Atp7a-regulated enzyme metalation and trafficking in the menkes disease puzzle

Copper is vital for numerous cellular functions affecting all tissues and organ systems in the body. The copper pump, ATP7A is critical for whole-body, cellular, and subcellular copper homeostasis, and dysfunction due to genetic defects results in Menkes disease. ATP7A dysfunction leads to copper deficiency in nervous tissue, liver, and blood but accumulation in other tissues. Site-specific cellular deficiencies of copper lead to loss of function of copper-dependent enzymes in all tissues, and the range of Menkes disease pathologies observed can now be explained in full by lack of specific copper enzymes. New pathways involving copper activated lysosomal and steroid sulfatases link patient symptoms usually related to other inborn errors of metabolism to Menkes disease. Additionally, new roles for lysyl oxidase in activation of molecules necessary for the innate immune system, and novel adapter molecules that play roles in ERGIC trafficking of brain receptors and other proteins, are emerging. We here summarize the current knowledge of the roles of copper enzyme function in Menkes disease, with a focus on ATP7A-mediated enzyme metalation in the secretory pathway. By establishing mechanistic relationships between copper-dependent cellular processes and Menkes disease symptoms in patients will not only increase understanding of copper biology but will also allow for the identification of an expanding range of copper-dependent enzymes and pathways. This will raise awareness of rare patient symptoms, and thus aid in early diagnosis of Menkes disease patients

Polyglutamine and Polyalanine Tracts Are Enriched in Transcription Factors of Plants

Polyglutamine (polyQ) tracts have been studied extensively for their roles in a number of human diseases such as Huntington\u27s or different Ataxias. However, it has also been recognized that polyQ tracts are abundant and may have important functional and evolutionary roles. Especially the association of polyQ and also polyalanine (polyA) tracts with transcription factors and their activation activity has been noted. While a number of examples for this association have been found for proteins from opisthokonts (animals and fungi), only a few studies exist for polyQ and polyA stretches in plants, and systematic investigations of the significance of these repeats in plant transcription factors are scarce. Here, we analyze the abundance and length of polyQ and polyA stretches in the conceptual proteomes of six plant species and examine the connection between polyQ and polyA tracts and transcription factors of the repeat-containing proteins. We show that there is an association of polyQ stretches with transcription factors in plants. In grasses, transcription factors are also significantly enriched in polyA stretches. While there is variation in the abundance, length, and association with certain functions of polyQ and polyA stretches between different species, no general differences in the evolution of these repeats could be observed between plants and opisthokonts

Critical Issues: Defining and Debunking Misconceptions in Health, Education, Criminal Justice, and Social Work/Social Services

The University of Houston Downtown Committee for the Journal of Family Strengths introduces Volume 18, Issue 1: Critical Issues: Defining and Debunking Misconceptions in Health, Education, Criminal Justice, and Social Work/Social Services

Exon duplications in the ATP7A gene: Frequency and Transcriptional Behaviour

<p>Abstract</p> <p>Background</p> <p>Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the <it>ATP7A </it>gene. Thirty-three Menkes patients in whom no mutation had been detected with standard diagnostic tools were screened for exon duplications in the <it>ATP7A </it>gene.</p> <p>Methods</p> <p>The <it>ATP7A </it>gene was screened for exon duplications using multiplex ligation-dependent probe amplification (MLPA). The expression level of <it>ATP7A </it>was investigated by real-time PCR and detailed analysis of the <it>ATP7A </it>mRNA was performed by RT-PCR followed by sequencing. In order to investigate whether the identified duplicated fragments originated from a single or from two different X-chromosomes, polymorphic markers located in the duplicated fragments were analyzed.</p> <p>Results</p> <p>Partial <it>ATP7A </it>gene duplication was identified in 20 unrelated patients including one patient with Occipital Horn Syndrome (OHS). Duplications in the <it>ATP7A </it>gene are estimated from our material to be the disease causing mutation in 4% of the Menkes disease patients. The duplicated regions consist of between 2 and 15 exons. In at least one of the cases, the duplication was due to an intra-chromosomal event. Characterization of the <it>ATP7A </it>mRNA transcripts in 11 patients revealed that the duplications were organized in tandem, in a head to tail direction. The reading frame was disrupted in all 11 cases. Small amounts of wild-type transcript were found in all patients as a result of exon-skipping events occurring in the duplicated regions. In the OHS patient with a duplication of exon 3 and 4, the duplicated out-of-frame transcript coexists with an almost equally represented wild-type transcript, presumably leading to the milder phenotype.</p> <p>Conclusions</p> <p>In general, patients with duplication of only 2 exons exhibit a milder phenotype as compared to patients with duplication of more than 2 exons. This study provides insight into exon duplications in the <it>ATP7A </it>gene.</p

Inwieweit können klassische Stabilitätsparameter durch rheologische Kenngrößen beschrieben werden und wie können diese vorhergesagt werden?

Ein grundlegendes Verständnis von Bodenverformungen auf der Meso- bzw. Makroskala setzt ein Verständnis für die auf der Mikroskala stattfindenden Prozesse voraus, weshalb die bodenkundliche Rheologie zunehmend an Bedeutung gewinnt. Mit Hilfe von deformationsgesteuerten Amplitudentests wurden die auf der Mikroskala relevanten, stabilitätsbeeinflussenden bodenchemischen Parameter bestimmt und Pedotransferfunktionen zur Ableitung der rheologischen Stabilitätskenngröße Integral z entwickelt. Darüber hinaus werden Lösungsansätze zur Extrapolation zwischen Mikro- und Mesoskala unter Berücksichtigung der Gefügecharakteristika aufgezeigt

"Eventless" InsP 3 -dependent SR-Ca 2+ Release Affecting Atrial Ca 2+ Sparks

Augmented inositol 1,4,5-trisphosphate receptor (InsP3R) function has been linked to a variety of cardiac pathologies, including cardiac arrhythmia. The contribution of inositol 1,4,5-trisphosphate-induced Ca2+ release (IP3ICR) in excitation-contraction coupling (ECC) under physiological conditions, as well as under cellular remodelling, remains controversial. Here we test the hypothesis that local IP3ICR directly affects ryanodine receptor (RyR) function and subsequent Ca2+-induced Ca2+ release in atrial myocytes. IP3ICR was evoked by UV-flash photolysis of caged InsP3 under whole-cell configuration of the voltage-clamp technique in atrial myocytes isolated from C57/BL6 mice. Photolytic release of InsP3 was accompanied by a significant increase in the Ca2+ release event frequency (4.14±0.72 vs. 6.20±0.76 events (100 μm)−1 s−1). These individual photolytically triggered Ca2+ release events were identified as Ca2+ sparks, which originated from RyR openings. This was verified by Ca2+ spark analysis and pharmacological separation between RyR and InsP3R-dependent sarcoplasmic reticulum (SR)-Ca2+ release (2-aminoethoxydiphenyl borate, xestospongin C, tetracaine). Significant SR-Ca2+ flux but eventless SR-Ca2+ release through InsP3R were characterized using SR-Ca2+ leak/SR-Ca2+ load measurements. These results strongly support the idea that IP3ICR can effectively modulate RyR openings and Ca2+ spark probability. We conclude that eventless and highly efficient InsP3-dependent SR-Ca2+ flux is the main mechanism of functional cross-talk between InsP3Rs and RyRs, which may be an important factor in the modulation of ECC sensitivity

Die rheologische Charakterisierung tidebeeinflusster Böden mittels Daten aus der Mikropenetrometrie

Mit Hilfe rheologischer Tests lassen sich mikrostrukturelle Prozesse in Böden und deren Einflussfaktoren relativ einfach und schnell beschreiben und quantifizieren. Dabei wird das visko-elastische Verhalten innerhalb eines Bodenmaterials im Wesentlichen von Textur, Wassergehalt und Trockenrohdichte bestimmt. Allerdings können rheologische Ergebnisse durchaus kontraintuitiv sein, was ihre bodenkundliche Interpretation schwierig machen kann. Da auch der Eindringwiderstand von Böden als Summenparameter u.a. von Wassergehalt, Textur und Trockenrohdichte beeinflusst wird, ist untersucht worden, ob vom Eindringwiderstand unmittelbar auf rheologische Eigenschaften geschlossen werden kann und vice versa. Die Analysen an Bodenmaterial von drei Standorten der Unteren Elbeniederung zeigten, dass sowohl der maximale Eindringwiderstand als auch die Schubspannung bei Erreichen des Fließpunktes bei Trockenrohdichten (ρt) ≥ 1,2 g cm-3 durch Entwässerung auf Feldkapazität und durch Erhöhung der ρt zum Teil signifikant zunehmen. Außerdem konnte ohne weitere Differenzierung nach Matrixpotenzial oder Trockenrohdichte eine logarithmische Beziehung zwischen Eindringwiderstand und Schubspannung bei Erreichen des Fließpunktes hergestellt werden, so dass von gemessenen Eindringwiderständen Rückschlüsse auf die rheologischen Eigenschaften von Böden gezogen werden können. Dies erleichtert die bodenkundliche Interpretation der rheologischen Ergebnisse und bestärkt die Praxisrelevanz rheologischer Analysen