TCR-engineered T cells: a model of inducible TCR expression to dissect the interrelationship between two TCRs

TCR gene-modified T cells for adoptive therapy simultaneously express the transgenic (tg) TCR and the endogenous TCR which might lead to mispaired TCRs with harmful unknown specificity and to a reduced function of TCR-tg T cells. We generated dual TCR T cells in two settings in which either TCR was constitutively expressed by a retroviral promoter while the second TCR expression was regulable by a tet-on system. Constitutively expressed TCR molecules were reduced on the cell surface depending on the induced TCR expression leading to strongly hampered function. Besides that, using fluorescence resonance energy transfer (FRET) we detected mispaired TCR dimers and different pairing behaviors of individual TCR chains with a mutual influence on TCR chain expression. The loss of function and mispairing could not be avoided by changing the TCR expression level or by introduction of an additional cysteine bridge. However, in polyclonal T cells, optimized TCR formats (cysteineization, codon optimization) enhanced correct pairing and function. We conclude from our data that (i) the level of mispairing depends on the individual TCRs and is not reduced by increasing the level of one TCR, and (ii) modifications (cysteineization, codon optimization) improve correct pairing but do not completely exclude mispairing (cysteineization)

TCR-engineered T cells: A model of inducible TCR expression to dissect the interrelationship between two TCRs

TCR gene modified T cells for adoptive therapy simultaneously express the Tg TCR and the endogenous TCR, which might lead to mispaired TCRs with harmful unknown specificity and to a reduced function of TCR-Tg T cells. We generated dual TCR T cells in two settings in which either TCR was constitutively expressed by a retroviral promoter while the second TCR expression was regulable by a Tet-on system. Constitutively expressed TCR molecules were reduced on the cell surface depending on the induced TCR expression leading to strongly hampered function. Besides that, using fluorescence resonance energy transfer we detected mispaired TCR dimers and different pairing behaviors of individual TCR chains with a mutual influence on TCR chain expression. The loss of function and mispairing could not be avoided by changing the TCR expression level or by introduction of an additional cysteine bridge. However, in polyclonal T cells, optimized TCR formats (cysteineization, codon optimization) enhanced correct pairing and function. We conclude from our data that (i) the level of mispairing depends on the individual TCRs and is not reduced by increasing the level of one TCR, and (ii) modifications (cysteineization, codon optimization) improve correct pairing but do not completely exclude mispairing (cysteineization)

The role of parental investments for cognitive and noncognitive skill formation : evidence for the first 11 years of life

This paper examines the impact of parental investments on the development of cognitive, mental and emotional skills during childhood using data from a longitudinal study, the Mannheim Study of Children at Risk, starting at birth. Our work offers three important innovations. First, we use reliable measures of the child’s cognitive, mental and emotional skills as well as accurate measures of parental investment. Second, we estimate latent factor models to account for unobserved characteristics of children. Third, we examine the skill development for girls and boys separately, as well as for children who were born with either organic or psychosocial risk. We find a decreasing impact of parental investments on cognitive and mental skills, while emotional skills seem to be unaffected by parental investment throughout childhood. Thus, initial inequality persists during childhood. Since families are the main sources of education during the first years of life, our results have important implications for the quality of the parent-child relationship

Hybrid RANS/LES Study of the Development of an Airfoil-Generated Vortex

In this work we investigate the requirements to simulate a generic, but still realistic lateral vortex that is generated by a flapping airfoil. Different modelling approaches, RANS and hybrid RANS/LES, as well as different strategies to design the grid are compared. The aim is to obtain a setup that allows a reasonable representation of the main vortex characteristics and to find a suitable strategy to model the generation and transport of the vortex within the framework of a scale resolving simulation. The results from the simulations are assessed using experimental data

Olefinic isothiocyanates and iminodithiocarbonates from the liverwort Corsinia coriandrina

The chemical investigation of the liverwort Corsinia coriandrina, Corsiniaceae, resulted in the isolation, structure elucidation and synthesis of four sulfur- and nitrogen-containing compounds. The coriandrins were identified as (Z)- and (E)-2-(4-methoxyphenyl)ethenyl isothiocyanates, while the O-methyltridentatols contain the corresponding (Z)- and (E)S,S-dimethyl 2-(4-methoxyphenyl)ethenyliminodithiocarbonate structures. ((c) Wiley-VCH Verlag GmbH T Co. KGaA, 69451 Weinheim, Germany, 2005)

Sesquiterpene constituents in Petasites hybridus

The essential oil of the rhizomes of Petasites hybridus (Asteraceae) was investigated by gas chromatography, mass spectrometry, 1- and 2-dimensional NMR techniques and chemical correlations. Two new sesquiterpene hydrocarbons, petasitene and pethybrene, could be identified. Petasitene is the parent sesquiterpene hydrocarbon to the known norsesquiterpene albene. The absolute configuration of petasitene could be assigned by conversion of natural albene to petasitene by partial synthesis. Pethybrene is a tricyclic sesquiterpene hydrocarbon, which rearranges to the structurally related alpha-isocomene under acidic conditions. Several sesquiterpenes were isolated from the hydrodistillation products of Petasites hybridus and investigated by spectroscopic methods and chemical correlations. (C) 2002 Elsevier Science Ltd. All rights reserved

Spirocyclopropane-type sesquiterpene hydrocarbons from Schinus terebinthifolius Raddi

The essential oil of Schinus terebinthifolius fruits was reinvestigated using GC and GC-MS techniques. Apart from several known compounds three sesquiterpene hydrocarbons with a carbon skeleton exhibiting the rare spiro(cyclopropane) moiety could be isolated by a combination of column chromatography and GLC. Structure assignments were carried out by NMR spectroscopy. These natural products are 9-spiro(cyclopropa)-4,4,8-trimethyl-2-methylenbicyclo[4.3.0]non-1(6)-ene (terepanene), 9-spiro(cyclopropa)-2,4,4,8-tetramethylbicyclo[4.3.0]nona-1,5-diene (teredenene), and (6R*,8R*)-9-spiro(cyclopropa)-2,4,4,8-tetramethylbicyclo[4.3.0]non-1-ene (terebinthene). (C) 2010 Elsevier Ltd. All rights reserved