Clinical manifestations typical of mitochondrial diseases are often present in various genetic syndromes associated with intellectual disability, a condition leading to deficit in cognitive functions ...and adaptive behaviors. Until now, the causative mechanism leading to intellectual disability is unknown and the progression of the condition is poorly understood. We first report latest advances on genetic and environmental regulation of mitochondrial function and its role in brain development. Starting from the structure, function and regulation of the oxidative phosphorylation apparatus, we review how mitochondrial biogenesis and dynamics play a central role in neurogenesis and neuroplasticity. We then discuss how dysfunctional mitochondria and alterations in reactive oxygen species homeostasis are potentially involved in the pathogenesis of various neurodevelopmental syndromes with a special focus on Down, Rett, Fragile X syndromes and autism spectrum disorders. Finally, we review and suggest novel therapeutic approaches aimed at improving intellectual disability by activating mitochondrial function and reducing oxidative stress to amiliorate the quality of life in the subjects affected.
Between January 2011 and April 2012, the Southeast Crater (SEC) on Mount Etna was the site of 25 episodes of lava fountaining, which led to the construction of a new pyroclastic cone on the eastern ...flank of the SEC. During these episodes lava overflows reached 4.3km in length with an area of 3.19km2 and a volume of 28×106m3. The new cone, informally called New Southeast Crater (NSEC), grew over a pre-existing subsidence depression (pit crater), which had been formed in 2007–2009. The evolution of the NSEC cone was documented from its start by repeated GPS surveys carried out both from a distance and on the cone itself, and by the acquisition of comparison photographs. These surveys reveal that after the cessation of the lava fountains in April 2012, the highest point of the NSEC stood 190m above the pre-cone surface, while the cone volume was about 19×106m3, representing 38% of the total (bulk) volume of the volcanic products including pyroclastic fallout erupted in 2011–2012, which is 50×106m3 (about 33×106m3 dense-rock equivalent). Growth of the new cone took place exclusively during the paroxysmal phases of the lava fountaining episodes, which were nearly always rather brief (on the average 2h). Overall, the paroxysmal phases of all 25 episodes represent 51h of lava fountaining activity — the time needed to build the cone. This is the fastest documented growth of a newborn volcanic cone both in terms of volume and height. Mean effusion rates during the lava fountaining episodes on 20 August 2011 (E11), as well as 12 and 24 April 2012 (E24 and E25) exceeded 500m3/s (with maximum rates of 980m3/s during E11) and thus they are among the highest effusion rates ever recorded at Etna. The composition of the erupted products varies in time, reflecting different rates of magma supply into the shallow feeding system, but without notable effects on the eruptive phenomenology. This implies that the dynamics leading to the episodic lava fountaining was largely, though not entirely, controlled by the repeated formation and collapse of a foam layer in the uppermost portion of the magmatic reservoir of the NSEC.
•The exceptional growth of a new summit scoria cone at Etna volcano.•The summit cone was built up in 51h of lava fountain activity.•A total volume of 50×106m3 was erupted during the 25 paroxysmal episodes.•Paroxysmal activity is driven by the collapse of a foam layer at the top of reservoir.
A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression ...can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson’s disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD.
Hydrogeology of continental southern Italy Pantaleone, De Vita; Vincenzo, Allocca; Fulvio, Celico ...
Journal of maps,
11/13/2018, Letnik:
14, Številka:
2
Journal Article
Recenzirano
Odprti dostop
This paper summarizes the results of a study focused on the hydrogeological characterization and recognition of groundwater resources in continental southern Italy, developed under the European ...INTERREG IIC Programme. The study reconstructed up-to-date scientific knowledge regarding aquifers, groundwater circulation schemes and groundwater resources exploitation in the administrative regions of southern Italy included in the Objective I (Molise, Campania, Basilicata, Puglia and Calabria). In this paper, the methodological approaches applied to synthesize and homogenize bibliographic data collected from the hydrogeological literature and to set a regional hydrogeological mapping are described. Results presented are three hydrogeological maps, 1:300,000 scale, showing hydrogeological units and groundwater flow schemes that are relevant in the regional hydrogeological context, and a brief description of principal types of aquifer and groundwater resources of continental southern Italy.
Functional and structural damages to mitochondria have been critically associated with the pathogenesis of Down syndrome (DS), a human multifactorial disease caused by trisomy of chromosome 21 and ...associated with neurodevelopmental delay, intellectual disability and early neurodegeneration. Recently, we demonstrated in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice -a widely used model of DS - a severe impairment of mitochondrial bioenergetics and biogenesis and reduced NPC proliferation. Here we further investigated the origin of mitochondrial dysfunction in DS and explored a possible mechanistic link among alteration of mitochondrial dynamics, mitochondrial dysfunctions and defective neurogenesis in DS. We first analyzed mitochondrial network and structure by both confocal and transmission electron microscopy as well as by evaluating the levels of key proteins involved in the fission and fusion machinery. We found a fragmentation of mitochondria due to an increase in mitochondrial fission associated with an up-regulation of dynamin-related protein 1 (Drp1), and a decrease in mitochondrial fusion associated with a down-regulation of mitofusin 2 (Mnf2) and increased proteolysis of optic atrophy 1 (Opa1). Next, using the well-known neuroprotective agent mitochondrial division inhibitor 1 (Mdivi-1), we assessed whether the inhibition of mitochondrial fission might reverse alteration of mitochondrial dynamics and mitochondrial dysfunctions in DS neural progenitors cells. We demonstrate here for the first time, that Mdivi-1 restores mitochondrial network organization, mitochondrial energy production and ultimately improves proliferation and neuronal differentiation of NPCs. This research paves the way for the discovery of new therapeutic tools in managing some DS-associated clinical manifestations.
•Mitochondrial network is impaired in neural progenitors cells (NPCs) from Ts65Dn model of DS.•Drp1-dependent mitochondrial fragmentation occurs during Ts65Dn NPCs proliferation.•Mitochondrial division inhibitor 1 (Mdivi-1) restores mitochondrial dynamics in Ts65Dn NPCs.•Mdivi-1 counteracts mitochondrial dysfunctions and in turn promotes in vitro neurogenesis.
Hepatitis E virus (HEV) is an emerging public health issue in industrialized countries. In the last decade the number of autochthonous human infections has increased in Europe. Genotype 3 (HEV-3) is ...typically zoonotic, being foodborne the main route of transmission to humans, and is the most frequently detected in Europe in both humans and animals (mainly pigs and wild boars). In Italy, the first autochthonous human case was reported in 1999; since then, HEV-3 has been widely detected in both humans and animals. Despite the zoonotic characteristic of HEV-3 is well established, the correlation between animal and human strains has been poorly investigated in Italy. In the present study, we compared the subtype distribution of HEV-3 in humans and animals (swine and wild boar) in the period 2000-2018 from Italy. The dataset for this analysis included a total of 96 Italian ORF2 sequences (300 nt long), including both NCBI database-derived (
= 64) and recent sequences (2016-2018,
= 32) obtained in this study. The results show that subtype 3f is the most frequent in humans and pigs, followed by the HEV-3e, HEV-3c and other unassignable HEV-3 strains. Diversely, in wild boar a wider group of HEV-3 subtypes have been detected, including HEV-3a, which has also been detected for the first time in a human patient in Central Italy in 2017, and a wide group of unassignable HEV-3 strains. The phylogenetic analysis including, besides Italian strains, also sequences from other countries retrieved from the NCBI database, indicated that human Italian sequences, in particular those of HEV-3f and HEV-3e, form significant clusters mainly with sequences of animal origin from the same country. Nevertheless, for HEV-3c, rarely detected in Italian pigs, human sequences from Italy are more correlated to human sequences from other European countries. Furthermore, clusters of near-identical human strains identified in a short time interval in Lazio Region (Central Italy) can be recognized in the phylogenetic tree, suggesting that multiple infections originating from a common source have occurred, and confirming the importance of sequencing support to HEV surveillance.
Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association ...study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (
) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (
) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at
,
, and
were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis.
SYNJ1
has been recently identified by two independent groups as the gene defective in a novel form of autosomal recessive, early-onset atypical parkinsonism (PARK20). Two consanguineous families were ...initially reported (one of Sicilian and one of Iranian origins), with the same
SYNJ1
homozygous mutation (c.773G > A, p.Arg258Gln) segregating with a similar phenotype of early-onset parkinsonism and additional atypical features. Here, we report the identification of the same
SYNJ1
homozygous mutation in two affected siblings of a third pedigree. Both siblings had mild developmental psychomotor delay, followed, during the third decade of life, by progressive parkinsonism, dystonia, and mild cognitive impairment. One sibling suffered one episode of generalized seizures. Neuroimaging studies revealed severe nigrostriatal dopaminergic defects, mild striatal and very mild cortical hypometabolism. Treatment with dopamine agonists and anticholinergics resulted in partial improvements. Genetic analyses revealed in both siblings the
SYNJ1
homozygous c.773G > A (p.Arg258Gln) mutation. Haplotype analysis suggests that the mutation has arisen independently in this family and the Sicilian PARK20 family previously described by us, in keeping with the hypothesis of a mutational hot spot. This is the third reported family with autosomal recessive, early-onset parkinsonism associated with the
SYNJ1
p.Arg258Gln mutation. This work contributes to the definition of the genetic and clinical aspects of PARK20. This newly recognized form must be considered in the diagnostic work-up of patients with early-onset atypical parkinsonism. The presence of seizures might represent a red flag to suspect PARK20.
Purpose
Cerebellar ataxias are a large and heterogeneous group of disorders. The evaluation of brain parenchyma via MRI plays a central role in the diagnostic assessment of these conditions, being ...mandatory to exclude the presence of other underlying causes in determining the clinical phenotype. Once these possible causes are ruled out, the diagnosis is usually researched in the wide range of hereditary or sporadic ataxias.
Methods
We here propose a review of the main clinical and conventional imaging findings of the most common hereditary degenerative ataxias, to help neuroradiologists in the evaluation of these patients.
Results
Hereditary degenerative ataxias are all usually characterized from a neuroimaging standpoint by the presence, in almost all cases, of cerebellar atrophy. Nevertheless, a proper assessment of imaging data, extending beyond the mere evaluation of cerebellar atrophy, evaluating also the pattern of volume loss as well as concomitant MRI signs, is crucial to achieve a proper diagnosis.
Conclusion
The integration of typical neuroradiological characteristics, along with patient’s clinical history and laboratory data, could allow the neuroradiologist to identify some conditions and exclude others, addressing the neurologist to the more appropriate genetic testing.
Negative outcomes of ageism in the context of the Canadian labor market are well documented. Older workers remain the target of age-based stereotypes and attitudes on the part of employers. This ...study aims at assessing (1) the extent to which quality and quantity intergroup contacts between younger and older workers as well as knowledge-sharing practices reduce ageist attitudes, in turn (2) how a decrease in ageist attitudes increase the level of workers' engagement and intentions to remain in the organization. Data were collected from 603 Canadian workers (aged 18 to 68 years old) from private and public organizations using an online survey measuring concepts under study. Results of a path analysis suggest that intergroup contacts and knowledge-sharing practices are associated with positive attitudes about older workers. More so, positive attitudes about older workers generate higher levels of work engagement, which in turn are associated with stronger intentions to remain with the organization. However, positive attitudes about older workers had no effect on intentions to remain in the workplace. Results are discussed in light of the intergroup contact theory.
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