Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency

Previous work has demonstrated that the function of extrahepatic cytochrome P450 CYP1A1 is dependent on the availability of heme. CYP1A1 is involved in the activation of polyaromatic hydrocarbons. In the present study we used a transgenic mouse model with chronic impairment of heme synthesis - female porphobilinogen deaminase-deficient (PBGD-/-) mice - to investigate the effects of limited heme in untreated and β-naphthoflavone (β-NF)-treated animals on the function of CYP1A1 in brain. The heme content of PBGD-/- mice was diminished in the liver and brain compared to wild types. In the liver, partial heme deficiency led to less potent induction of CYP1A1 mRNA after β-NF treatment. In the brain, CYP1A1 protein was detected not only at the endoplasmic reticulum (ER), but also in the cytosol of PBGD-/- mice. Furthermore, 7-deethylation of ethoxyresorufin, an indicator of CYP1A1 metabolic activity, could be restored by heme in cytosol of PBGD-/- mouse brain. Independent of the genotype, we found only one cyp1a1 gene product, indicating that the cytosolic appearance of CYP1A1 most likely did not originate from mutant alleles. We conclude that heme deficiency in the brain leads to incomplete heme saturation of CYP1A1, which causes its improper incorporation into the ER membrane and persistence in the cytosol. It is suggested that diseases caused by relative heme deficiency, such as hepatic porphyrias, may lead to impaired hemoprotein function in brai

Non-Hausdorff Symmetries of C*-algebras

Symmetry groups or groupoids of C*-algebras associated to non-Hausdorff spaces are often non-Hausdorff as well. We describe such symmetries using crossed modules of groupoids. We define actions of crossed modules on C*-algebras and crossed products for such actions, and justify these definitions with some basic general results and examples.Comment: very minor changes. To appear in Math. An

Localisation and colocalisation of KK-theory at sets of primes

Given a set of prime numbers S, we localise equivariant bivariant Kasparov theory at S and compare this localisation with Kasparov theory by an exact sequence. More precisely, we define the localisation at S to be KK^G(A,B) tensored with the ring of S-integers Z[S^-1]. We study the properties of the resulting variants of Kasparov theory.Comment: 16 page

Equivariant Lefschetz maps for simplicial complexes and smooth manifolds

Let X be a locally compact space with a continuous proper action of a locally compact group G. Assuming that X satisfies a certain kind of duality in equivariant bivariant Kasparov theory, we can enrich the classical construction of Lefschetz numbers to equivariant K-homology classes. We compute the Lefschetz invariants for self-maps of finite-dimensional simplicial complexes and of self-maps of smooth manifolds. The resulting invariants are independent of the extra structure used to compute them. Since smooth manifolds can be triangulated, we get two formulas for the same Lefschetz invariant in these cases. The resulting identity is closely related to the equivariant Lefschetz Fixed Point Theorem of Luck and Rosenberg.Comment: Minor revisions, affecting some theorem number

The Baum-Connes Conjecture via Localisation of Categories

We redefine the Baum-Connes assembly map using simplicial approximation in the equivariant Kasparov category. This new interpretation is ideal for studying functorial properties and gives analogues of the assembly maps for all equivariant homology theories, not just for the K-theory of the crossed product. We extend many of the known techniques for proving the Baum-Connes conjecture to this more general setting

Murine Features of Neurogenesis in the Human Hippocampus across the Lifespan from 0 to 100 Years

BACKGROUND: Essentially all knowledge about adult hippocampal neurogenesis in humans still comes from one seminal study by Eriksson et al. in 1998, although several others have provided suggestive findings. But only little information has been available in how far the situation in animal models would reflect the conditions in the adult and aging human brain. We therefore here mapped numerous features associated with adult neurogenesis in rodents in samples from human hippocampus across the entire lifespan. Such data would not offer proof of adult neurogenesis in humans, because it is based on the assumption that humans and rodents share marker expression patterns in adult neurogenesis. Nevertheless, together the data provide valuable information at least about the presence of markers, for which a link to adult neurogenesis might more reasonably be assumed than for others, in the adult human brain and their change with increasing age. METHODS AND FINDINGS: In rodents, doublecortin (DCX) is transiently expressed during adult neurogenesis and within the neurogenic niche of the dentate gyrus can serve as a valuable marker. We validated DCX as marker of granule cell development in fetal human tissue and used DCX expression as seed to examine the dentate gyrus for additional neurogenesis-associated features across the lifespan. We studied 54 individuals and detected DCX expression between birth and 100 years of age. Caveats for post-mortem analyses of human tissues apply but all samples were free of signs of ischemia and activated caspase-3. Fourteen markers related to adult hippocampal neurogenesis in rodents were assessed in DCX-positive cells. Total numbers of DCX expressing cells declined exponentially with increasing age, and co-expression of DCX with the other markers decreased. This argued against a non-specific re-appearance of immature markers in specimen from old brains. Early postnatally all 14 markers were co-expressed in DCX-positive cells. Until 30 to 40 years of age, for example, an overlap of DCX with Ki67, Mcm2, Sox2, Nestin, Prox1, PSA-NCAM, Calretinin, NeuN, and others was detected, and some key markers (Nestin, Sox2, Prox1) remained co-expressed into oldest age. CONCLUSIONS: Our data suggest that in the adult human hippocampus neurogenesis-associated features that have been identified in rodents show patterns, as well as qualitative and quantitative age-related changes, that are similar to the course of adult hippocampal neurogenesis in rodents. Consequently, although further validation as well as the application of independent methodology (e.g. electron microscopy and cell culture work) is desirable, our data will help to devise the framework for specific research on cellular plasticity in the aging human hippocampus

Multilevel Contracts for Trusted Components

This article contributes to the design and the verification of trusted components and services. The contracts are declined at several levels to cover then different facets, such as component consistency, compatibility or correctness. The article introduces multilevel contracts and a design+verification process for handling and analysing these contracts in component models. The approach is implemented with the COSTO platform that supports the Kmelia component model. A case study illustrates the overall approach.Comment: In Proceedings WCSI 2010, arXiv:1010.233

The numerical renormalization group method for quantum impurity systems

In the beginning of the 1970's, Wilson developed the concept of a fully non-perturbative renormalization group transformation. Applied to the Kondo problem, this numerical renormalization group method (NRG) gave for the first time the full crossover from the high-temperature phase of a free spin to the low-temperature phase of a completely screened spin. The NRG has been later generalized to a variety of quantum impurity problems. The purpose of this review is to give a brief introduction to the NRG method including some guidelines of how to calculate physical quantities, and to survey the development of the NRG method and its various applications over the last 30 years. These applications include variants of the original Kondo problem such as the non-Fermi liquid behavior in the two-channel Kondo model, dissipative quantum systems such as the spin-boson model, and lattice systems in the framework of the dynamical mean field theory.Comment: 55 pages, 27 figures, submitted to Rev. Mod. Phy

Constraints on the nearby exoplanet Eps Ind Ab from deep near/mid-infrared imaging limits

© ESO 2021. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1051/0004-6361/202140730The past decade has seen increasing efforts in detecting and characterising exoplanets by high contrast imaging in the near/mid-infrared, which is the optimal wavelength domain for studying old, cold planets. In this work, we present deep AO imaging observations of the nearby Sun-like star $\epsilon$ Ind A with NaCo ($L^{\prime}$) and NEAR (10-12.5 microns) instruments at VLT, in an attempt to directly detect its planetary companion whose presence has been indicated from radial velocity (RV) and astrometric trends. We derive brightness limits from the non-detection of the companion with both instruments, and interpret the corresponding sensitivity in mass based on both cloudy and cloud-free atmospheric and evolutionary models. For an assumed age of 5 Gyr for the system, we get detectable mass limits as low as 4.4 $M_{\rm J}$ in NaCo $L^{\prime}$ and 8.2 $M_{\rm J}$ in NEAR bands at 1.5\arcsec from the central star. If the age assumed is 1 Gyr, we reach even lower mass limits of 1.7 $M_{\rm J}$ in NaCo $L^{\prime}$ and 3.5 $M_{\rm J}$ in NEAR bands, at the same separation. However, based on the dynamical mass estimate (3.25 $M_{\rm J}$) and ephemerides from astrometry and RV, we find that the non-detection of the planet in these observations puts a constraint of 2 Gyr on the lower age limit of the system. NaCo offers the highest sensitivity to the planetary companion in these observations, but the combination with the NEAR wavelength range adds a considerable degree of robustness against uncertainties in the atmospheric models. This underlines the benefits of including a broad set of wavelengths for detection and characterisation of exoplanets in direct imaging studies.Peer reviewe

Graph-based description of tertiary lymphoid organs at single-cell level

Our aim is to complement observer-dependent approaches of immune cell evaluation in microscopy images with reproducible measures for spatial composition of lymphocytic infiltrates. Analyzing such patterns of inflammation is becoming increasingly important for therapeutic decisions, for example in transplantation medicine or cancer immunology. We developed a graph-based assessment of lymphocyte clustering in full whole slide images. Based on cell coordinates detected in the full image, a Delaunay triangulation and distance criteria are used to build neighborhood graphs. The composition of nodes and edges are used for classification, e.g. using a support vector machine. We describe the variability of these infiltrates on CD3/CD20 duplex staining in renal biopsies of long-term functioning allografts, in breast cancer cases, and in lung tissue of cystic fibrosis patients. The assessment includes automated cell detection, identification of regions of interest, and classification of lymphocytic clusters according to their degree of organization. We propose a neighborhood feature which considers the occurrence of edges with a certain type in the graph to distinguish between phenotypically different immune infiltrates. Our work addresses a medical need and provides a scalable framework that can be easily adjusted to the requirements of different research questions