Abstract Mutations in SPG11 account for the most common form of autosomal recessive hereditary spastic paraplegia (HSP), characterized by a gait disorder associated with various brain alterations. ...Mutations in the same gene are also responsible for rare forms of Charcot-Marie-Tooth (CMT) disease and progressive juvenile-onset amyotrophic lateral sclerosis (ALS). To elucidate the physiopathological mechanisms underlying these human pathologies, we disrupted the Spg11 gene in mice by inserting stop codons in exon 32, mimicking the most frequent mutations found in patients. The Spg11 knockout mouse developed early-onset motor impairment and cognitive deficits. These behavioral deficits were associated with progressive brain atrophy with the loss of neurons in the primary motor cortex, cerebellum and hippocampus, as well as with accumulation of dystrophic axons in the corticospinal tract. Spinal motor neurons also degenerated and this was accompanied by fragmentation of neuromuscular junctions and muscle atrophy. This new Spg11 knockout mouse therefore recapitulates the full range of symptoms associated with SPG11 mutations observed in HSP, ALS and CMT patients. Examination of the cellular alterations observed in this model suggests that the loss of spatacsin leads to the accumulation of lipids in lysosomes by perturbing their clearance from these organelles. Altogether, our results link lysosomal dysfunction and lipid metabolism to neurodegeneration and pinpoint a critical role of spatacsin in lipid turnover.
Preserving water resources and limiting pollution are central environmental issues in the current context of intense anthropization. Among organic pollutants, polycyclic aromatic hydrocarbons (PAHs) ...are commonly analysed as part of water quality assessments. After being emitted into the atmosphere, these persistent organic pollutants are deposited on the continental surface, where they are transported to the aquatic environment by run-off and infiltration waters. Mainly due to anthropogenic emissions, PAHs can therefore be considered as a proxy for human activities. Urban secondary carbonate deposits (USCDs), similar to cave speleothems, have recently been studied for their potential as natural archives of water quality. However, USCDs have never been used to trace water organic pollution and only a few studies on PAHs in speleothems are available. This study focuses on a well-dated USCD covering the last 300 years from the Great Aqueduct of Belleville (north-east of Paris, France). The aim is to determine the nature and variation of trapped organic compounds over time and to discuss their origin, transport, and link with changes in soil occupation due to human activities. To do so, high-resolution solid-phase UV fluorescence imaging analyses were combined with chemical analyses of PAHs and organic carbon carried out on low-weight samples. The results show that PAHs have been present in urban surface water for 300 years. Over the last few decades, a 7-fold increase is observed, accompanied by a change in the pollution source, enriched in high-molecular-weight PAHs, probably linked to urban dust. This study also reveals modes of transport directly influenced by changes in the soil occupation that are very different from those usually encountered in natural environments. This work thus paves the way for a better long-term understanding of the impact of human activity on the transfer of pollutants to sub-surface waters.
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•Speleothems are used to reconstruct surface water PAHs and organic matter content.•PAHs have been present in urban surface water for 300 years.•A major increase and a change of source occurred from the mid-20th century.•Natural organic matter quality varies over time as a result of changes in land use.
The Chauvet cave (UNESCO World Heritage site, France) is located in the Ardèche Gorge, a unique physical and cultural landscape. Its setting within the gorge-overlooking a meander cutoff containing a ...natural arch called the Pont d'Arc-is also remarkable. Investigating possible associations between sites' physical and cultural settings, chronologies of human occupation, and access conditions has become a major theme in archeological research. The present study aims to reconstruct the landscape of the Pont d'Arc meander cutoff during the Upper Paleolithic, when humans were present in the Chauvet Cave. We used uranium-series and electron spin resonance analyses to date the formation of the Pont d'Arc natural arch in the Combe d'Arc meander cutoff, near the Chauvet Cave. Results show that the meander became totally cutoff between 108 and 138 ka (95%). Hence, the natural arch formed before the Upper Paleolithic and the first known human presence in the Chauvet Cave, dated to 37 ka cal BP. These results allowed us to reconstruct a key part of the landscape surrounding the Chauvet Cave when it was being used by Upper-Paleolithic societies.
Cognitive impairment seems to be frequent in intracerebral hemorrhage (ICH) survivors, but remains widely understudied. In this study, we investigated the frequency and patterns of vascular cognitive ...disorders (VCDs) in patients with cerebral amyloid angiopathy (CAA)-related and deep ICH compared to patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD) and healthy controls.
We prospectively recruited 20 patients with CAA-related lobar ICH, 20 with deep ICH, 20 with MCI-AD and 17 healthy controls. Patients with cognitive decline pre-ICH were excluded from the analysis. Each participant underwent a comprehensive neuropsychological assessment and a structural brain MRI. Cognitive assessment was performed at a median delay of 4 months after the acute phase in ICH patients, and more than 6 months after the first complaint in MCI-AD patients. Cognitive profiles were compared between groups. The prevalence of VCDs in the ICH groups was estimated using the recent VASCOG criteria.
"Mild" and "major VCDs" were respectively observed in 87.5% and 2.5% of all ICH patients. Every patient in the CAA group had mild VCDs. No significant difference was observed in cognitive functioning between CAA-related and deep ICH patients. The most impaired process in the CAA group was naming, with a mean (±standard deviation) z-score of -5.2 ±5.5, followed by processing speed (-4.1±3.3), executive functioning (-2.6 ±2.5), memory (-2.4 ±3.5) and attention (-0.9 ±1.3). This cognitive pattern was different from the MCI-AD patients, but the groups were only different in gestural praxis, and by construction, in memory processes.
VCDs are frequent after ICH. Cognitive patterns of patients with deep or CAA-related ICH did not differ, but there was impaired performance in specific domains distinct from the effects of Alzheimer's disease.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01619709.
The endoplasmic reticulum (ER) forms contacts with the lysosomal compartment, regulating lysosome positioning and motility. The movements of lysosomes are controlled by the attachment of molecular ...motors to their surface. However, the molecular mechanisms by which ER controls lysosome dynamics are still elusive. Here, using mouse brain extracts and mouse embryonic fibroblasts, we demonstrate that spatacsin is an ER-resident protein regulating the formation of tubular lysosomes, which are highly dynamic. Screening for spatacsin partners required for tubular lysosome formation showed spatacsin to act by regulating protein degradation. We demonstrate that spatacsin promotes the degradation of its partner AP5Z1, which regulates the relative amount of spastizin and AP5Z1 at lysosomes. Spastizin and AP5Z1 contribute to regulate tubular lysosome formation, as well as their trafficking by interacting with anterograde and retrograde motor proteins, kinesin KIF13A and dynein/dynactin subunit p150Glued, respectively. Ultimately, investigations in polarized mouse cortical neurons in culture demonstrated that spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking. Collectively, our results identify spatacsin as a protein regulating the directionality of lysosome trafficking.
The Gulf of Aqaba transform plate boundary is a source of destructive teleseismic earthquakes. Seismicity is concentrated in the central sub-basin and decreases to both the north and south. Although ...principally a strike-slip plate boundary, the faulted margins of the Gulf display largely dip-slip extensional movement and accompanying footwall uplift. We have constrained rates of this uplift by measurements of elevated Pleistocene coral terraces. In particular the terrace that formed during the last interglacial (~125 ka) is found discontinuously along the length of the Gulf at elevations of 3 to 26 m. Global sea level was ~7 m higher than today at 125 ka indicating net maximum tectonic uplift of ~19 m with an average rate of ~0.015 cm/yr. Uplift has been greatest adjacent to the central sub-basin and like the seismicity decreases to the north and south. We suggest that the present pattern of a seismically active central region linked to more aseismic areas in the north and south has therefore persisted for at least the past 125 kyr. Consequently the potential for future destructive earthquakes in the central Gulf is greater than in the sub-basins to the north and south.
Here, the potential for rapid and accurate U–Th dating technique of marine aragonite skeletons (deep-sea corals,
Lophelia pertusa) and secondary calcite deposits (speleothems and stalagmites) has ...been explored using inductively coupled plasma-quadrupole mass spectrometry (ICP-QMS). The analytical procedure includes a largely simplified chemical separation technique for uranium (U) and thorium (Th) using UTEVA resin. The developed technique permits simultaneous quantification of uranium
238U and thorium
232Th concentrations and their respective isotopic composition, required for U-series disequilibrium dating. Up to 50 U–Th dates per day can be achieved through ICP-QMS with
δ
234U and
δ
230Th reproducibility (2
σ) of 3–4‰ and 1%, respectively. The high sensitivity (>
3.0
×
10
5
cps/ppb) together with low background (<
0.5
cps) on each mass between 228 and 236
amu allowed U–Th dating of ancient deep-water corals (15–260
kyr) and stalagmites (30–85
kyr) at precision levels of less than 2%. Consequently, the combination of simplified chemistry using UTEVA with state-of-the-art ICP-QMS isotopic measurements that do not require a U–Th separation step now provides an extremely rapid and low-cost U-series dating technology. The level of precision is most convenient for numerous geochronological applications, such as the determination of climatic influences on ecosystem development and carbonate precipitation. As a first-example application we present ICP-QMS U–Th dates of North Atlantic deep-water coral fragments retrieved in the southeastern Porcupine Seabight (MD01-2463G, Mound Thérèse), indicating a purely interglacial growth of deep-water corals on so-called carbonate mounds over several climate cycles.
In this article, we propose an approach to reconstruct the timing of human activity at Points Cave, an Upper Paleolithic rock art site located in the middle of the Ardèche River Gorge (Rhône valley, ...France), based on the dating and characterisation of a stalagmite containing soot. Points Cave (‘Grotte aux Points’ in French), also called the ‘little sister of Chauvet Cave’, is famous for its parietal art including a series of dots made of palm prints. A large number of stalagmites formed in the cave during the last 500 ka. However, quarrying of the cave floors during historic times led to the partial destruction of the sedimentary deposits, and many of the stalagmites were found lying on the floor. In particular, one of them (STM‐18‐04) showed the presence of at least four dark layers in cross‐section, which appeared as possible remnants of fire‐related activities in the cave. Despite being present at the same site, no other specific link between STM‐18‐04 and the rock art has been documented. This stalagmite, however, allows us to identify phases of human presence, located at the cave entrance. To do so, we performed a series of analyses to determine its period of growth and the nature of the dark layers that it contains. Scanning electron microscopy and Raman microspectroscopy confirmed that the dark layers include soot, and uranium‐series dating indicated that the fire events occurred, respectively, around 14,200–14,100 and 12,500 years ago, in agreement with the radiocarbon ages of charcoal specimens recovered from the excavation areas nearby. We thus highlighted phases of human activity at the site during the Upper Magdalenian and/or beginning of the Epipaleolithic. By comparing our results with the regional paleoclimatic record, the soot layers trapped in the stalagmite appear to be synchronous with two cold periods, likely the Older Dryas and the Younger Dryas.
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