Travelling Together: A Unifying Pathomechanism for ALS

Axonal transport is critical for neuronal homeostasis and relies on motor complexes bound to cargoes via specific adaptors. However, the mechanisms responsible for the spatiotemporal regulation of axonal transport are not completely understood. A recent study by Liao et al. contributes to filling this gap by reporting that RNA granules ‘hitchhike’ on LAMP1-positive organelles using annexin A11 as a tether

Analysis of Signaling Endosome Composition and Dynamics Using SILAC in Embryonic Stem Cell-Derived Neurons

Neurons require efficient transport mechanisms such as fast axonal transport to ensure neuronal homeostasis and survival. Neurotrophins and their receptors are conveyed via fast axonal retrograde transport of signaling endosomes to the soma, where they elicit transcriptional responses. Despite the essential roles of signaling endosomes in neuronal differentiation and survival, little is known about their molecular identity, dynamics, and regulation. Gaining a better mechanistic understanding of these organelles and their kinetics is crucial, given the growing evidence linking vesicular trafficking deficits to neurodegeneration. Here, we exploited an affinity purification strategy using the binding fragment of tetanus neurotoxin (HCT) conjugated to monocrystalline iron oxide nanoparticles (MIONs), which in motor neurons, is transported in the same carriers as neurotrophins and their receptors. To quantitatively assess the molecular composition of HCT-containing signaling endosomes, we have developed a protocol for triple Stable Isotope Labeling with Amino acids in Cell culture (SILAC) in embryonic stem cell-derived motor neurons. After HCT internalization, retrograde carriers were magnetically isolated at different time points and subjected to mass-spectrometry and Gene Ontology analyses. This purification strategy is highly specific, as confirmed by the presence of essential regulators of fast axonal transport in the make-up of these organelles. Our results indicate that signaling endosomes undergo a rapid maturation with the acquisition of late endosome markers following a specific time-dependent kinetics. Strikingly, signaling endosomes are specifically enriched in proteins known to be involved in neurodegenerative diseases and neuroinfection. Moreover, we highlighted the presence of novel components, whose precise temporal recruitment on signaling endosomes might be essential for proper sorting and/or transport of these organelles. This study provides the first quantitative proteomic analysis of signaling endosomes isolated from motor neurons and allows the assembly of a functional map of these axonal carriers involved in long-range neuronal signaling

Growth performance in heavy lambs experimentally treated with 17 β-estradiol

European and Italian legislation have banned use of growth promoters in livestock since 1988, but epidemiological data show that anabolic drugs are still being used illegally. Recent surveys carried out on the cattle farms in Northern Italy have confirmed the presence of growthpromoting hormones. Authors report data on growth performances in 80 Valle del Belice×Comisana weaned lambs experimentally treated with 17 beta-estradiol with 0.5 ml solution of oil Depot Estradiol ® (containing 5 mg of 17β- estradiol valerate) by intramuscular injection into the thigh. The experiment was founded by the National Ministry of Health, to validate histological test for surveillance and control of growth-promoting hormones in sheep. This study confirmed the strong correlation between clinical and anatomopathological features and growth performances of treated animals. Otherwise, no significant differences were found on in vivo performance of the lambs. Estradiol treatment showed heavier shoulders and necks on treated lambs, while the loins were significantly lighter. Moreover, lambestradiol- treated groups showed lower separable and inseparable fat percentage than lamb-control groups

Familial fetal-type rhabdomyoma of the tricuspid valve in the neonate: Malignant course for a benign disease

Familial fetal-type rhabdomyoma of the tricuspid valve in the neonate: malignant course for a benign disease

Tyrosine 65 is photolabeled by 8-azidoadenine and 8-azidoadenosine at the NAD binding site of diphtheria toxin.

8-Azidoadenine and 8-azidoadenosine, two photoactivatable derivatives of adenine and adenosine, are competitive inhibitors of diphtheria toxin of similar potency with respect to their parent compounds. On irradiation, the two tritium-labeled photoactivatable azidoadenines bind covalently and specifically to an enzymic fragment of diphtheria toxin that is known to bind to NAD. This photolabeling is protected by the enzyme substrate NAD. The radiolabeled protein was fragmented, and the radioactive fragments were sequenced. Tyr-65 is labeled specifically by both photoreagents, and its labeling was reduced strongly when NAD was present during irradiation. Labeling is also reduced strongly by adenine, adenosine, and nicotinamide. These results suggest that Tyr-65 is at the NAD binding site of diphtheria toxin and that the competitive inhibitors adenine, adenosine, and nicotinamide bind to the same portion of the catalytic center of the toxin

Geology of the Saint-Marcel valley metaophiolites (Northwestern Alps, Italy)

The geological map of the Saint-Marcel valley at the scale of 1:20,000 illustrates the tectonic setting of metaophiolites from the southern Aosta Valley, in the Italian side of the Western Alpine belt. The map highlights the sharp contact between the metaophiolitic basement and its metasedimentary cover, which mainly consists of quartzites, marbles, and calcschists. In spite of the Alpine tectonics, this contact is regarded as deriving from the original oceanic crust/sediments interface. Metaophiolites mostly consist of metabasalts hosting Fe\u2013Cu sulphide mineralisations, characterised by high-pressure metamorphic imprint. These rocks likely represent the shallowest portion of the Tethyan oceanic lithosphere created near the axis of the slow-spreading ridge where hydrothermal fluid circulation was active. Selected key-sections through metasediments reveal a consistent internal lithostratigraphy, in spite of the pervasive metamorphic and tectonic reworking acting during the Alpine evolution. Metasediments reflect various sedimentation episodes starting from pelagic and proximal settings to the onset of the orogenic stage. The Saint-Marcel valley metasediments thus reflect a changing in the sedimentation environments through time and space during the overall geologic evolutio

Pareto versus lognormal: a maximum entropy test

It is commonly found that distributions that seem to be lognormal over a broad range change to a power-law (Pareto) distribution for the last few percentiles. The distributions of many physical, natural, and social events (earthquake size, species abundance, income and wealth, as well as file, city, and firm sizes) display this structure. We present a test for the occurrence of power-law tails in statistical distributions based on maximum entropy. This methodology allows one to identify the true data-generating processes even in the case when it is neither lognormal nor Pareto. The maximum entropy approach is then compared with other widely used methods and applied to different levels of aggregation of complex systems. Our results provide support for the theory that distributions with lognormal body and Pareto tail can be generated as mixtures of lognormally distributed units

Linking inflammation and hypertension in humans: studies in Bartter's/Gitelman's syndrome patients

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Bimodal regulation of axonal transport by the GDNF-RET signalling axis in healthy and diseased motor neurons

Deficits in axonal transport are one of the earliest pathological outcomes in several models of amyotrophic lateral sclerosis (ALS), including SOD1G93A mice. Evidence suggests that rescuing these deficits prevents disease progression, stops denervation, and extends survival. Kinase inhibitors have been previously identified as transport enhancers, and are being investigated as potential therapies for ALS. For example, inhibitors of p38 mitogen-activated protein kinase and insulin growth factor receptor 1 have been shown to rescue axonal transport deficits in vivo in symptomatic SOD1G93A mice. In this work, we investigated the impact of RET, the tyrosine kinase receptor for glial cell line-derived neurotrophic factor (GDNF), as a modifier of axonal transport. We identified the fundamental interplay between RET signalling and axonal transport in both wild-type and SOD1G93A motor neurons in vitro. We demonstrated that blockade of RET signalling using pharmacological inhibitors and genetic knockdown enhances signalling endosome transport in wild-type motor neurons and uncovered a divergence in the response of primary motor neurons to GDNF compared with cell lines. Finally, we showed that inhibition of the GDNF-RET signalling axis rescues in vivo transport deficits in early symptomatic SOD1G93A mice, promoting RET as a potential therapeutic target in the treatment of ALS