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We report photometric observations of Comet 103P/Hartley 2 during its 2023 apparition. Our campaign, conducted from August through December 2023, combined data from a global network of citizen astronomers coordinated by Unistellar and the Association Française d'Astronomie. Photometry was derived using an automated pipeline for eVscope observations in partnership with the SETI Institute and aperture photometry via AstroLab Stellar. We find that the comet's peak reduced brightness, measured at \\(G_{\\rm min} = 10.24 \\pm 0.47\\), continues a long-term fading trend since 1991. The decline in activity follows a per-apparition minimum magnitude increase of \\(\\Delta G_{\\rm min} = 0.59 \\pm 0.11\\) mag, corresponding to an approximately \\(42\\%\\) reduction in brightness each return. This trend implies that the comet's active fraction has declined by about an order of magnitude since 1991 and may indicate that Hartley 2 is no longer hyperactive by definition. The fading is consistent with progressive volatile depletion rather than orbital effects. These results offer insight into the evolutionary processes shaping Jupiter-family comets.

Centronuclear myopathies (CNMs) are rare congenital muscle disorders with no effective treatment. Previous studies showed that tamoxifen improved muscle function in mice modeling CNMs caused by variants in MTM1, BIN1 and DNM2. Here, we investigated whether tamoxifen administration improves muscle function and pathology in the severe recessive Ryr1TM/indel mouse model of RYR1-related CNM. Contractile performance, histological analyses and protein levels were assessed in Ryr1TM/indel mice and control littermates (wild type) treated with either a tamoxifen-enriched diet (65 mg/kg of food) or a control diet for 5 weeks, beginning at 3 weeks of age. Ryr1TM/indel mice displayed muscle weakness, reduced myofiber size and a high number of fibers with nuclei in abnormal position, regardless of the treatment. Force production during repeated contractions was reduced in tamoxifen-treated Ryr1TM/indel mice compared to that in untreated Ryr1TM/indel mice. The levels of CNM proteins (DNM2 and BIN1) were unchanged following the treatment. Tamoxifen did not improve muscle dysfunction, atrophy or histological hallmarks in Ryr1TM/indel mice. Our data indicate that tamoxifen supplementation is not beneficial and may negatively impact muscle function in this model of CNM, suggesting limited therapeutic value for patients with RYR1 mutations.

Centronuclear and myotubular myopathies (CNMs) are rare, inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily caused by mutations in , , or . The molecular mechanisms driving CNM are only partially understood, and no curative therapies are available. To elucidate molecular pathways involved in CNMs, we present an integrative multi-omics analysis across several CNM mouse models untreated or treated with pre-clinical strategies, combining transcriptomic, proteomic, and metabolomic datasets with curated interaction, metabolic, tissue, and phenotype knowledge using network-based approaches. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules commonly altered in three CNM genetic forms. Modules correlated with improved muscle function were enriched for processes such as muscle contraction, RNA metabolism, and oxidative phosphorylation, whereas modules linked to disease severity were enriched for immune response, innervation, vascularization, and fatty acid oxidation. We further integrated transcriptomic, proteomic, and metabolomic data from the mouse model with public knowledge bases into a multilayer network, and explored it using a random walk with restart approach. These analyses highlighted metabolites closely connected to CNM phenotypes, some of which may represent candidates for nutritional or pharmacological modulation. Our findings illustrate how integrative multi-omics and network analyses reveal both pathogenic and protective pathways in CNM and provide a foundation for identifying novel therapeutic opportunities.

Mitochondrial diseases are genetic disorders that lead to impaired mitochondrial function, resulting in exercise intolerance and muscle weakness. In patients, muscle fatigue due to defects in mitochondrial oxidative capacities commonly precedes muscle weakness. In mice, deletion of the fast-twitch skeletal muscle-specific Tfam gene (Tfam KO) leads to a deficit in respiratory chain activity, severe muscle weakness and early death. Here, we performed a time-course study of mitochondrial and muscular dysfunctions in 11- and 14-week-old Tfam KO mice, i.e. before and when mice are about to enter the terminal stage, respectively. Although force in the unfatigued state was reduced in Tfam KO mice compared to control littermates (wild type) only at 14 weeks, during repeated submaximal contractions fatigue was faster at both ages. During fatiguing stimulation, total phosphocreatine breakdown was larger in Tfam KO muscle than in wild-type muscle at both ages, whereas phosphocreatine consumption was faster only at 14 weeks. In conclusion, the Tfam KO mouse model represents a reliable model of lethal mitochondrial myopathy in which impaired mitochondrial energy production and premature fatigue occur before muscle weakness and early death.

The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill-defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these modifications were associated with profound changes in lipid composition, alteration of endoplasmic reticulum (ER) morphology and activation of the unfolded protein response pathway. In vivo, treatment with a chemical chaperone or deletion of the ER stress sensor kinase IRE1α in myeloid cells decreased AS03-induced cytokine production and its capacity to elicit high affinity antigen-specific antibodies. In summary, our results indicate that IRE1α is a sensor for the metabolic changes induced by AS03 in monocytic cells and may constitute a canonical pathway that could be exploited for the design of novel vaccine adjuvants. Adjuvants: ER stress is critical for adjuvant efficacy Adjuvants are the ‘secret sauce’ of vaccines—by stimulating the innate arm of the immune system they potentiate activation of adaptive immunity; however, their mode of action is incompletely understood. A team led by Stanislas Goriely at the Université Libre de Bruxelles studied the functional basis of a major class of clinically-applied adjuvant—AS03—an oil-in-water emulsion adjuvant used in human influenza vaccines. Using an in vivo mouse model and cell lines they observe that AS03 triggered downregulation of genes controlling lipid metabolism. At the same time there was an increase in an ER-stress signature likely as a result of accumulation of intracellular lipid content in myeloid cells such as macrophages. ER stress was critical for the production of inflammatory cytokines by macrophages and the subsequent generation of robust and specific antibody responses following vaccination. Selective enhancement of ER stress might therefore lead to superior vaccines while minimizing side effects.

Supercapacitors offer a wide range of applications for space flight. The aim of this activity was to pursue life tests on commercial off the shelf (COTS) supercapacitors from different manufacturers, to evaluate their performance after long term vacuum exposure and to investigate balancing designs for the use of these cells in banks of supercapacitors (BOSC). This study enabled to select the most suitable part for space applications and to confirm the design rules at unit level and deratings at component level, which need to be applied. All those complementary results have paved the way to the on-going activities related to Nesscap 10F qualification and associated modular Bank Of Supercapacitors development for space applications.

Nemaline myopathy (NM), the most common non-dystrophic congenital disease of skeletal muscle, can be caused by mutations in the skeletal muscle α-actin gene (ACTA1) (~25% of all NM cases and up to 50% of severe forms of NM). Muscle function of the recently generated transgenic mouse model carrying the human Asp286Gly mutation in the ACTA1 gene (Tg(ACTA1)(Asp286Gly)) has been mainly investigated in vitro. Therefore, we aimed at providing a comprehensive picture of the in vivo hindlimb muscle function of Tg(ACTA1)(Asp286Gly) mice by combining strictly noninvasive investigations. Skeletal muscle anatomy (hindlimb muscles, intramuscular fat volumes) and microstructure were studied using multimodal magnetic resonance imaging (Dixon, T2, Diffusion Tensor Imaging [DTI]). Energy metabolism was studied using 31-phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS). Skeletal muscle contractile performance was investigated while applying a force-frequency protocol (1-150 Hz) and a fatigue protocol (6 min-1.7 Hz). Tg(ACTA1)(Asp286Gly) mice showed a mild muscle weakness as illustrated by the reduction of both absolute (30%) and specific (15%) maximal force production. Dixon MRI did not show discernable fatty infiltration in Tg(ACTA1)(Asp286Gly) mice indicating that this mouse model does not reproduce human MRI findings. Increased T2 values were observed in Tg(ACTA1)(Asp286Gly) mice and might reflect the occurrence of muscle degeneration/regeneration process. Interestingly, T2 values were linearly related to muscle weakness. DTI experiments indicated lower λ2 and λ3 values in Tg(ACTA1)(Asp286Gly) mice, which might be associated to muscle atrophy and/or the presence of histological anomalies. Finally (31)P-MRS investigations illustrated an increased anaerobic energy cost of contraction in Tg(ACTA1)(Asp286Gly) mice, which might be ascribed to contractile and non-contractile processes. Overall, we provide a unique set of information about the anatomic, metabolic and functional consequences of the Asp286Gly mutation that might be considered as relevant biomarkers for monitoring the severity and/or the progression of NM and for assessing the efficacy of potential therapeutic interventions.

L-tyrosine supplementation may provide benefit to nemaline myopathy (NM) patients, however previous studies are inconclusive, with no elevation of L-tyrosine levels in blood or tissue reported. We evaluated the ability of L-tyrosine treatments to improve skeletal muscle function in all three published animal models of NM caused by dominant skeletal muscle α-actin ( ACTA1 ) mutations. Highest safe L-tyrosine concentrations were determined for dosing water and feed of wildtype zebrafish and mice respectively. NM Tg ACTA1 D286G - eGFP zebrafish treated with 10 μM L-tyrosine from 24 hours to 6 days post fertilization displayed no improvement in swimming distance. NM Tg ACTA1 D286G mice consuming 2% L-tyrosine supplemented feed from preconception had significant elevations in free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) when examined at 6–7 weeks old. However indicators of skeletal muscle integrity (voluntary exercise, bodyweight, rotarod performance) were not improved. Additionally no benefit on the mechanical properties, energy metabolism, or atrophy of skeletal muscles of 6–7 month old Tg ACTA1 D286G and KI Acta1 H40Y mice eventuated from consuming a 2% L-tyrosine supplemented diet for 4 weeks. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.

X-linked myotubular myopathy (XLMTM) due to MTM1 mutations is a rare and often lethal congenital myopathy. Its downstream molecular and cellular mechanisms are currently incompletely understood. The most abundant protein in muscle, myosin, has been implicated in the pathophysiology of other congenital myopathies. Hence, in the present study, we aimed to define whether myosin is also dysfunctional in XLMTM and whether it thus may constitute a potential drug target. To this end, we used skeletal muscle tissue from human patients and canine/mouse models; we performed Mant-ATP chase experiments coupled with X-ray diffraction analyses and LC/MS-based proteomics studies. In XLMTM humans, we found that myosin molecules are structurally disordered and preferably adopt their ATP-consuming biochemical state. This phosphorylation-related (mal)adaptation was mirrored by a striking remodelling of the myofibre energetic proteome in XLMTM dogs. In line with these, we confirmed an accrued myosin ATP consumption in mice lacking MTM1. Hence, we treated these, with a myosin ATPase inhibitor, mavacamten. After a four-week treatment period, we observed a partial restoration of the myofibre proteome, especially proteins involved in cytoskeletal, sarcomeric and energetic pathways. Altogether, our study highlights myosin inhibition as a new potential drug mechanism for the complex XLMTM muscle phenotype.X-linked myotubular myopathy (XLMTM) due to MTM1 mutations is a rare and often lethal congenital myopathy. Its downstream molecular and cellular mechanisms are currently incompletely understood. The most abundant protein in muscle, myosin, has been implicated in the pathophysiology of other congenital myopathies. Hence, in the present study, we aimed to define whether myosin is also dysfunctional in XLMTM and whether it thus may constitute a potential drug target. To this end, we used skeletal muscle tissue from human patients and canine/mouse models; we performed Mant-ATP chase experiments coupled with X-ray diffraction analyses and LC/MS-based proteomics studies. In XLMTM humans, we found that myosin molecules are structurally disordered and preferably adopt their ATP-consuming biochemical state. This phosphorylation-related (mal)adaptation was mirrored by a striking remodelling of the myofibre energetic proteome in XLMTM dogs. In line with these, we confirmed an accrued myosin ATP consumption in mice lacking MTM1. Hence, we treated these, with a myosin ATPase inhibitor, mavacamten. After a four-week treatment period, we observed a partial restoration of the myofibre proteome, especially proteins involved in cytoskeletal, sarcomeric and energetic pathways. Altogether, our study highlights myosin inhibition as a new potential drug mechanism for the complex XLMTM muscle phenotype.