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National audience; En situation d’impesanteur ou d’alitement, astronautes et patients hospitalisés subissent une réduction considérable de leur activité musculaire, qualifiée d’hypoactivité, qui impacte directement leur état de santé. En raison de son implication dans le transport et le stockage tissulaire de l’oxygène, tout comme dans le métabolisme énergétique, le fer et son métabolisme pourraient jouer un rôle essentiel dans certaines des altérations physiologiques associées à l’hypoactivité. Sa redistribution de manière anormale pourrait, en effet, contribuer à l’anémie et au stress oxydant hautement délétère observé dans certains organes en situation d’hypoactivité (c.-à-d., os et muscle squelettique). Dans ce contexte, l’objectif de cette revue de synthèse est de présenter les connaissances actuelles concernant la régulation du métabolisme du fer en réponse à l’hypoactivité, et d’ouvrir des pistes de réflexion pour améliorer la prise en charge nutritionnelle des astronautes et des patients alités.

Gut microbiota, a major contributor to human health, is influenced by physical activity and diet, and displays a functional cross-talk with skeletal muscle. Conversely, few data are available on the impact of hypoactivity, although sedentary lifestyles are widespread and associated with negative health and socio-economic impacts. The study aim was to determine the effect of Dry Immersion (DI), a severe hypoactivity model, on the human gut microbiota composition. Stool samples were collected from 14 healthy men before and after 5 days of DI to determine the gut microbiota taxonomic profiles by 16S metagenomic sequencing in strictly controlled dietary conditions. The α and β diversities indices were unchanged. However, the operational taxonomic units associated with the Clostridiales order and the Lachnospiraceae family, belonging to the Firmicutes phylum, were significantly increased after DI. Propionate, a short-chain fatty acid metabolized by skeletal muscle, was significantly reduced in post-DI stool samples. The finding that intestine bacteria are sensitive to hypoactivity raises questions about their impact and role in chronic sedentary lifestyles.

New findings - What is the central question of this study? Could skeletal muscle be involved in microgravity-induced iron misdistribution by modulating expression of hepcidin, the master regulator of iron metabolism? What is the main finding and its importance? We demonstrate, in rats, that hepcidin upregulation is not a transient adaptation associated with early exposure to microgravity and that intermittent reloading does not limit microgravity-induced iron misdistribution despite having a beneficial effect on soleus muscle wasting. Abstract - In humans, exposure to microgravity during spaceflight causes muscle atrophy, changes in iron storage and a reduction in iron availability. We previously observed that during 7 days of simulated microgravity in rats, hepcidin plays a key role in iron misdistribution, and we suggested that a crosstalk between skeletal muscle and liver could regulate hepcidin synthesis in this context. In the present study in rats, we investigated the medium-term effects of simulated microgravity on iron metabolism. We also tested whether intermittent reloading (IR) to target skeletal muscle atrophy limits iron misdistribution efficiently. For this purpose, Wistar rats underwent 14 days of hindlimb unloading (HU) combined or not combined with daily IR. At the end of this period, the serum iron concentration and transferrin saturation were significantly reduced, whereas hepatic hepcidin mRNA was upregulated. However, the main signalling pathways involved in hepcidin synthesis in the liver (BMP-small mothers against decapentaplegic (SMAD), interleukin-6-STAT3 and ERK1/2) were unaffected. Unlike what was observed after 7 days of HU, the iron concentration in the spleen, liver and skeletal muscle was comparable between control animals and those that underwent HU or HU plus IR for 14 days. Despite its beneficial effect on soleus muscle atrophy and slow-to-fast myosin heavy chain distribution, IR did not significantly prevent a reduction in iron availability and hepcidin upregulation. Altogether, these results highlight that iron availability is durably reduced during longer exposure to simulated microgravity and that the related hepcidin upregulation is not a transient adaptation to these conditions. The results also suggest that skeletal muscle does not necessarily play a key role in the iron misdistribution that occurs during simulated microgravity.

CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934, a total of 32 compounds, composed of single-ring, 5,6-, and 6,6-fused heteroaromatic cores, were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. Compared to GSK650394 and STO-609, 13 compounds displayed similar or better CAMKK2 inhibitory potency in vitro, while compounds 13g and 45 had improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge-binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs.

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle–brain, liver–brain and gut–brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise–brain communication and their benefits for physiology and brain function.

CAMKK2 is a serine/threonine kinase and an activator of AMPK whose dysregulation is linked with multiple diseases. Unfortunately, STO-609, the tool inhibitor commonly used to probe CAMKK2 signaling, has limitations. To identify promising scaffolds as starting points for the development of high-quality CAMKK2 chemical probes, we utilized a hinge-binding scaffold hopping strategy to design new CAMKK2 inhibitors. Starting from the potent but promiscuous disubstituted 7-azaindole GSK650934 (CAMKK2 IC50 = 3 nM), a total of 32 compounds, composed of single ring, 5,6-, and 6,6-fused heteroaromatic cores were synthesized. The compound set was specifically designed to probe interactions with the kinase hinge-binding residues. These compounds were evaluated in vitro in biochemical and cellular assays for CAMKK2 inhibition. Compared to GSK650394 and STO-609, thirteen of our compounds displayed similar or better CAMKK2 inhibitory potency in vitro, while compounds 13g and 45 had greatly improved selectivity for CAMKK2 across the kinome. Our systematic survey of hinge binding chemotypes identified several potent and selective inhibitors of CAMKK2 to serve as starting points for medicinal chemistry programs aimed at the identification of CAMKK2 chemical probes and clinical candidates

International audience; The objective of the present study was to determine the effects of dry immersion, an innovative ground-based human model of simulated microgravity and extreme physical inactivity, on iron homeostasis and distribution. Twenty young healthy men were recruited and submitted to 5 days of dry immersion (DI). Fasting blood samples and MRI were performed before and after DI exposure to assess iron status, as well as hematological responses. DI increased spleen iron concentrations (SIC), whereas hepatic iron store (HIC) was not affected. Spleen iron sequestration could be due to the concomitant increase in serum hepcidin levels (P

Background A new problematic on the gut microbiota of the astronauts and the effects of microgravity emerged recently as that bacteria community is sensitive to physical (in)activity which could be hampered during spaceflights. Therefore, the objective of our study was thus to determine the effects of dry immersion, an innovative ground-based human model of simulated microgravity, on human gut microbiota composition. We collected stools from 14 healthy men before and after 5 days of Dry Immersion to determine taxonomic profiles by 16S metagenomic.Results Our analyses show preservation of α–diversity through Observed, Chao1, Shannon and InvSimpson indices. β–diversity is also not impacted by Dry Immersion as represented by PCoA plots with Jaccard, Bray-Curtis and UniFrac indices. Phyla abundances for OTUs associated to BacteroidetesP, FirmicutesP, ProteobacteriaP and ActinobacteriaP are also preserved. Interestingly, metagenomics analysis of the 32 families and 44 associated genera underscored that OTUs associated to ClostridialesO order and LachnospiraceaeF family are increased (p FirmicutesP phylum.Conclusion The diversity and global composition of the gut microbiome remained unaltered in response to Dry Immersion confirming the robustness of gut microbiota. However, it’s sufficient to led to several significant changes at the lower taxonomy levels. This suggests that the human gut microbiota, with its known strong impact on human health and performance, is a potential biological target of microgravity and underscores the need to investigate further this new field of research on gut microbiota – microgravity.Trial registration: ClinicalTrials.gov Identifier NCT03915457- Registered 16 April 2019 - Retrospectively registered - https://clinicaltrials.gov/ct2/show/NCT03915457.

We address the challenge in depositing ultra-thin GaAs cells (

As single-junction Si solar cells approach their practical efficiency limits, a new pathway is necessary to increase efficiency in order to realize more cost-effective photovoltaics. Integrating III–V cells onto Si in a multijunction architecture is a promising approach that can achieve high efficiency while leveraging the infrastructure already in place for Si and III–V technology. In this Letter, we demonstrate a record 15.3%-efficient 1.7 eV GaAsP top cell on GaP/Si, enabled by recent advances in material quality in conjunction with an improved device design and a high-performance antireflection coating. We further present a separate Si bottom cell with a 1.7 eV GaAsP optical filter to absorb most of the visible light with an efficiency of 6.3%, showing the feasibility of monolithic III–V/Si tandems with >20% efficiency. Through spectral efficiency analysis, we compare our results to previously published GaAsP and Si devices, projecting tandem GaAsP/Si efficiencies of up to 25.6% based on current state...

NEW FINDINGS: What is the central question of this study? Although microgravity is well known to reduce circulating iron in astronauts, the underlying mechanism is still unknown. We investigated whether hepcidin, a key hormone regulating iron metabolism, could be involved in this deleterious effect. What is the main finding and its importance? We show that hindlimb suspension, a model of microgravity, stimulates the production of hepcidin in liver of rats. In agreement with the biological role of hepcidin, we found a decrease of circulating iron and an increase of spleen iron content in hindlimb-unloaded rats. Consequently, our study supports the idea that hepcidin could play a role in the alteration of iron metabolism parameters observed during spaceflight. During spaceflight, humans exposed to microgravity exhibit an increase of iron storage and a reduction of circulating iron. Such perturbations could promote oxidative stress and anaemia in astronauts. The mechanism by which microgravity modulates iron metabolism is still unknown. Herein, we hypothesized that microgravity upregulates hepcidin, a hormone produced by the liver that is the main controller of iron homeostasis. To test this hypothesis, rats were submitted to hindlimb unloading (HU), the reference model to mimic the effects of microgravity in rodents. After 7 days, the mRNA level of hepcidin was increased in the liver of HU rats (+74%, P = 0.001). In agreement with the biological role of hepcidin, we found an increase of spleen iron content (+78%, P = 0.030) and a decrease of serum iron concentration (-35%, P = 0.002) and transferrin saturation (-25%, P = 0.011) in HU rats. These findings support a role of hepcidin in microgravity-induced iron metabolism alteration. Furthermore, among the signalling pathways inducing hepcidin mRNA expression, we found that only the interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) axis was activated by HU, as shown by the increase of phospho-STAT3 (+193%, P

International audience; Hereditary aceruloplasminemia (HA), related to mutations in the ceruloplasmin (Cp) gene, leads to iron accumulation. Ceruloplasmin ferroxidase activity being considered essential for macrophage iron release, macrophage iron overload is expected, but it is not found in hepatic and splenic macrophages in humans. Our objective was to get a better understanding of the mechanisms leading to iron excess in HA. A clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated protein 9 (Cas9) knockout of the Cp gene was performed on Sprague-Dawley rats. We evaluated the iron status in plasma, the expression of iron metabolism genes, and the status of other metals whose interactions with iron are increasingly recognized. In Cp rats, plasma ceruloplasmin and ferroxidase activity were absent, together with decreased iron concentration and transferrin saturation. Similarly as in humans, the hepatocytes were iron overloaded conversely to hepatic and splenic macrophages. Despite a relative hepcidin deficiency in Cp rats and the loss of ferroxidase activity, potentially expected to limit the interaction of iron with transferrin, no increase of plasma non-transferrin-bound iron level was found. Copper was decreased in the spleen, whereas manganese was increased in the plasma. These data suggest that the reported role of ceruloplasmin cannot fully explain the iron hepatosplenic phenotype in HA, encouraging the search for additional mechanisms.-Kenawi, M., Rouger, E., Island, M.-L., Leroyer, P., Robin, F., Remy, S., Tesson, L., Anegon, I., Nay, K., Derbré, F., Brissot, P., Ropert, M., Cavey, T., Loréal, O. Ceruloplasmin deficiency does not induce macrophagic iron overload lessons from a new rat model of hereditary aceruloplasminemia.

International audience; Gut microbiota is involved in the development of several chronic diseases, including diabetes, obesity, and cancer, through its interactions with the host organs. It has been suggested that the cross talk between gut microbiota and skeletal muscle plays a role in different pathological conditions, such as intestinal chronic inflammation and cachexia. However, it remains unclear whether gut microbiota directly influences skeletal muscle function. In this work, we studied the impact of gut microbiota modulation on mice skeletal muscle function and investigated the underlying mechanisms. We determined the consequences of gut microbiota depletion after treatment with a mixture of a broad spectrum of antibiotics for 21 days and after 10 days of natural reseeding. We found that, in gut microbiota-depleted mice, running endurance was decreased, as well as the extensor digitorum longus muscle fatigue index in an ex vivo contractile test. Importantly, the muscle endurance capacity was efficiently normalized by natural reseeding. These endurance changes were not related to variation in muscle mass, fiber typology, or mitochondrial function. However, several pertinent glucose metabolism markers, such as ileum gene expression of short fatty acid chain and glucose transporters G protein-coupled receptor 41 and sodium-glucose cotransporter 1 and muscle glycogen level, paralleled the muscle endurance changes observed after treatment with antibiotics for 21 days and reseeding. Because glycogen is a key energetic substrate for prolonged exercise, modulating its muscle availability via gut microbiota represents one potent mechanism that can contribute to the gut microbiota-skeletal muscle axis. Taken together, our results strongly support the hypothesis that gut bacteria are required for host optimal skeletal muscle function.

International audience; Accumulating evidence indicates that the MDM2 oncoprotein promotes tumorigenesis beyond its canonical negative effects on the p53 tumor suppressor, but these p53-independent functions remain poorly understood. Here, we show that a fraction of endogenous MDM2 is actively imported in mitochondria to control respiration and mitochondrial dynamics independently of p53. Mitochondrial MDM2 represses the transcription of NADH-dehydrogenase 6 (MT-ND6) in vitro and in vivo, impinging on respiratory complex I activity and enhancing mitochondrial ROS production. Recruitment of MDM2 to mitochondria increases during oxidative stress and hypoxia. Accordingly, mice lacking MDM2 in skeletal muscles exhibit higher MT-ND6 levels, enhanced complex I activity, and increased muscular endurance in mild hypoxic conditions. Furthermore, increased mitochondrial MDM2 levels enhance the migratory and invasive properties of cancer cells. Collectively, these data uncover a previously unsuspected function of the MDM2 oncoprotein in mitochondria that play critical roles in skeletal muscle physiology and may contribute to tumor progression.

Tandem solar cells are one of the most promising ways to exceeding the one-sun efficiency limit of single-junction (SJ) solar cells. However, compared to SJ solar cells, tandem solar cells often experience larger energy yield losses in the field, due to variations in operating conditions (i.e. spectrum, irradiance and operating temperature). We determine the energy yield losses of dual-junction and SJ GaAs solar cells, which are potential candidates for thin-film on silicon tandem solar cells. Our measurements show that a GaAs SJ cell has an annual energy yield of 3.0% more than with standard testing conditions (STC), whereas the investigated GaAs/GaAs dual-junction cell has an annual energy yield loss of 11.2% compared with STC.

We have investigated wide-bandgap, metamorphic GaAs1-xPx and InyGa1-yP solar cells on GaAs as potential subcell materials for future 4-6 junction devices. We identified and characterized morphological defects in tensile GaAs1-xPx graded buffers that lead to a local reduction in carrier collection and a global increase in threading dislocation density (TDD). Through adjustments to the graded buffer structure, we minimized the formation of morphological defects and, hence, obtained TDDs ≈ 106 cm-2 for films with lattice mismatch ≤1.2%. Metamorphic InyGa1-y P solar cells were grown on these optimized GaAs1-xPx graded buffers with bandgaps (Eg) as high as 2.07 eV and open-circuit voltages (Voc) as large as 1.49 V. Such high bandgap materials will be necessary to serve as the top subcell in future 4-6 junction devices. We have also shown that the relaxed GaAs1-xPx itself could act as an efficient lower subcell in a multijunction device. GaAs0.66P0.34 single-junction solar cells with Eg = 1.83 eV were fabricated with Voc = 1.28 V. Taken together, we have demonstrated that GaAs1-xPx graded buffers are an appropriate platform for low-TDD, metamorphic GaAs1-xPx and InyGa1-yP solar cells, covering a wide bandgap range.

We demonstrate metamorphic 1.66 eV GaAs 0.77 P 0.23 solar cells grown by molecular beam epitaxy on exact (001) GaP/Si templates. Cascading such a cell with a 1.1 eV Si junction enables theoretical efficiencies of > 37% under the AM1.5G spectrum. We optimized the initial GaP growth on pseudomorphic GaP/Si templates to promote maximum strain relaxation with minimal nucleation of new threading dislocations. Electron beam-induced current studies of our cells reveal a threading dislocation density (TDD) of 7.8×106 cm−2, about 18% lower than our prior results on GaP/Si. The lower TDD has contributed to a low bandgap-voltage offset (W OC =E G /q-V OC ) of 0.55 V, which is 40 mV lower than our previous report, and represents significant progress for GaAs y P 1−y /GaP/Si metamorphic solar cells.

We have grown, via molecular beam epitaxy (MBE), the first metamorphic In0.26Ga0.74P solar cells with a 2.19 eV direct bandgap on GaP to serve as the top cell in a multi-junction device. Calculations show that the incorporation of a 2.0-2.2 eV top cell into future 4-6 junction cells could enable efficiencies as high as 60%. GaAsxP1-x graded buffers enabled a moderate threading dislocation density of 6×106 cm-2 in the In0.26Ga0.74P solar cells. Open circuit voltages (Voc) as high as 1.42 V were observed under approximate AM1.5G illumination. Little work has been reported on the MBE growth of such high-bandgap InyGa1-yP, and we believe that this Voc can be improved through systematic optimization of growth conditions. Although these devices were not optimized for current collection, we obtain an efficiency of 3.13%, surpassing that of the best GaP solar cells. Finally, as this composition is near the direct-indirect crossover point, we analyzed the low-energy cutoff of the external quantum efficiency spectrum and infer that our In0.26Ga0.74P cells are still in the direct regime.

We demonstrate metamorphic 1.73 eV GaAs0.72P0.28 solar cells grown by molecular beam epitaxy on high-quality GaP/Si templates and compare them to cells co-grown on bulk GaP. Cascading such a cell with a 1.1 eV Si junction in the substrate could enable a theoretical efficiency of 37% under the AM1.5G spectrum. Electron beam-induced current studies of our cells reveal a threading dislocation density (TDD) of ~1×107 cm-2 for cells on GaP/Si, which is significantly lower than previous reports. We believe that the combination of a highly optimized GaP/Si starting substrate with a well-designed metamorphic buffer enables these relatively low TDDs. Open-circuit voltages as high as 1.10 V were obtained, leading to a bandgap-voltage offset of 0.63 V. This bandgap-voltage offset is also lower than in previous reports, in qualitative agreement with the observation of lower TDD. Direct comparison with cells on bulk GaP confirm the relation between TDD and bandgap-voltage offset, indicating that more investigations to further reduce TDD in GaAsP single-junction cells are required to fulfill the ultimate goal of dual-junction integration on Si.

In this work, we demonstrate metamorphic GaAs x P 1−x /GaP solar cells grown by molecular beam epitaxy for potential dual-junction integration with Si. We investigate the appropriate substrate orientation and growth conditions necessary to obtain smooth surface morphology with high open-circuit voltage (V oc ). Growing nearly identical GaAs x P 1−x /GaP (x=0.65±0.01) cells at three different substrate temperatures allowed us to investigate the dislocation dynamics in the graded buffer, revealing that we are not in the ideal glide-limited regime. We expect this is due to thread interactions with morphological defects. To satisfy the design requirements of the ideal dual-junction device, we grew 1.71 eV GaAs 0.73 P 0.27 /GaP cells, attaining a high V oc of 1.15 V. With increased short-circuit current through the addition of a window layer and antireflection coating, the GaAs x P 1−x cells presented here cascaded with Si could reach efficiencies as high as 30%.

We demonstrate metamorphic ∼1.7 eV GaAsxP1−x (x = 0.71 − 0.73) solar cells on high-quality GaP/Si templates and compare them to cells co-grown on bulk GaP. Both n+-emitter/p-base and p+-emitter/n-base polarities are explored. Cells with n-type bases demonstrate current-voltage characteristics that are similar to p-type base cells, but with blue-shifted peak quantum efficiencies. Threading dislocation densities for cells on GaP/Si were 0.92 − 1.3 × 107 cm−2, significantly lower than previous reports but higher than cells grown on bulk GaP. An open-circuit voltage of 1.12 V was obtained for a 1.71 eV cell on Si, leading to a promising bandgap-voltage offset of 0.59 V.