C9orf72-mediated ALS and FTD: multiple pathways to disease

The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression

Miocene-Pliocene age of cave Snežna Jama na Raduhi, Southern Alps, Slovenia

Snežna jama cave is 1,600 m long horizontal cave at about 1,500 m a.s.l. in Raduha Massif (Kamnik-Savinja Alps) rich in cave deposits (both allogenic sediments and massive flowstones). The cave size, shape and deposits show (1) formation of the cave in different conditions, and (2) its substantial age. A 4.8 m deep pit was excavated in allogenic sediments. Samples were taken both for palaeomagnetic analysis and palaeontological screening. Sediments consist of rhythmically arranged layers deposited in phreatic conditions. Fragments of rodent teeth and a well-preserved molar of genus Baranomys were identified. Fossil remains indicate mammalian zone MN 16 and MN 14. A high-resolution palaeomagnetic analysis revealed total of 3 principal normal polarized and 2 principal reverse polarized magnetozones. If we accept the palaeontologic calibration, the deposition took place within Gauss and Gilbert chrons, from about 2.6 to more than 5 Ma. Long sedimentation period is in concordance with the cave rocky relief that shows phreatic and epiphreatic morphology and predates the main uplift of the area for about 900 m

Groundwater flow near the Shoal Site, Sand Springs Range, Nevada: Impact of density-driven flow

The nature of flow from a highland recharge area in a mountain range in north-central Nevada to discharge areas on either side of the range is evaluated to refine a conceptual model of contaminant transport from an underground nuclear test conducted beneath the range. The test, known as the Shoal event, was conducted in 1963 in granitic rocks of the Sand Springs Range. Sparse hydraulic head measurements from the early 1960s suggest flow from the shot location to the east to Fairview Valley, while hydrochemistry supports flow to salt pans in Fourmile Flat to the west. Chemical and isotopic data collected from water samples and during well-logging arc best explained by a reflux brine system on the west side of the Sand Springs Range, rather than a typical local flow system where all flow occurs from recharge areas in the highlands to a central discharge area in a playa. Instead, dense saline water from the playa is apparently being driven toward the range by density contrasts. The data collected between the range and Fourmile Flat suggest the groundwater is a mixture of younger, fresher recharge water with older brine. Chemical contrasts between groundwater in the east and west valleys reflect the absence of re-flux water in Fairview Valley because the regional discharge area is distant and thus there is no accumulation of salts. The refluxing hydraulic system probably developed after the end of the last pluvial period and differences between the location of the groundwater divide based on hydraulic and chemical indicators could reflect movement of the divide as the groundwater system adjusts to the new reflux condition

Invertebrate fossils from cave sediments: a new proxy for pre-Quaternary paleoenvironments

Five samples of clastic sediments from interior cave facies taken in three Slovenian relic caves (Trhlovca, Račiška pečina, and a cave in Črnotiče Quarry, Classical Karst, SW Slovenia) provided invertebrate fossil remains. Most of them belong to Oribatida but sparse individuals of Cladocera and insects were also identified. They represent the first pre-Quaternary invertebrate fossils found in sediments of continental temperate climate. The Pliocene/Pleistocene age of the sediments was determined by paleomagnetic dating chronologically calibrated by micromammal biostratigraphy. Invertebrate fossils could be validated as new proxy for the study of cave sediments due to their suitability for ecological and paleogeographic correlations in caves and outside the caves. They also bring additional information about cave formation and karst hydraulic regime in the area. Although the number of remains was very low, it is evidence that climatic conditions in caves allow a better preservation of fossil remains of some groups as compared to most of the surface habitats. This may open a new direction in the study of cave sediments

Exercise-induced effects on a gym atmosphere

We report results of analysis of a month-long measurement of indoor air and environment quality parameters in one gym during sporting activities such as football, basketball, volleyball, badminton, boxing, and fitness. We have determined an average single person's contribution to the increase of temperature, humidity, and dust concentration in the gym air volume of 12500 m3: during 90-min exercise performed at an average heart rate of 143 ± 10 bpm, a single person evaporated 0.94 kg of water into the air by sweating, contributed 0.03 K to the air temperature rise and added 1.5 μg/m3 and 5 ng/m3 to the indoor concentration of inhalable particles (PM10) and Ca concentration, respectively. As the breathing at the observed exercise intensity was about three times faster with respect to the resting condition and as the exercise-induced PM10 concentration was about two times larger than outdoors, a sportsman in the gym would receive about a sixfold higher dose of PM10 inside than he/she would have received at rest outside.Fil: Žitnik, M.. Institute Jožef Stefan; Eslovenia. University of Ljubljana. Faculty of Mathematics and Physics; EsloveniaFil: Bučar, K.. Institute Jožef Stefan; EsloveniaFil: Hiti, B.. Institute Jožef Stefan; EsloveniaFil: Barba, Ž.. Institute Jožef Stefan; EsloveniaFil: Rupnik, Z.. Institute Jožef Stefan; EsloveniaFil: Založnik, A.. Institute Jožef Stefan; EsloveniaFil: Žitnik, E.. University of Ljubljana. Faculty of Medicine; EsloveniaFil: Rodriguez, Luis Miguel. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Mihevc, I.. University of Ljubljana. Faculty of Electrical Engineering; EsloveniaFil: Žibert, J.. Univerza Na Primorskem.; Esloveni

Vasculocentric Axonal NfH in Small Vessel Disease.

Cerebral small vessel disease (SVD) causes lacunar stroke and vascular cognitive impairment in older people. The pathogenic pathways from vessel pathology to parenchymal damage in SVD are unknown. Neurofilaments are axonal structural proteins. Neurofilament-light (NfL) is an emerging biomarker for neurological disease. Here, we examined the high molecular weight form neurofilament-heavy (NfH) and quantified a characteristic pattern of peri-arterial (vasculocentric) NfH labeling. Subcortical frontal and parietal white matter from young adult controls, aged controls, and older people with SVD or severe Alzheimer disease (n = 52) was immunohistochemically labeled for hyperphosphorylated NfH (pNfH). The extent of pNfH immunolabeling and the degree of vasculocentric axonal pNfH were quantified. Axonal pNfH immunolabeling was sparse in young adults but a common finding in older persons (controls, SVD, or AD). Axonal pNfH was often markedly concentrated around small penetrating arteries. This vasculocentric feature was more common in older people with SVD than in those with severe AD (p = 0.004). We conclude that axonal pNfH is a feature of subcortical white matter in aged brains. Vasculocentric axonal pNfH is a novel parenchymal lesion that is co-located with SVD arteriopathy and could be a consequence of vessel pathology