Comparison of overdeepened structures in formerly glaciated areas of the northern Alpine foreland and northern central Europe

Overdeepened structures occur in formerly and presently glaciated regions around the earth and are usually referred to as overdeepenings or tunnel valleys. The existence of such troughs has been known for more than a century, and they have been attributed to similar formation processes where subglacial meltwater plays a decisive role. This comparison highlights that (foreland) overdeepenings and tunnel valleys further occur in similar dimensions and share many characteristics such as gently sinuous shapes in plan view, undulating long profiles with terminal adverse slopes, and varying cross-sectional morphologies. The best explored examples of overdeepened structures are situated in and around the European Alps and in the central European lowlands. Especially in the vicinity of the Alps, some individual troughs are well explored, allowing for a reconstruction of their infill history, whereas only a few detailed studies, notably such involving long drill core records, have been presented from northern central Europe. We suggest that more such studies could significantly further our understanding of subglacial erosion processes and the regional glaciation histories and aim to promote more intense exchange and discussion between the respective scientific communities.</p

An Editor for Helping Novices to Learn Standard ML

This paper describes a novel editor intended as an aid in the learning of the functional programming language Standard ML. A common technique used by novices is programming by analogy whereby students refer to similar programs that they have written before or have seen in the course literature and use these programs as a basis to write a new program. We present a novel editor for ML which supports programming by analogy by providing a collection of editing commands that transform old programs into new ones. Each command makes changes to an isolated part of the program. These changes are propagated to the rest of the program using analogical techniques. We observed a group of novice ML students to determine the most common programming errors in learning ML and restrict our editor such that it is impossible to commit these errors. In this way, students encounter fewer bugs and so their rate of learning increases. Our editor, C Y NTHIA, has been implemented and is due to be tested on st..

No evidence for substrate accumulation in Parkinson brains with GBA mutations

To establish whether Parkinson's disease (PD) brains previously described to have decreased glucocerebrosidase activity exhibit accumulation of the lysosomal enzyme's substrate, glucosylceramide, or other changes in lipid composition

The meaning of confidence for older people living with frailty

© 2017 THE JOANNA BRIGGS INSTITUTE. EXECUTIVE SUMMARYBackground In many countries, the oldest old (those aged 85 years and older) are now the fastest growing proportion of the total population. This oldest population will increasingly be living with the clinical condition of frailty. Frailty syndromes negatively impact on the person as they do the healthcare systems supporting them. Within healthcare literature "loss of confidence" is occasionally connected to older people living with frailty, but ambiguously described. Understanding the concept of confidence within the context of frailty could inform interventions to meet this growing challenge. Objectives The objective of this systematic review was to explore the meaning of confidence from the perspective of older people living with frailty through synthesis of qualitative evidence to inform healthcare practice, research and policy. Inclusion criteria Types of participants Studies that included frail adults, aged over 60 years, experiencing acute hospital and or post-acute care in the last 12 months. Phenomena of interest The concept of "confidence" and its impact on the physical health and mental well-being of older people living with frailty. Context Studies that reported on the older person's descriptions, understanding and meaning of confidence in relation to their frailty or recent healthcare experiences. Types of studies Studies of qualitative design and method. Search strategy A three step search strategy was used. The search strategy explored published studies and gray literature. Publications in English from the last 20 years were considered for inclusion. Methodological quality All included articles were assessed by two independent reviewers using the Joanna Briggs Institute Qualitative Assessment Review Instrument (JBI-QARI). Data extraction Data were extracted from included studies using the data extraction tools developed by the Joanna Briggs Institute. Data synthesis Qualitative research findings were collated using a meta-aggregative approach and JBI-QARI software. Results Synthesized findings of this review were drawn from just four research studies that met the inclusion criteria. Only six findings contributed to the creation of three categories. These informed a single synthesized finding: Vulnerability, described as a fragile state of well-being that is exposed to the conflicting tensions between physical, emotional and social factors. These tensions have the capability to enhance or Erode this state. Conclusions Assertions that an understanding of the concept confidence has been reached cannot be made. The review data offer limited insight into the concept of confidence being described by the cohort of older people living with frailty

Motesanib inhibits Kit mutations associated with gastrointestinal stromal tumors

<p>Abstract</p> <p>Background</p> <p>Activating mutations in Kit receptor tyrosine kinase or the related platelet-derived growth factor receptor (PDGFR) play an important role in the pathogenesis of gastrointestinal stromal tumors (GIST).</p> <p>Methods</p> <p>This study investigated the activity of motesanib, an inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; PDGFR; and Kit, against primary activating Kit mutants and mutants associated with secondary resistance to imatinib. Single- and double-mutant isoforms of Kit were evaluated for their sensitivity to motesanib or imatinib in autophosphorylation assays and in Ba/F3 cell proliferation assays.</p> <p>Results</p> <p>Motesanib inhibited Kit autophosphorylation in CHO cell lines expressing primary activating mutations in exon 9 (AYins503-504, IC₅₀= 18 nM) and exon 11 (V560 D, IC₅₀= 5 nM; Δ552-559, IC₅₀= 1 nM). Motesanib also demonstrated activity against kinase domain mutations conferring imatinib resistance (V560D/V654A, IC₅₀= 77 nM; V560D/T670I, IC₅₀= 277 nM; Y823 D, IC₅₀= 64 nM) but failed to inhibit the imatinib-resistant D816V mutant (IC₅₀> 3000 nM). Motesanib suppressed the proliferation of Ba/F3 cells expressing Kit mutants with IC₅₀values in good agreement with those observed in the autophosphorylation assays.</p> <p>Conclusions</p> <p>In conclusion, our data suggest that motesanib possesses inhibitory activity against primary Kit mutations and some imatinib-resistant secondary mutations.</p

A Drosophila

Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD. Here we describe a novel Drosophila model of GD that lacks the two fly GBA1 orthologs. This knock-out model recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of glucosylceramide in the fly brain. We also demonstrate a block in autophagy flux in association with reduced lifespan, age-dependent locomotor deficits and accumulation of autophagy substrates in dGBA-deficient fly brains. Furthermore, mechanistic target of rapamycin (mTOR) signaling is downregulated in dGBA knock-out flies, with a concomitant upregulation of Mitf gene expression, the fly ortholog of mammalian TFEB, likely as a compensatory response to the autophagy block. Moreover, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, locomotor, and oxidative stress phenotypes. Together, our results demonstrate that this dGBA1-deficient fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the potential therapeutic benefits of rapamycin in neuronopathic GD. These results also have important implications for the role of autophagy and mTOR signaling in GBA1-associated PD

Ablation of the pro-inflammatory master regulator miR-155 does not mitigate neuroinflammation or neurodegeneration in a vertebrate model of Gaucher's disease

Bi-allelic mutations in the glucocerebrosidase gene (GBA1) cause Gaucher's disease, the most common human lysosomal storage disease. We previously reported a marked increase in miR-155 transcript levels and early microglial activation in a zebrafish model of Gaucher's disease (gba1−/−). miR-155 is a master regulator of inflammation and has been implicated in a wide range of different neurodegenerative disorders. The observed miR-155 upregulation preceded the subsequent development of widespread pathology with marked neuroinflammation, closely resembling human Gaucher's disease pathology. We now report similar increases of miR-155 expression in mammalian models of GD, confirming that miR-155 upregulation is a shared feature in glucocerebrosidase (GCase) deficiency across different species. Using CRISPR/Cas9 mutagenesis we then generated a miR-155 mutant zebrafish line (miR-155−/−) with completely abolished miR-155 expression. Unexpectedly, loss of miR-155 did not mitigate either the reduced lifespan or the robust inflammatory phenotypes of gba1−/− mutant zebrafish. Our data demonstrate that neither neuroinflammation nor disease progression in GCase deficiency are dependent on miR-155 and suggest that miR-155 inhibition would not be a promising therapeutic target in Gaucher's disease

Osteoprotegerin: A Novel Secreted Protein Involved in the Regulation of Bone Density

AbstractA novel secreted glycoprotein that regulates bone resorption has been identified. The protein, termed Osteoprotegerin (OPG), is a novel member of the TNF receptor superfamily. In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation. These same effects are observed upon administration of recombinant OPG into normal mice. In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. Furthermore, OPG blocks ovariectomy-associated bone loss in rats. These data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity

Unexpected phenotypic and molecular changes of combined glucocerebrosidase and acid sphingomyelinase deficiency

Heterozygous variants in GBA1, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD). Moreover, sporadic PD patients also have a substantial reduction of GCase activity. Genetic variants of SMPD1 are also overrepresented in PD cohorts, whereas a reduction of its encoded enzyme (acid sphingomyelinase or ASM) activity is linked to an earlier age of PD onset. Despite both converging on the ceramide pathway, how the combined deficiencies of both enzymes might interact to modulate PD has yet to be explored. Therefore, we created a double-knockout (DKO) zebrafish line for both gba1 (or gba) and smpd1 to test for an interaction in vivo, hypothesising an exacerbation of phenotypes in the DKO line compared to those for single mutants. Unexpectedly, DKO zebrafish maintained conventional swimming behaviour and had normalised neuronal gene expression signatures compared to those of single mutants. We further identified rescue of mitochondrial Complexes I and IV in DKO zebrafish. Despite having an unexpected rescue effect, our results confirm ASM as a modifier of GBA1 deficiency in vivo. Our study highlights the need for validating how genetic variants and enzymatic deficiencies may interact in vivo

Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts

PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy