Contact guidance enhances the quality of a tissue engineered corneal stroma

Corneal stroma is a very complex structure, composed of 200 lamellae of oriented collagen fibers. This highly complex nature of cornea is known to be important for its transparency and mechanical integrity. Thus, an artificial cornea design has to take into account this complex structure. In this study, behavior of human corneal keratocytes on collagen films patterned with parallel channels was investigated. Keratocytes proliferated well on films and reached confluency after 7 days in the incubation medium. Nearly all of the cells responded to the patterns and were aligned in contrast to the cells on unpatterned surfaces. Collagen type I and keratan sulfate secreted by keratocytes on patterned films appeared to be aligned in the direction of the patterns. The films showed an intermediate degradation over the course of a month. On the whole, transparency of the films increased with degradation and decreased by the presence of the cells. The decrease was, however, low and transparency level was maintained on the patterned films while on the unpatterned films a sharp decrease in transparency was followed by an improvement. This was due to the more organized distribution of cells and the oriented secretion of extracellular matrix molecules on patterned collagen films. Thus, these results suggest that application of contact guidance in cornea tissue engineering may facilitate the remodeling process, hence decrease the rehabilitation period. © 2007 Wiley Periodicals, Inc

Mechanistic studies of the modulation of cleavage activity of topoisomerase I by DNA adducts of mono- and bi-functional PtII complexes

Using electrophoresis and replication mapping, we show that the presence of DNA adducts of bifunctional antitumor cisplatin or monodentate [PtCl(dien)]Cl (dien = diethylenetriamine) in the substrate DNA inhibits eukaryotic topoisomerase 1 (top1) action, the adducts of cisplatin being more effective. The presence of camptothecin in the samples of platinated DNA markedly enhances effects of Pt–DNA adducts on top1 activity. Interestingly, the effects of Pt–DNA adducts on the catalytic activity of top1 in the presence of camptothecin differ depending on the sequence context. A multiple metallation of the short nucleotide sequences on the scissile strand, immediately downstream of the cleavage site impedes the cleavage by top1. On the other hand, DNA cleavage by top1 at some cleavage sites which were not platinated in their close proximity is notably enhanced as a consequence of global platination of DNA. We suggest that this enhancement of DNA cleavage by top1 may consist in its inability to bind to other cleavage sites platinated in their close neighborhood; thus, more molecules of top1 may become available for cleavage at the sites where top1 normally cleaves and where platination does not interfere

Explicit Orbit Classification of Reducible Jordan Algebras and Freudenthal Triple Systems

We determine explicit orbit representatives of reducible Jordan algebras and of their corresponding Freudenthal triple systems. This work has direct application to the classification of extremal black hole solutions of N = 2, 4 locally supersymmetric theories of gravity coupled to an arbitrary number of Abelian vector multiplets in D = 4, 5 space-time dimensions.Comment: 18 pages. Updated to match published versio

Chiral unitary approach to S-wave meson baryon scattering in the strangeness S=0 sector

We study the S-wave interaction of mesons with baryons in the strangeness S=0 sector in a coupled channel unitary approach. The basic dynamics is drawn from the lowest order meson baryon chiral Lagrangians. Small modifications inspired by models with explicit vector meson exchange in the t-channel are also considered. In addition the pi pi N channel is included and shown to have an important repercussion in the results, particularly in the isospin 3/2 sector.Comment: 23 pages, LaTeX, 21 figure

Differential cross section measurement of eta photoproduction on the proton from threshold to 1100 MeV

The differential cross section for the reaction p(gamma, eta p) has been measured from threshold to 1100 MeV photon laboratory energy. For the first time, the region of the S11(1535) resonance is fully covered in a photoproduction experiment and allows a precise extraction of its parameters at the photon point. Above 1000 MeV, S-wave dominance vanishes while a P-wave contribution is observed whose nature will have to be clarified. These high precision data together with the already measured beam asymmetry data will provide stringent constraints on the extraction of new couplings of baryon resonances to the eta meson.Comment: 10 pages, 5 figures, submitted to Phys. Letters B. Typos corrected. Some more information on the S11(1535) parameter

Patterns of Hybrid Loss of Imprinting Reveal Tissue- and Cluster-Specific Regulation

Background: Crosses between natural populations of two species of deer mice, Peromyscus maniculatus (BW), and P. polionotus (PO), produce parent-of-origin effects on growth and development. BW females mated to PO males (bw6po) produce growth-retarded but otherwise healthy offspring. In contrast, PO females mated to BW males (PO6BW) produce overgrown and severely defective offspring. The hybrid phenotypes are pronounced in the placenta and include PO6BW conceptuses which lack embryonic structures. Evidence to date links variation in control of genomic imprinting with the hybrid defects, particularly in the PO6BW offspring. Establishment of genomic imprinting is typically mediated by gametic DNA methylation at sites known as gDMRs. However, imprinted gene clusters vary in their regulation by gDMR sequences. Methodology/Principal Findings: Here we further assess imprinted gene expression and DNA methylation at different cluster types in order to discern patterns. These data reveal PO6BW misexpression at the Kcnq1ot1 and Peg3 clusters, both of which lose ICR methylation in placental tissues. In contrast, some embryonic transcripts (Peg10, Kcnq1ot1) reactivated the silenced allele with little or no loss of DNA methylation. Hybrid brains also display different patterns of imprinting perturbations. Several cluster pairs thought to use analogous regulatory mechanisms are differentially affected in the hybrids. Conclusions/Significance: These data reinforce the hypothesis that placental and somatic gene regulation differs significantly, as does that between imprinted gene clusters and between species. That such epigenetic regulatory variatio

Beyond the marrow:insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors

Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM development (HR = 2.4, p = 0.011) using data from a large CoMMpass dataset. We identified downregulation of CXCR4 and enhanced cell proliferation, along with reduced expression of therapeutic targets (CD38, SLAMF7, GPRC5D, FCRH5), potentially explaining diminished efficacy of immunotherapy. Conversely, we identified significantly upregulated EZH2 and CD70 as potential future therapeutic options. For the first time, we report on the tumor microenvironment of EMM, revealing CD8+ T cells and NK cells as predominant immune effector cells using single-cell sequencing. Finally, this is the first longitudinal study in EMM revealing the molecular changes from the time of diagnosis to EMM relapse.</p

Vector meson production and nucleon resonance analysis in a coupled-channel approach for energies m_N < sqrt(s) < 2 GeV I: pion-induced results and hadronic parameters

We present a nucleon resonance analysis by simultaneously considering all pion- and photon-induced experimental data on the final states gamma N, pi N, 2 pi N, eta N, K Lambda, K Sigma, and omega N for energies from the nucleon mass up to sqrt(s) = 2 GeV. In this analysis we find strong evidence for the resonances P_{31}(1750), P_{13}(1900), P_{33}(1920), and D_{13}(1950). The omega N production mechanism is dominated by large P_{11}(1710) and P_{13}(1900) contributions. In this first part, we present the results of the pion-induced reactions and the extracted resonance and background properties with emphasis on the difference between global and purely hadronic fits.Comment: 54 pages, 26 figures, discussion extended, typos corrected, references updated, to appear in Phys. Rev.

Genetic risk for schizophrenia and psychosis in Alzheimer disease

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD

D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile

Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients