectual foundations, practical relevance, and institutional standing of the social sciences were, in some important respects, at odds with his NSF policy work. Although remembered as a quantitative evangelist and advocate for the unity-of-science viewpoint, Alpert was in fact an urbane critic of natural-science envy, social scientific certainty, and what he saw as excessive devotion to quantitative methods.     

An equivalent 1D nanochannel model to describe ion transport in multilayered graphene membranes

Multilayered graphene-based membranes are promising for a variety of applications related to ion or molecule transport, such as energy storage and water treatment. However, the complex three-dimensional cascading nanoslit-like structure embedded in the membrane makes it difficult to interpret and rationalize experimental results, quantitatively compare with the traditional membrane systems, and quantitatively design new membrane structures. In this paper, systematic numerical simulations were performed to establish an equivalent onedimensional(1 D) nanochannel model to represent the structure of multilayered graphene membranes. We have established a quantitative relationship between effective diffusion length Leffand cross-section area Aeffof the1 D model and our recently developed two dimensional(2 D) representative microstructure for graphene membranes. We find that only in the cases of a relatively large lateral size L( ~100 nm) and a small slit size h( 2 nm), the effective diffusion length Leffand Aeffcan be calculated by an over-simplified but often used model. Otherwise, they show complex dependence on all three structural parameters of the 2 D structural model.Our equivalent 1 D nano-channel model can reproduce experimental results very well except for h 0.5 nm. The discrepancy could be attributed to the anomalous behaviour of molecules under nano-confinement that is not considered in our simulations. This model can also be extended to multilayered membranes assembled by other2 D materials.     

The GUS reporter gene system

The GUS reporter gene system is already a powerful tool for the assessment of gene activity in transgenic plants. Further developments may lead to routine in vivo analysis and fusion genetics.