Neuronal Intermediate Filaments in Amyotrophic Lateral Sclerosis

Neuronal intermediate filaments (NIFs) are the most abundant cytoskeletal element in mature neurons. They are composed of different protein subunits encoded by separate genes such as neurofilament light chain (NFL), neurofilament medium chain (NFM), neurofilament heavy chain (NFH), ɑ‐internexin and peripherin. NIFs are dynamic structures playing important functions in cell architecture and differentiation, interactions between proteins or subcellular organelles, and in axonal calibre determination and myelination. Consequently, their presence modulates electrophysiological properties of axons. NIFs have long been assigned a role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Indeed, accumulation and abnormal phosphorylation of NIF subunits in motor neuron are one of the major pathological features in both sporadic and familial forms of the disease. Moreover, mutations in the NFH and peripherin genes and elevated cerebrospinal fluid NIF levels reported in ALS cases, associated with studies in transgenic mice, provided the evidence that primary defects in NIFs could be causative for motor neuron disease. However, the processes leading to the NIF abnormalities and the links to the pathogenesis of ALS remain unclear, leaving a challenging open field for further investigations in this highly disabilitating disease. Here, we review the main characteristics of these NIFs and their involvement in the pathomechanisms of ALS

The uneven weight distribution between predators and prey: Comparing gut fill between terrestrial herbivores and carnivores

The general observation that secondary consumers ingest highly digestible food and have simple short guts and small abdominal cavities intuitively results in the assumption that mammalian carnivores carry less digesta in their gut compared to herbivores. Due to logistic constraints, this assumption has not been tested quantitatively so far. In this contribution, we estimated the dry matter gut contents (DMC) for 25 species of the order Carnivora (including two strictly herbivorous ones, the giant and the red panda) using the physical ‘Occupancy Principle’, based on a literature data collection on dry matter intake (DMI), apparent dry matter digestibility (aD DM) and retention time (RT), and compared the results to an existing collection for herbivores. Scaling exponents with body mass (BM) for both carnivores and herbivores were in the same range with DMI ~ BM0.75; aD DM ~ BM0; RT ~ BM0.11 and DMC ~ BM0.88. The trophic level (carnivore vs herbivore) significantly affected all digestive physiology parameters except for RT. Numerically, the carnivore DMI level reached 77%, the RT 32% and DMC only 29% of the corresponding herbivore values, whereas the herbivore aD DM only reached 82% of that of carnivores. Thus, we quantitatively show that carnivores carry less inert mass or gut content compared to herbivores, which putatively benefits them in predator-prey interactions and might have contributed to the evolution towards unguligradism in herbivores. As expected, the two panda species appeared as outliers in the dataset with low aD DM and RT for a herbivore but extremely high DMI values, resulting in DMC in the lower part of the herbivore range. Whereas the difference in DMI and DMC scaling in herbivores might allow larger herbivores to compensate for lower diet quality by ingesting more, this difference may allow larger carnivores not to go for less digestible prey parts, but mainly to increase meal intervals, i.e. not having to hunt on a daily basis

Metabo-lipidomics of Fibroblasts and Mitochondrial-Endoplasmic Reticulum Extracts from ALS Patients Shows Alterations in Purine, Pyrimidine, Energetic, and Phospholipid Metabolisms

Amyotrophic lateral sclerosis (ALS) is characterized by a wide metabolic remodeling, as shown by recent metabolomics and lipidomics studies performed in samples from patient cohorts and experimental animal models. Here, we explored the metabolome and lipidome of fibroblasts from sporadic ALS patients (n = 13) comparatively to age- and sex-matched controls (n = 11), and the subcellular fraction containing the mitochondria and endoplasmic reticulum (mito-ER), given that mitochondrial dysfunctions and ER stress are important features of ALS patho-mechanisms. We also assessed the mitochondrial oxidative respiration and the mitochondrial genomic (mtDNA) sequence, although without yielding significant differences. Compared to controls, ALS fibroblasts did not exhibit a mitochondrial respiration defect nor an increased proportion of mitochondrial DNA mutations. In addition, non-targeted metabolomics and lipidomics analyses identified 124 and 127 metabolites, and 328 and 220 lipids in whole cells and the mito-ER fractions, respectively, along with partial least-squares-discriminant analysis (PLS-DA) models being systematically highly predictive of the disease. The most discriminant metabolomic features were the alteration of purine, pyrimidine, and energetic metabolisms, suggestive of oxidative stress and of pro-inflammatory status. The most important lipidomic feature in the mito-ER fraction was the disturbance of phosphatidylcholine PC (36:4p) levels, which we had previously reported in the cerebrospinal fluid of ALS patients and in the brain from an ALS mouse model. Thus, our results reveal that fibroblasts from sporadic ALS patients share common metabolic remodeling, consistent with other metabolic studies performed in ALS, opening perspectives for further exploration in this cellular model in ALS

The role of the basic state in the ENSO-monsoon relationship and implications for predictability

The impact of systematic model errors on a coupled simulation of the Asian Summer monsoon and its interannual variability is studied. Although the mean monsoon climate is reasonably well captured, systematic errors in the equatorial Pacific mean that the monsoon-ENSO teleconnection is rather poorly represented in the GCM. A system of ocean-surface heat flux adjustments is implemented in the tropical Pacific and Indian Oceans in order to reduce the systematic biases. In this version of the GCM, the monsoon-ENSO teleconnection is better simulated, particularly the lag-lead relationships in which weak monsoons precede the peak of El Nino. In part this is related to changes in the characteristics of El Nino, which has a more realistic evolution in its developing phase. A stronger ENSO amplitude in the new model version also feeds back to further strengthen the teleconnection. These results have important implications for the use of coupled models for seasonal prediction of systems such as the monsoon, and suggest that some form of flux correction may have significant benefits where model systematic error compromises important teleconnections and modes of interannual variability

Abundant electrical myotonia and left ventricular noncompaction: Unusual features of Danon disease due to a novel mutation in LAMP2 gene

International audienc

Current mechanistic insights into the CCCP-induced cell survival response

The ring-substituted derivatives of carbonyl cyanide phenylhydrazone, CCCP and FCCP, are routinely used for the analysis of the mitochondrial function in living cells, tissues, and isolated mitochondrial preparations. CCCP and FCCP are now being increasingly used for investigating the mechanisms of autophagy by inducing mitochondrial degradation through the disruption of the mitochondrial membrane potential (ΔΨm). Sustained perturbation of ΔΨm, which is normally tightly controlled to ensure cell proliferation and survival, triggers various stress pathways as part of the cellular adaptive response, the main components of which are mitophagy and autophagy. We here review current mechanistic insights into the induction of mitophagy and autophagy by CCCP and FCCP. In particular, we analyze the cellular modifications produced by the activation of two major pathways involving the signaling of the nuclear factor erythroid 2-related factor 2 (Nrf2) and the transcription factor EB (TFEB), and discuss the contribution of these pathways to the integrated cellular stress response

The extreme physical properties of the CoRoT-7b super-Earth

International audience► Here, we discuss the extreme physical properties possible for the first characterized rocky super-Earth, CoRoT-7b ( = 1.58 , = 5.7 ). ► We make the working hypothesis that the planet is rocky with no volatiles in its atmosphere, and derive the physical properties that result. ► The dayside is very hot (2500 K at the sub-stellar point) while the nightside is very cold (∼ 50 K). The sub-stellar point is as hot as the tungsten filament of an incandescent bulb, resulting in the melting and distillation of silicate rocks and the formation of a lava ocean. ► These possible features of CoRoT-7b should be common to many small and hot planets, including Kepler-10b. They define a new class of objects that we propose to name ''Lava-ocean planets''

Primary fibroblasts derived from sporadic amyotrophic lateral sclerosis patients do not show ALS cytological lesions

OBJECTIVE: Sporadic amyotrophic lateral sclerosis (sALS) is a fatal neurodegenerative disorder affecting upper and lower motor neurons. In view of the heterogeneous presentation of the disease, one of the current challenges is to identify diagnostic and prognostic markers in order to diagnose sALS at early stage and to stratify patients in trials. In this study, we sought to identify cytological hallmarks of sALS in patient-derived fibroblasts with the aim of finding new clinical-related markers of the disease. METHODS: Primary fibroblasts were prospectively collected from patients affected with classical, rapid, and slow forms of sALS. TDP-43 localization, cytoskeleton distribution, mitochondrial network architecture, and stress granules formation were analyzed using 3D fluorescence microscopy and new super-resolution imaging. Intracellular reactive oxygen species (ROS) production was assessed using live imaging techniques. RESULTS: Six sALS patients (two classical, two rapid, and two slow) and four age-matched controls were included. No difference in fibroblasts cell growth, morphology, and distribution was noticed. The analysis of TDP-43 did not reveal any mislocalization nor aggregation of the protein. The cytoskeleton was harmoniously distributed among the cells, without any inclusion noticed, and no difference was observed regarding the mitochondrial network architecture. Basal ROS production and response to induced stress were similar among patient and control fibroblasts. CONCLUSIONS: ALS cytological lesions are absent in patient-derived fibroblasts and thus cannot contribute as diagnostic nor prognostic markers of the disease

The PreVOCA experiment: modeling the lower troposphere in the Southeast Pacific

The Preliminary VOCALS Model Assessment (PreVOCA) aims to assess contemporary atmospheric modeling of the subtropical South East Pacific, with a particular focus on the clouds and the marine boundary layer (MBL). Models results from fourteen modeling centers were collected including operational forecast models, regional models, and global climate models for the month of October 2006. Forecast models and global climate models produced daily forecasts, while most regional models were run continuously during the study period, initialized and forced at the boundaries with global model analyses. Results are compared in the region from 40° S to the equator and from 110° W to 70° W, corresponding to the Pacific coast of South America. Mean-monthly model surface winds agree well with QuikSCAT observed winds and models agree fairly well on mean weak large-scale subsidence in the region next to the coast. However they have greatly differing geographic patterns of mean cloud fraction with only a few models agreeing well with MODIS observations. Most models also underestimate the MBL depth by several hundred meters in the eastern part of the study region. The diurnal cycle of liquid water path is underestimated by most models at the 85° W 20° S stratus buoy site compared with satellite, consistent with previous modeling studies. The low cloud fraction is also underestimated during all parts of the diurnal cycle compared to surface-based climatologies. Most models qualitatively capture the MBL deepening around 15 October 2006 at the stratus buoy, associated with colder air at 700 hPa

Carbon stable isotope analysis of cereal remains as a way to reconstruct water availability: preliminary results

Reconstructing past water availability, both as rainfall and irrigation, is important to answer questions about the way society reacts to climate and its changes and the role of irrigation in the development of social complexity. Carbon stable isotope analysis of archaeobotanical remains is a potentially valuable method for reconstructing water availability. To further define the relationship between water availability and plant carbon isotope composition and to set up baseline values for the Southern Levant, grains of experimentally grown barley and sorghum were studied. The cereal crops were grown at three stations under five different irrigation regimes in Jordan. Results indicate that a positive but weak relationship exists between irrigation regime and total water input of barley grains, but no relationship was found for sorghum. The relationship for barley is site-specific and inter-annual variation was present at Deir ‘Alla, but not at Ramtha and Khirbet as-Samra