Structure-mechanics relationships of collagen fibrils in the Osteogenesis Imperfecta Mouse model

The collagen molecule, which is the building block of collagen fibrils, is a triple helix of two α1(I) chains and one α2(I) chain. However, in the severe mouse model of osteogenesis imperfecta (OIM), deletion of the COL1A2 gene results in the substitution of the α2(I) chain by one α1(I) chain. As this substitution severely impairs the structure and mechanics of collagen-rich tissues at the tissue and organ level, the main aim of this study was to investigate how the structure and mechanics are altered in OIM collagen fibrils. Comparing results from atomic force microscopy imaging and cantilever-based nanoindentation on collagen fibrils from OIM and wild-type (WT) animals, we found a 33% lower indentation modulus in OIM when air-dried (bound water present) and an almost fivefold higher indentation modulus in OIM collagen fibrils when fully hydrated (bound and unbound water present) in phosphate-buffered saline solution (PBS) compared with WT collagen fibrils. These mechanical changes were accompanied by an impaired swelling upon hydration within PBS. Our experimental and atomistic simulation results show how the structure and mechanics are altered at the individual collagen fibril level as a result of collagen gene mutation in OIM. We envisage that the combination of experimental and modelling approaches could allow mechanical phenotyping at the collagen fibril level of virtually any alteration of collagen structure or chemistry.United States. Dept. of Defense. Presidential Early Career Award for Scientists and EngineersNational Science Foundation (U.S.) (CAREER Award

Neuroprotective effects of minocycline on double-stranded RNA-induced neurotoxicity in cultured cortical neurons

1. Minocycline, memantine,and glycoconjugate were assessed for their ability to protect cultured primary cortical neurons against double-stranded RNA-induced neurotoxicity. 2. Minocycline but not memantine or glycoconjugate protected cultured cells and warrants further investigation.published_or_final_versio

Studies of chain substitution caused sub-fibril level differences in stiffness and ultrastructure of wildtype and oim/oim collagen fibers using multifrequency-AFM and molecular modeling.

Molecular alteration in type I collagen, i.e., substituting the α2 chain with α1 chain in tropocollagen molecule, can cause osteogenesis imperfecta (OI), a brittle bone disease, which can be represented by a mouse model (oim/oim). In this work, we use dual-frequency Atomic Force Microscopy (AFM) and incorporated with molecular modeling to quantify the ultrastructure and stiffness of the individual native collagen fibers from wildtype (+/+) and oim/oim diseased mice humeri. Our work presents direct experimental evidences that the +/+ fibers have highly organized and compact ultrastructure and corresponding ordered stiffness distribution. In contrast, oim/oim fibers have ordered but loosely packed ultrastructure with uncorrelated stiffness distribution, as well as local defects. The molecular model also demonstrates the structural and molecular packing differences between +/+ and oim/oim collagens. The molecular mutation significantly altered sub-fibril structure and mechanical property of collagen fibers. This study can give the new insight for the mechanisms and treatment of the brittle bone disease

On the Alexandrov Topology of sub-Lorentzian Manifolds

It is commonly known that in Riemannian and sub-Riemannian Geometry, the metric tensor on a manifold defines a distance function. In Lorentzian Geometry, instead of a distance function it provides causal relations and the Lorentzian time-separation function. Both lead to the definition of the Alexandrov topology, which is linked to the property of strong causality of a space-time. We studied three possible ways to define the Alexandrov topology on sub-Lorentzian manifolds, which usually give different topologies, but agree in the Lorentzian case. We investigated their relationships to each other and the manifold's original topology and their link to causality.Comment: 20 page

Slightly Non-Minimal Dark Matter in PAMELA and ATIC

We present a simple model in which dark matter couples to the standard model through a light scalar intermediary that is itself unstable. We find this model has several notable features, and allows a natural explanation for a surplus of positrons, but no surplus of anti-protons, as has been suggested by early data from PAMELA and ATIC. Moreover, this model yields a very small nucleon coupling, well below the direct detection limits. In this paper we explore the effect of this model in both the early universe and in the galaxy.Comment: 7 pages, 6 figures, v3: updated for new data, added discussion of Ferm

Vascular Proteomics Reveal Novel Proteins Involved in SMC Phenotypic Change: OLR1 as a SMC Receptor Regulating Proliferation and Inflammatory Response

Neointimal hyperplasia of vascular smooth muscle cells (VSMC) plays a critical role in atherosclerotic plaque formation and in-stent restenosis, but the underlying mechanisms are still incompletely understood. We performed a proteomics study to identify novel signaling molecules organizing the VSMC hyperplasia. The differential proteomics analysis in a balloon- induced injury model of rat carotid artery revealed that the expressions of 44 proteins are changed within 3 days post injury. The combination of cellular function assays and a protein network analysis further demonstrated that 27 out of 44 proteins constitute key signaling networks orchestrating the phenotypic change of VSMC from contractile to epithelial-like synthetic. Among the list of proteins, the in vivo validation specifically revealed that six proteins (Rab 15, ITR, OLR1, PDH beta, PTP epsilon) are positive regulators for VSMC hyperplasia. In particular, the OLR1 played dual roles in the VSMC hyperplasia by directly mediating oxidized LDL-induced monocyte adhesion via NF-kappa B activation and by assisting the PDGF-induced proliferation/migration. Importantly, OLR1 and PDGFR beta were associated in close proximity in the plasma membrane. Thus, this study elicits the protein network organizing the phenotypic change of VSMC in the vascular injury diseases such as atherosclerosis and discovers OLR1 as a novel molecular link between the proliferative and inflammatory responses of VSMCs.1133Ysciescopu

Higgs production in CP-violating supersymmetric cascade decays: probing the `open hole' at the Large Hadron Collider

A benchmark CP-violating supersymmetric scenario (known as 'CPX-scenario' in the literature) is studied in the context of the Large Hadron Collider (LHC). It is shown that the LHC, with low to moderate accumulated luminosity, will be able to probe the existing `hole' in the $m_{h_1}$-$\tan\beta$ plane, which cannot be ruled out by the LEP data. We explore the parameter space with cascade decay of third generation squarks and gluino with CP-violating decay branching fractions. We propose a multi-channel analysis to probe this parameter space some of which are background free at an integrated luminosity of 5-10 fb$^{-1}$. Specially, multi-lepton final states (3\l,\, 4\l and like sign di-lepton) are almost background free and have $5\sigma$ reach for the corresponding signals with very early data of LHC for both 14 TeV and 7 TeV center of mass energy.Comment: 24 pages, 9 figures, references added as in the journal versio

Persistence of magnetic field driven by relativistic electrons in a plasma

The onset and evolution of magnetic fields in laboratory and astrophysical plasmas is determined by several mechanisms, including instabilities, dynamo effects and ultra-high energy particle flows through gas, plasma and interstellar-media. These processes are relevant over a wide range of conditions, from cosmic ray acceleration and gamma ray bursts to nuclear fusion in stars. The disparate temporal and spatial scales where each operates can be reconciled by scaling parameters that enable to recreate astrophysical conditions in the laboratory. Here we unveil a new mechanism by which the flow of ultra-energetic particles can strongly magnetize the boundary between the plasma and the non-ionized gas to magnetic fields up to 10-100 Tesla (micro Tesla in astrophysical conditions). The physics is observed from the first time-resolved large scale magnetic field measurements obtained in a laser wakefield accelerator. Particle-in-cell simulations capturing the global plasma and field dynamics over the full plasma length confirm the experimental measurements. These results open new paths for the exploration and modelling of ultra high energy particle driven magnetic field generation in the laboratory

Inactivation of myosin binding protein C homolog in zebrafish as a model for human cardiac hypertrophy and diastolic dysfunction

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