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Age‐related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three‐dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block‐face scanning electron microscopy (SBF‐SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age‐related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age‐related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age‐related structural changes in mitochondria and further suggest that exercise may mitigate age‐related structural decline through modulation of mitofusin 2. Changes in mitochondrial structure and dynamics during aging provide a mechanism for the development of age‐related sarcopenia, a condition characterized by muscle mass loss. Through the creation of three‐dimensional models of mitochondria from quadriceps muscle tissue taken from old and young humans, a loss in mitochondrial complexity was observed to occur during aging. A decrease in the expression of mitochondrial fusion protein mitofusin 2 (MFN‐2) in older populations may drive these mitochondrial structural changes. A Drosophila model with the MFN‐2 ortholog knocked down demonstrated a loss of mitochondrial complexity and lower quality cristae, which parallel changes in mitochondria observed in older humans. The use of an in vitro cell exercise model showed that the mechanism by which exercise counteracts the effects of sarcopenia, age‐related disease may be due to increased expression of MFN‐2 during exercise.

Age‐related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three‐dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block‐face scanning electron microscopy (SBF‐SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age‐related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age‐related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila , knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age‐related structural changes in mitochondria and further suggest that exercise may mitigate age‐related structural decline through modulation of mitofusin 2.

Cover legend: The cover image is based on the article 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN‐2‐Mediated Changes by Estevão Scudese et al., https://doi.org/10.1111/acel.70054

Over 725 steganography tools are available over the Internet, each providing a method for covert transmission of secret messages. This research presents four steganalysis advancements that result in an algorithm that identifies the steganalysis tool used to embed a secret message in a JPEG image file. The algorithm includes feature generation, feature preprocessing, multi-class classification and classifier fusion. The first contribution is a new feature generation method which is based on the decomposition of discrete cosine transform (DCT) coefficients used in the JPEG image encoder. The generated features are better suited to identifying discrepancies in each area of the decomposed DCT coefficients. Second, the classification accuracy is further improved with the development of a feature ranking technique in the preprocessing stage for the kernel Fisher's discriminant (KFD) and support vector machines (SVM) classifiers in the kernel space during the training process. Third, for the KFD and SVM two-class classifiers a classification tree is designed from the kernel space to provide a multi-class classification solution for both methods. Fourth, by analyzing a set of classifiers, signature detectors, and multi-class classification methods a classifier fusion system is developed to increase the detection accuracy of identifying the embedding method used in generating the steganography images. Based on classifying stego images created from research and commercial JPEG steganography techniques, F5, JP Hide, JSteg, Model-based, Model-based Version 1.2, OutGuess, Steganos, StegHide and UTSA embedding methods, the performance of the system shows a statistically significant increase in classification accuracy of 5%. In addition, this system provides a solution for identifying steganographic fingerprints as well as the ability to include future multi-class classification tools.

The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as ‘silent’ ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.Chemical proteomics identified covalent ligands targeting an isoform-restricted allosteric cysteine in JAK1. The compounds inhibit JAK1-dependent signaling in immune cells with unprecedented selectivity.

The fibroblast growth factor (FGF)-FGF receptor (FGFR) signaling system plays critical roles in a variety of normal developmental and physiological processes. It is also well documented that dysregulation of FGF-FGFR signaling may have important roles in tumor development and progression. The FGFR4-FGF19 signaling axis has been implicated in the development of hepatocellular carcinomas (HCCs) in mice, and potentially in humans. In this study, we demonstrate that FGFR4 is required for hepatocarcinogenesis; the progeny of FGF19 transgenic mice, which have previously been shown to develop HCCs, bred with FGFR4 knockout mice fail to develop liver tumors. To further test the importance of FGFR4 in HCC, we developed a blocking anti-FGFR4 monoclonal antibody (LD1). LD1 inhibited: 1) FGF1 and FGF19 binding to FGFR4, 2) FGFR4-mediated signaling, colony formation, and proliferation in vitro, and 3) tumor growth in a preclinical model of liver cancer in vivo. Finally, we show that FGFR4 expression is elevated in several types of cancer, including liver cancer, as compared to normal tissues. These findings suggest a modulatory role for FGFR4 in the development and progression of hepatocellular carcinoma and that FGFR4 may be an important and novel therapeutic target in treating this disease.

Bacteria of the SAR11 clade constitute up to one half of all microbial cells in the oxygen-rich surface ocean. SAR11 bacteria are also abundant in oxygen minimum zones (OMZs), where oxygen falls below detection and anaerobic microbes have vital roles in converting bioavailable nitrogen to N 2 gas. Anaerobic metabolism has not yet been observed in SAR11, and it remains unknown how these bacteria contribute to OMZ biogeochemical cycling. Here, genomic analysis of single cells from the world’s largest OMZ revealed previously uncharacterized SAR11 lineages with adaptations for life without oxygen, including genes for respiratory nitrate reductases (Nar). SAR11 nar genes were experimentally verified to encode proteins catalysing the nitrite-producing first step of denitrification and constituted ~40% of OMZ nar transcripts, with transcription peaking in the anoxic zone of maximum nitrate reduction activity. These results link SAR11 to pathways of ocean nitrogen loss, redefining the ecological niche of Earth’s most abundant organismal group. Bacteria of the SAR11 clade constitute up to one half of all marine microbes and are thought to require oxygen for growth; here, a subgroup of SAR11 bacteria are shown to thrive in ocean oxygen minimum zones and to encode abundant respiratory nitrate reductases. An anoxic niche for SAR11 bacteria SAR11 bacteria, the most abundant type of microbe in the world's oceans, are thought to require oxygen for growth, yet they are also abundant in waters where oxygen levels are low. Frank Stewart and colleagues show here that a subgroup of SAR11 bacteria that thrives in ocean oxygen minimum zones have adapted to the microaerobic/anaerobic conditions there, and they encode abundant respiratory nitrate reductases that perform the first step in denitrification. These results redefine the ecological niche of Earth's most abundant organismal group and suggest that they are substantial contributors to nitrogen loss in oxygen minimum zones.

Mitochondria take up Ca 2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca 2+ signalling and cell death 1 , 2 . In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for Ca 2+ transport 3 – 8 . To prevent detrimental Ca 2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca 2+ concentrations to switch MCU on and off 9 , 10 . Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca 2+ -activated states. These structures define the architecture of this multicomponent Ca 2+ -uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca 2+ uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca 2+ overload. Cryo-electron microscopy reveals the structures of the mitochondrial calcium uniporter holocomplex in low- and high-calcium conditions, showing the gating mechanism that underlies uniporter activation in response to intracellular calcium signals.

Most commercial microfluidic droplet generators rely on the planar flow-focusing configuration implemented in polymer or glass chips. The planar geometry, however, suffers from many limitations and drawbacks, such as the need of specific coatings or the use of dedicated surfactants, depending on the fluids in play. On the contrary, and thanks to their axisymmetric geometry, glass capillary-based droplet generators are a priori not fluid-dependent. Nevertheless, they have never reached the market because their assembly requires fastidious and not scalable fabrication techniques. Here we present a new device, called Raydrop, based on the alignment of two capillaries immersed in a pressurized chamber containing the continuous phase. The dispersed phase exits one of the capillaries through a 3D-printed nozzle placed in front of the extraction capillary for collecting the droplets. This non-embedded implementation of an axisymmetric flow-focusing is referred to non-embedded co-flow-focusing configuration. Experimental results demonstrate the universality of the device in terms of the variety of fluids that can be emulsified, as well as the range of droplet radii that can be obtained, without neither the need of surfactant nor coating. Additionally, numerical computations of the Navier-Stokes equations based on the quasi-steadiness assumption allow to provide an explanation to the underlying mechanism behind the drop formation and the mechanism of the dripping to jetting transition. Excellent predictions were also obtained for the droplet radius, as well as for the dripping-jetting transition, when varying the geometrical and fluid parameters, showing the ability of this configuration to enventually enhance the dripping regime. The monodispersity ensured by the dripping regime, the robustness of the fabrication technique, the optimization capabilities from the numerical modelling and the universality of the configuration confer to the Raydrop technology a very high potential in the race towards high-throughput droplet generation processes.

Applying a new, more sensitive single-cell transcriptomics method to diagnosis, remission and progression samples from patients with chronic myeloid leukemia reveals insight into the heterogeneity of cells that resist treatment with targeted therapy, as well as into the dynamics of disease progression and its effects on nontransformed hematopoietic stem cells. Recent advances in single-cell transcriptomics are ideally placed to unravel intratumoral heterogeneity and selective resistance of cancer stem cell (SC) subpopulations to molecularly targeted cancer therapies. However, current single-cell RNA-sequencing approaches lack the sensitivity required to reliably detect somatic mutations. We developed a method that combines high-sensitivity mutation detection with whole-transcriptome analysis of the same single cell. We applied this technique to analyze more than 2,000 SCs from patients with chronic myeloid leukemia (CML) throughout the disease course, revealing heterogeneity of CML-SCs, including the identification of a subgroup of CML-SCs with a distinct molecular signature that selectively persisted during prolonged therapy. Analysis of nonleukemic SCs from patients with CML also provided new insights into cell-extrinsic disruption of hematopoiesis in CML associated with clinical outcome. Furthermore, we used this single-cell approach to identify a blast-crisis-specific SC population, which was also present in a subclone of CML-SCs during the chronic phase in a patient who subsequently developed blast crisis. This approach, which might be broadly applied to any malignancy, illustrates how single-cell analysis can identify subpopulations of therapy-resistant SCs that are not apparent through cell-population analysis.