204 research outputs found
Bank Default Risk Propagation along Supply Chains: Evidence from the U.K.
How does banks’ default risk affect the probability of default of non-financial businesses? The literature has addressed this question by focusing on the direct effects on the banks’ corporate customers – demonstrating the existence of bank-induced incre
A Review of Copy Number Variants in Inherited Neuropathies
The rapid development in the last 10-15 years of microarray technologies, such as oligonucleotide
array Comparative Genomic Hybridization (CGH) and Single Nucleotide Polymorphisms
(SNP) genotyping array, has improved the identification of fine chromosomal structural variants, ranging
in length from kilobases (kb) to megabases (Mb), as an important cause of genetic differences
among healthy individuals and also as disease-susceptibility and/or disease-causing factors. Structural
genomic variations due to unbalanced chromosomal rearrangements are known as Copy-Number
Variants (CNVs) and these include variably sized deletions, duplications, triplications and translocations.
CNVs can significantly contribute to human diseases and rearrangements in several dosagesensitive
genes have been identified as an important causative mechanism in the molecular aetiology
of Charcot-Marie-Tooth (CMT) disease and of several CMT-related disorders, a group of inherited
neuropathies with a broad range of clinical phenotypes, inheritance patterns and causative genes. Duplications
or deletions of the dosage-sensitive gene PMP22 mapped to chromosome 17p12 represent
the most frequent causes of CMT type 1A and Hereditary Neuropathy with liability to Pressure Palsies
(HNPP), respectively. Additionally, CNVs have been identified in patients with other CMT types
(e.g., CMT1X, CMT1B, CMT4D) and different hereditary poly- (e.g., giant axonal neuropathy) and
focal- (e.g., hereditary neuralgic amyotrophy) neuropathies, supporting the notion of hereditary peripheral
nerve diseases as possible genomic disorders and making crucial the identification of fine
chromosomal rearrangements in the molecular assessment of such patients. Notably, the application of
advanced computational tools in the analysis of Next-Generation Sequencing (NGS) data has emerged
in recent years as a powerful technique for identifying a genome-wide scale complex structural variants
(e.g., as the ones resulted from balanced rearrangements) and also smaller pathogenic (intragenic)
CNVs that often remain beyond the detection limit of most conventional genomic microarray analyses;
in the context of inherited neuropathies where more than 70 disease-causing genes have been
identified to date, NGS and particularly Whole-Genome Sequencing (WGS) hold the potential to reduce
the number of genomic assays required per patient to reach a diagnosis, analyzing with a single
test all the Single Nucleotide Variants (SNVs) and CNVs in the genes possibly implicated in this
heterogeneous group of disorders
Enhancement of photoelectrochemical and optical characteristics using a TiO2 nanoparticles interlayer in MEH-PPV heterojunction devices
International audienc
Severe axonal neuropathy is a late manifestation of SPG11
Complex hereditary spastic paraplegia (HSP) is a clinically heterogeneous group of disorders usually inherited in an autosomal recessive manner. In the past, complex recessive spastic paraplegias have been frequently associated with SPG11 mutations but also with defects in SPG15, SPG7 and a handful of other rare genes. Pleiotropy exists in HSP genes, exemplified in the recent association of SPG11 mutations with CMT2. In this study, we performed whole exome sequence analysis and identified two siblings with novel compound heterozygous frameshift SPG11 mutations. The mutations segregated with disease were not present in control databases and analysis of skin fibroblast derived mRNA indicated that the SPG11 truncated mRNA species were not degraded significantly by non-sense mediated mRNA decay. These siblings had severe early-onset spastic paraplegia but later in their disease developed severe axonal neuropathy, neuropathic pain and blue/black foot discolouration likely caused by a combination of the severe neuropathy with autonomic dysfunction and peripheral oedema. We also identified a similar late-onset axonal neuropathy in a Cypriot SPG11 family. Although neuropathy is occasionally present in SPG11, in our SPG11 patients reported here it was particularly severe, highlighting the association of axonal neuropathy with SPG11 and the late manifestation of axonal peripheral nerve damage
Adaptive regulation of riboflavin transport in heart: effect of dietary riboflavin deficiency in cardiovascular pathogenesis
Deficiency or defective transport of riboflavin (RF) is known to cause neurological disorders, cataract, cardiovascular anomalies, and various cancers by altering the biochemical pathways. Mechanisms and regulation of RF uptake process is well characterized in the cells of intestine, liver, kidney, and brain origin, while very little is known in the heart. Hence, we aimed to understand the expression and regulation of RF transporters (rRFVT-1 and rRFVT-2) in cardiomyocytes during RF deficiency and also investigated the role of RF in ischemic cardiomyopathy and mitochondrial dysfunction in vivo. Riboflavin uptake assay revealed that RF transport in H9C2 is (1) significantly higher at pH 7.5, (2) independent of Na+ and (3) saturable with a Km of 3.746 µM. For in vivo studies, male Wistar rats (110–130 g) were provided riboflavin deficient food containing 0.3 ± 0.05 mg/kg riboflavin for 7 weeks, which resulted in over expression of both RFVTs in mRNA and protein level. RF deprivation resulted in the accumulation of cardiac biomarkers, histopathological abnormalities, and reduced mitochondrial membrane potential which evidenced the key role of RF in the development of cardiovascular pathogenesis. Besides, adaptive regulation of RF transporters upon RF deficiency signifies that RFVTs can be considered as an effective delivery system for drugs against cardiac diseases
Analysis of the prion protein gene in multiple system atrophy
Neurodegenerative diseases are a very diverse group of disorders but they share some common mechanisms such as abnormally misfolded proteins with prion-like propagation and aggregation. Creutzfeldt-Jakob disease (CJD) is the most prevalent prion disease in humans. In the sporadic form of CJD the only known risk factor is the codon 129 polymorphism. Recent reports suggested that α-synuclein in multiple system atrophy (MSA) has similar pathogenic mechanisms as the prion protein. Here we present 1 Italian family with MSA and prion disease. Also, cases of concurrent MSA and prion pathology in the same individual or family suggest the possibility of molecular interaction between prion protein and α-synuclein in the process of protein accumulation and neurodegeneration, warranting further investigations. We assessed the PRNP gene by whole-exome sequencing in 264 pathologically confirmed MSA cases and 462 healthy controls to determine whether the 2 diseases share similar risk factors. We then analyzed codon 129 polymorphism by Sanger sequencing and compared with previously published results in sporadic CJD. Homozygosity at codon 129 was present in 50% of pathologically confirmed MSA cases and in 58% of normal controls (odds ratio, 0.7 (95% confidence interval of 0.5-0.9)) compared with 88.2% in sporadic CJD. Our data show that the homozygous state of position 129 in the PRNP is not a risk factor for MSA. No other variants in the PRNP gene were associated with increased risk for MSA
Adrenaline induces calcium signal in astrocytes and vasoconstriction via activation of monoamine oxidase
Adrenaline or epinephrine is a hormone playing an important role in physiology. It is produced de-novo in the brain in very small amounts compared to other catecholamines, including noradrenaline. Although the effects of adrenaline on neurons have been extensively studied, much less is known about the action of this hormone on astrocytes. Here, we studied the effects of adrenaline on astrocytes in primary co-culture of neurons and astrocytes. Application of adrenaline induced calcium signal in both neurons and astrocytes, but only in neurons this effect was dependent on α- and β-receptor antagonists. The effects of adrenaline on astrocytes were less dependent on adrenoreceptors: the antagonist carvedilol had only moderate effect on the calcium signal and the agonist of adrenoreceptors methoxamine induced a signal only in small proportion of the cells. We found that adrenaline in astrocytes activates phospholipase C and subsequent release of calcium from the endoplasmic reticulum. Calcium signal in astrocytes is initiated by the metabolism of adrenaline by the monoamine oxidase (MAO), which activates reactive oxygen species production and induces lipid peroxidation. Inhibitor of MAO selegiline inhibited both adrenaline-induced calcium signal in astrocytes and the vasoconstriction that indicates an important role for monoamine oxidase in adrenaline-induced signalling and function
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