Experimental and theoretical analysis of hydrogen bonding in two-dimensional chiral 4′,4′′′′-(1,4-Phenylene)bis(2,2′:6′,2″-terpyridine) self-assembled nanoarchitecture

ABSTRACT: The two-dimensional self-assembly of 4′,4⁗- (1,4-phenylene)bis(2,2′:6′,2″-terpyridine) molecules is exper- imentally and theoretically investigated. Scanning tunneling microscopy (STM) shows that this molecular building block forms a compact chiral supramolecular network on graphite at the 1-octanol/graphite interface. The molecules adopt a side- by-side arrangement inside the organic domains. In contrast, the molecules are arranged perpendicularly at the domain boundary. Detailed theoretical analysis based on the density functional theory (DFT) shows that these arrangements are stabilized by double and single hydrogen bonds between pyridine groups. Only the molecular peripheral pyridine groups are involved in the hydrogen bonds stabilizing the long-range ordered molecular nanoarchitectures

Fabrication of a Complex Two-Dimensional Adenine Perylene-3,4,9,10-tetracarboxylic Dianhydride Chiral Nanoarchitecture through Molecular Self-Assembly

International audienceThe two-dimensional self-assembly of a nonsymmetric adenine DNA base mixed with symmetric perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) molecules is investigated using scanning tunneling microscopy (STM). We experimentally observe that these two building blocks form a complex close-packed chiral supramolecular network on Au(111). The unit cell of the adenine PTCDA nanoarchitecture is composed of 14 molecules. The high stability of this structure relies on PTCDA PTCDA and PTCDA adenine hydrogen bonding. Detailed theoretical analysis based on the density functional theory (DFT) calculations reveals that adenine molecules work as a "glue", providing additional strengthening to the PTCDA-based skeleton of this sophisticated multicomponent nanoarchitecture. At the same time, we find that orientation and chirality of adenine molecules across the monolayer is likely to vary, leading to a disorder in the atomistic structure of the entire assembly

Understanding the disorder of the DNA base cytosine on the Au(111) surface

Using ultrahigh vacuum scanning tunneling microscopy (STM) and ab initio density functional theory, we have investigated in detail structures formed by cytosine on the Au(111) surface in clean ultrahigh vacuum conditions. In spite of the fact that the ground state of this DNA base on the surface is shown to be an ordered arrangement of cytosine one-dimensional branches (filaments), this structure has never been observed in our STM experiments. Instead, disordered structures are observed, which can be explained by only a few elementary structural motifs: filaments, five- and sixfold rings, which randomly interconnect with each other forming bent chains, T junctions, and nanocages. The latter may have trapped smaller structures inside. The formation of such an unusual assembly is explained by simple kinetic arguments as a liquid-glass transition. © 2008 American Institute of Physics

NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis

Aims  NOS1AP single-nucleotide polymorphisms (SNPs) correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action-potential duration (APD) to facilitate arrhythmias. Here we test (i) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; (ii) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency. Methods and results  In GP-CMs, NOS1 was inhibited by S-Methyl-L-thiocitrulline acetate (SMTC) or Vinyl-L-NIO hydrochloride (L-VNIO); LQT1 was mimicked by IKs blockade (JNJ303) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harbouring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139), respectively. In GP-CMs, NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay, and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed ‘transient inward current’ events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs. AS) hiPSC-CMs, APD was longer and ICaL larger; NOS1AP and NOS1 expression and co-localization were decreased. Conclusion  The minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes

Generation of two human induced pluripotent stem cell (hiPSC) lines from a long QT syndrome South African founder population.

Abstract We generated PSMi001-A and PSMi008-A hiPSC lines from two individuals belonging to a South African (SA) founder population in which the malignant KCNQ1-A341V mutation cosegregates with the Long QT Syndrome (LQTS) phenotype. PSMi001-A was derived from an asymptomatic KCNQ1-A341V mutation carrier, whereas PSMi008-A was derived from a healthy non-mutation carrier, heterozygous for the minor variant rs16847548 on the NOS1AP gene, associated with QT prolongation in the general population, and with a greater risk for cardiac arrest in the affected members of the SA founder population. The hiPSCs, generated using the Yamanaka's retroviruses, display pluripotent stem cell features and trilineage differentiation potential

Juventud, educación y desigualdad en contextos de vulnerabilidad social : Reflexiones a partir de un proyecto de extensión universitaria

El trabajo presenta una serie de reflexiones sistemáticas, producto de la experiencia de trabajo educativo-comunitario con jóvenes pobres de un barrio periférico platense, encuadrado en un proyecto de extensión universitaria de carácter interdisciplinario. De modo general, se analizan los actuales procesos de socialización de los jóvenes que viven en contextos de vulnerabilidad social y la vinculación de esos procesos con la persistencia de distintas formas de diferenciación social. Al respecto, se plantea la cuestión de la desigualdad en las múltiples formas de "vivir" la pobreza y cuáles son las distintas condiciones que marcan rasgos de diferenciación. En forma particular, se discute sobre la dificultad de "asociar" la educación con la pobreza. Frente al imaginario social en el cual prevalecía la estimación de la educación como un bien de gran importancia, en tanto base para conseguir una posición económica, social y en definitiva, base fundamental para el ejercicio de una ciudadanía plena, en el trabajo concreto con estos jóvenes la educación y particularmente, la escolarización, aparecen como distantes y diluidas. El círculo viciado de desigualdad y falta de oportunidades se completa con la imposibilidad de entrar al mercado laboral y lleva a que estos jóvenes atraviesen su juventud sin historia ni futuro. Nos preguntamos entonces en qué medida, bajo qué condiciones y con qué limitaciones, el desafío que asumimos puede hacer de la educación un puente hacia el desarrollo integral de los sujetos y sus comunidadesFacultad de Humanidades y Ciencias de la Educació

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi003-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1

Abstract We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 51 years old female patient homozygous for the mutation c.535 G>A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1), not associated with deafness. The hiPSCs, generated using four retroviruses each encoding for a reprogramming factor OCT4, SOX2, KLF4, cMYC, are pluripotent and can differentiate into spontaneously beating cardiomyocytes (hiPSC-CMs)

Generation of the human induced pluripotent stem cell (hiPSC) line PSMi006-A from a patient affected by an autosomal recessive form of Long QT Syndrome type 1

We generated human induced pluripotent stem cells (hiPSCs) from dermal fibroblasts of a 40 years old female patient homozygous for the mutation c.535 G > A p.G179S on the KCNQ1 gene, causing a severe form of autosomal recessive Long QT Syndrome type 1 (AR-LQT1). The hiPSCs, generated using classical approach of the four retroviruses enconding the reprogramming factors OCT4, SOX2, cMYC and KLF4, display pluripotent stem cell characteristics, and differentiate into cell lineages of all three germ layers: endoderm, mesoderm and ectoderm. Keywords: Endoderm, Mesoderm, Ectoder

Identification of distinct human invariant natural killer T-cell response phenotypes to alpha-galactosylceramide.

Background Human CD1d-restricted, invariant natural killer T cells (iNKT) are a unique class of T lymphocytes that recognise glycolipid antigens such as α-galactosylceramide (αGalCer) and upon T cell receptor (TCR) activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with αGalCer and interleukin 2 (IL-2) in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon. Results Although all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4) to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population. Conclusion (i) in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii) two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii) donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or with the CD1d ligand utilised, (iv) addition of IL-4 to 'poor' but not 'strong' responder donor cultures significantly increased their in-vitro iNKT cell expansion to αGalCer