Combined MRI and 31P-MRS Investigations of the ACTA1(H40Y) Mouse Model of Nemaline Myopathy Show Impaired Muscle Function and Altered Energy Metabolism

Nemaline myopathy (NM) is the most common disease entity among non-dystrophic skeletal muscle congenital diseases. Mutations in the skeletal muscle α-actin gene (ACTA1) account for ∼25% of all NM cases and are the most frequent cause of severe forms of NM. So far, the mechanisms underlying muscle weakness in NM patients remain unclear. Additionally, recent Magnetic Resonance Imaging (MRI) studies reported a progressive fatty infiltration of skeletal muscle with a specific muscle involvement in patients with ACTA1 mutations. We investigated strictly noninvasively the gastrocnemius muscle function of a mouse model carrying a mutation in the ACTA1 gene (H40Y). Skeletal muscle anatomy (hindlimb muscles and fat volumes) and energy metabolism were studied using MRI and ³¹Phosphorus magnetic resonance spectroscopy. Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (from 1–150 Hz) and a fatigue protocol (80 stimuli at 40 Hz). H40Y mice showed a reduction of both absolute (−40%) and specific (−25%) maximal force production as compared to controls. Interestingly, muscle weakness was associated with an improved resistance to fatigue (+40%) and an increased energy cost. On the contrary, the force frequency relationship was not modified in H40Y mice and the extent of fatty infiltration was minor and not different from the WT group. We concluded that the H40Y mouse model does not reproduce human MRI findings but shows a severe muscle weakness which might be related to an alteration of intrinsic muscular properties. The increased energy cost in H40Y mice might be related to either an impaired mitochondrial function or an alteration at the cross-bridges level. Overall, we provided a unique set of anatomic, metabolic and functional biomarkers that might be relevant for monitoring the progression of NM disease but also for assessing the efficacy of potential therapeutic interventions at a preclinical level.     

p58IPK-Mediated Attenuation of the Proapoptotic PERK-CHOP Pathway Allows Malignant Progression upon Low Glucose

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Highlights? Transformation-associated glucose shortage triggers ER stress ? The ER stress acts as barrier to malignancy by triggering UPR-dependent apoptosis ? p58^IPK expression removes the UPR barrier by attenuating its PERK-CHOP branch ? This adaptive mechanism enables implementation of UPR cytoprotective features     

TRYPTOPHAN TRANSPORT ACROSS THE BLOOD-BRAIN BARRIER DURING ACUTE HEPATIC FAILURE

Abstract— Tryptophan transport across the blood-brain barrier was studied using a single injection dual isotope label technique, in the following three conditions: normal rats, rats with portacaval shunts, and rats with portacaval shunts followed 65 h later by hepatic artery ligation. In both normal rats and those with acute hepatic failure the tryptophan transport system was found to be comprised of two kinetically distinct components. One component was saturable and obeyed Michaelis-Menten kinetics (normal: V_max= 19.5 nmol.min^?1.g^?1. K_m= 113 μM; hepatic failure: V_max, = 33.8 nmol.min^?1.g^?1, K_m= 108 μM), and the second was a high capacity system which transported tryptophan in direct proportion to concentration over the range tested (normal: K= 0.026 ml.min^?1.g^?1; hepatic failure: K= 0.067 ml.min^?1.g^?1). Since the saturable low capacity component transports several neutral amino acids, and their collective plasma concentration is high in relation to the individual K_ms, tryptophan transport by this component is reduced by competitive inhibition under physiological conditions. Thus it was calculated that in normal rats approx 40% of tryptophan influx occurs via the high capacity system. During acute hepatic failure transport via both components was increased substantially, approximately doubling the rate of tryptophan penetration of the blood-brain barrier at all concentrations tested. The contribution by the high capacity component became even more significant than in normal rats, accounting for about 75% of all tryptophan passage from plasma to brain. Brain tryptophan content was 29.9 nmol/g in normal rats and rose to 45.2 nmol/g in rats with portacaval shunts and 50.5 nmol/g in those with acute hepatic failure, correlating with the increased rate of tryptophan transport. In a previous study we found that plasma competing amino acids were greatly increased during acute hepatic failure. Calculations predict that these increased concentrations would cause a reduction in tryptophan transport by the low capacity system. However, because of the increase in the rate of transport by the high capacity component, net tryptophan entry across the blood-brain barrier was actually increased. This increased rate of transport clearly contributes to the increased content of brain tryptophan found during hepatic failure.     

SIRT1 regulates macrophage self‐renewal

Mature differentiated macrophages can self‐maintain by local proliferation in tissues and can be extensively expanded in culture under specific conditions, but the mechanisms of this phenomenon remain only partially defined. Here, we show that SIRT1, an evolutionary conserved regulator of life span, positively affects macrophage self‐renewal ability in vitro and in vivo. Overexpression of SIRT1 during bone marrow‐derived macrophage differentiation increased their proliferative capacity. Conversely, decrease of SIRT1 expression by shRNA inactivation, CRISPR/Cas9 mediated deletion and pharmacological inhibition restricted macrophage self‐renewal in culture. Furthermore, pharmacological SIRT1 inhibition in vivo reduced steady state and cytokine‐induced proliferation of alveolar and peritoneal macrophages. Mechanistically, SIRT1 inhibition negatively regulated G1/S transition, cell cycle progression and a network of self‐renewal genes. This included inhibition of E2F1 and Myc and concomitant activation of FoxO1, SIRT1 targets mediating cell cycle progression and stress response, respectively. Our findings indicate that SIRT1 is a key regulator of macrophage self‐renewal that integrates cell cycle and longevity pathways. This suggests that macrophage self‐renewal might be a relevant parameter of ageing.     

A knowledge-driven agent-centred framework for data mining in EMG

In this paper, we present a multi-agent framework for data mining in electromyography. This application, based on a web interface, provides a set of functionalities allowing to manipulate 1000 medical cases and more than 25,000 neurological tests stored in a medical database. The aim is to extract medical information using data mining algorithms and to supply a knowledge base with pertinent information. The multi-agent platform gives the possibility to distribute the data management process between several autonomous entities. This framework provides a parallel and flexible data manipulation.     

B cell positive selection by soluble self-antigen

It is well established that autoreactive B cells undergo negative selection. This stands in paradox with the high frequency of so-called natural autoreactive B cells producing low affinity polyreactive autoantibodies with recurrent specificities, suggesting that these B cells are selected on the basis of their autoreactivity. We previously described two transgenic mouse lines (with and without IgD) producing a human natural autoantibody (nAAb) that binds ssDNA and human Fcgamma. In the absence of human IgG, nAAb-transgenic B cells develop normally. By crossing these mice with animals expressing knockin chimeric IgG with the human Fcgamma, we now show that the constitutive expression of chimeric IgG promotes the increase of nAAb-expressing B cells. This positive selection is critically dependent on the presence of IgD, occurs in the spleen, and concerns all mature B cell subsets, with a relative preferential enrichment of marginal zone B cells. These data support the view that soluble self-Ags can result in positive clonal selection.     

Spatial synchrony in the response of a long range migratory species (Salmo salar) to climate change in the North Atlantic Ocean

A major challenge in understanding the response of populations to climate change is to separate the effects of local drivers acting independently on specific populations, from the effects of global drivers that impact multiple populations simultaneously and thereby synchronize their dynamics. We investigated the environmental drivers and the demographic mechanisms of the widespread decline in marine survival rates of Atlantic salmon (Salmo salar) over the last four decades. We developed a hierarchical Bayesian life cycle model to quantify the spatial synchrony in the marine survival of 13 large groups of populations (called stock units, SU) from two continental stock groups (CSG) in North America (NA) and Southern Europe (SE) over the period 1971–2014. We found strong coherence in the temporal variation in postsmolt marine survival among the 13 SU of NA and SE. A common North Atlantic trend explains 37% of the temporal variability of the survivals for the 13 SU and declines by a factor of 1.8 over the 1971–2014 time series. Synchrony in survival trends is stronger between SU within each CSG. The common trends at the scale of NA and SE capture 60% and 42% of the total variance of temporal variations, respectively. Temporal variations of the postsmolt survival are best explained by the temporal variations of sea surface temperature (SST, negative correlation) and net primary production indices (PP, positive correlation) encountered by salmon in common domains during their marine migration. Specifically, in the Labrador Sea/Grand Banks for populations from NA, 26% and 24% of variance is captured by SST and PP, respectively and in the Norwegian Sea for populations from SE, 21% and 12% of variance is captured by SST and PP, respectively. The findings support the hypothesis of a response of salmon populations to large climate‐induced changes in the North Atlantic simultaneously impacting populations from distant continental habitats.     

Antibacterial activity of sugar maple autumn-shed leaf extract: Identification of the active compound

Ethanolic crude extract prepared from autumn-shed leaves of sugar maple (Acer saccharum Marsh.) was recently shown to have antibacterial activity against Pseudomonas cichorii and Xanthomonas campestris pv. vitians, two bacteria causing diseases in lettuce production. In this study, antibacterial activity of sugar maple autumn-shed leaves (SMASL) extract was further investigated. SMASL ethanolic crude extract was fractionated using HPLC system and geraniin was identified as the antibacterial compound by UPLC/Q-Tof-MS system. Geraniin, an ellagitannin, was then purified from SMASL crude extract using a glass chromatographic C18-reversed phase silica gel column (purification Step 1) and a semi-preparative HPLC system equipped with 5 μm XTerra Prep MS C18 column (purification Step 2). Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of purified geraniin (purity of 96%) against P. cichorii and X. campestris pv. vitians were determined. X. campestris pv. vitians (MIC of 0.024 mg ml⁻¹ and MBC of 3.125 mg ml⁻¹) was more sensitive to geraniin than P. cichorii (MIC of 0.781 mg ml⁻¹ and MBC of 6.25 mg ml⁻¹). In the present study, geraniin is reported for the first time as the main antibacterial compound present in SMASL.     

Estimating the long-term repeatability of food-hoarding behaviours in an avian predator

Food-hoarding behaviour is widespread in the animal kingdom and enables predictable access to food resources in unpredictable environments. Within species, consistent variation among individuals in food-hoarding behaviours may indicate the existence of individual strategies, as it likely captures intrinsic differences in how individuals cope with risks (e.g. starvation, pilferage). Using 17 years of data, we estimated the long-term repeatability of 10 food-hoarding behaviours in a population of Eurasian pygmy owls (Glaucidium passerinum), a small avian predator subject to high temporal fluctuations in its main prey abundance. We found low repeatability in the proportion of shrews and the average prey mass stored for both sexes, while females were moderately repeatable in the mass and the number of prey items stored. These two pairs of behaviours were tightly correlated among individuals and might represent two different sets of individual strategies to buffer against starvation risks.