Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI

Business Models and E-Services: an Ontological Approach in a Cross-border Environment

Monograph's chapter

Alteration of NF-κB activity leads to mitochondrial apoptosis after infection with pathological prion protein

Nuclear factor kappa B (NF-κB) is a key regulator of the immune response, but in almost the same manner it is involved in induction of inflammation, proliferation and regulation of apoptosis. In the central nervous system activated NF-κB plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-κB is well characterized, there is poor knowledge on the role of NF-κB in prion disease. We found binding but no transcriptional activity of the transcription factor in vitro. Characterizing the mechanism of cell death after infection with pathological prion protein increased caspase-9 and caspase-3 activity was detected and the lack of NF-κB activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-κB after prion infection of Nfkb1–/–, Nfkb2–/– and Bcl3–/– mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-κB2- and Bcl-3-deficient mice, which is in line with a reduced neuroprotective activity in prion infection. Based on our findings, we propose a model whereby the alteration of NF-κB activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis

The role of tenascin-C in tissue injury and tumorigenesis

The extracellular matrix molecule tenascin-C is highly expressed during embryonic development, tissue repair and in pathological situations such as chronic inflammation and cancer. Tenascin-C interacts with several other extracellular matrix molecules and cell-surface receptors, thus affecting tissue architecture, tissue resilience and cell responses. Tenascin-C modulates cell migration, proliferation and cellular signaling through induction of pro-inflammatory cytokines and oncogenic signaling molecules amongst other mechanisms. Given the causal role of inflammation in cancer progression, common mechanisms might be controlled by tenascin-C during both events. Drugs targeting the expression or function of tenascin-C or the tenascin-C protein itself are currently being developed and some drugs have already reached advanced clinical trials. This generates hope that increased knowledge about tenascin-C will further improve management of diseases with high tenascin-C expression such as chronic inflammation, heart failure, artheriosclerosis and cancer

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Roles of professionals within the early intervention system : gaps and overlaps in roles of service providers working with children ages birth to 3

Includes bibliographical references (pages [35]-36)M.A. (Master of Arts

The structural basis for processing of unnatural base pairs by DNA polymerases

Unnatural base pairs (UBPs) greatly increase the diversity of DNA and RNA which furthers a broad range of molecular biological and biotechnological approaches. Different candidates have been developed whereby alternative hydrogen-bonding patterns and hydrophobic and packing interactions turned out to be the most promising base-pairing concepts to date. Key in many applications is the highly efficient and selective acceptance of artificial base pairs by DNA polymerases that enables amplification of the modified DNA. In this Review we highlight computational as well as experimental studies that were performed to characterize the pairing behavior of UBPs in free duplex DNA or bound to the active site of KlenTaq DNA polymerase. The structural studies on the one hand elucidate how base pairs lacking hydrogen bonds are accepted by these enzymes and on the other hand highlight the influence of one or several consecutive UBPs on the structure of a DNA double helix. Understanding these concepts facilitates optimization of future UBPs for the manifold fields of applications.publishe

Effects of professional development in language support for ECEC professionals and teachers

In Kindertageseinrichtungen und Schulen wird dem pädagogischen Personal in Bezug auf Sprachförderung ein hoher Qualifizierungsbedarf attestiert; zugleich gibt es wenig gesichertes empirisches Wissen über die Wirkungen entsprechender Fortbildungen. Das Fortbildungsangebot und die Teilnehmenden sind heterogen. Um die Heterogenität der Teilnehmenden zu entschlüsseln, wurden im BiSS-Evaluationsprojekt „SPRÜNGE“ (Sprachförderung im Übergang Kindergarten – Grundschule evaluieren) auf Grundlage einer Typenbildung von N = 27 Fach- und Lehrkräften Unterschiede in ihren Sprachförderkompetenzen und im Fortbildungsbesuch empirisch-quantitativ mittels des Online-Tests SprachKoPF überprüft und für zwei Sprachfördertypen ihre handlungsleitenden Orientierungen in Bezug auf die Wirkungen von Fortbildungen rekonstruiert. Bei diesen beiden, stark fortgebildeten Sprachfördertypen konnten differenzierbare Deutungen zu den Wirkungen von Fortbildungen herausgearbeitet werden, wobei einerseits eine stärkere Kita-Orientierung und andererseits eine stärkere Schulorientierung als (implizite) Referenz deutlich wird. Zudem ließen sich Gelingensbedingungen von Fortbildungen wie „Praxisrelevanz“, die als allgemeingültig angenommen werden, typenspezifisch ausdifferenzieren. Mit der multiperspektivischen Untersuchung der differentiellen Wirkungen von Fortbildungen leistet das Projekt einen explorativen Beitrag zu einer quantitativ und qualitativ ausgerichteten Wirkungsforschung am Übergang Kita-Grundschule.In kindergarten and school, pedagogical staff is considered to have a high need for qualification in language support; at the same time, there is hardly any empirical knowledge about the effectiveness of such professional development. Both the professional development offered and the participants are heterogeneous. In order to decipher the heterogeneity of the participants, the BiSS evaluation project “SPRÜNGE” used the online test SprachKoPF to empirically-quantitatively examine differences in their language support skills and in their attendance at professional development on the basis of a typology of N = 27 ECEC staff and teachers. Second, for two language support types, their action-guiding orientations regarding the effects of professional development were reconstructed. In the case of these two highly trained language support types, differentiable interpretations with regard to the effects of professional development could be worked out, with a stronger kindergarten orientation on the one hand and a stronger school orientation on the other as an (implicit) reference. In addition, conditions for the success of professional development, such as “practical relevance”, which are assumed to be generally valid, can be differentiated according to type. With the multi-perspectival investigation of the differential effects of professional development, the project makes an explorative contribution to quantitative and qualitative impact research at the transition from kindergarten to primary school