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The monocytic/macrophage system is essential for skeletal muscle homeostasis, but its dysregulation contributes to the pathogenesis of muscle degenerative disorders. Despite our increasing knowledge of the role of macrophages in degenerative disease, it still remains unclear how macrophages contribute to muscle fibrosis. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six novel clusters. Unexpectedly, none corresponded to traditional definitions of M1 or M2 macrophage activation. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 and spp1. Spatial transcriptomics and computational inferences of intercellular communication indicated that spp1 regulates stromal progenitor and macrophage interactions during muscular dystrophy. Galectin-3 + macrophages were chronically activated in dystrophic muscle and adoptive transfer assays showed that the galectin-3 + phenotype was the dominant molecular program induced within the dystrophic milieu. Histological examination of human muscle biopsies revealed that galectin-3 + macrophages were also elevated in multiple myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining the transcriptional programs induced in muscle macrophages, and reveal spp1 as a major regulator of macrophage and stromal progenitor interactions.

Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in muscle disease remains unclear. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six clusters and unexpectedly found that none corresponded to traditional definitions of M1 or M2 macrophages. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 (gal-3) and osteopontin (Spp1). Spatial transcriptomics, computational inferences of intercellular communication, and in vitro assays indicated that macrophage-derived Spp1 regulates stromal progenitor differentiation. Gal-3+ macrophages were chronically activated in dystrophic muscle, and adoptive transfer assays showed that the gal-3+ phenotype was the dominant molecular program induced within the dystrophic milieu. Gal-3+ macrophages were also elevated in multiple human myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining their transcriptional programs and reveal Spp1 as a major regulator of macrophage and stromal progenitor interactions.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Background: Nausea and vomiting is a common entity of pregnancy. 7 out of 10 women experience some level of NVP. Gastric cancer with pregnancy in one of a rarest cause of NVP complicating pregnancy worldwide. Case: A 25 years primigravida presented to Dr. Bhimrao Ambedkar Memorial hospital with severe IUGR and severe vomiting, tolerating liquid diet only. She was thin built, brittle discolored rough hairs with cracked lips and angular cheilosis. She had tachycardia but BP was normal. All her routine investigations were within normal range except mildly elevated liver enzymes. She was investigated for her persistent vomiting with consultation from physician and surgeon. USG whole abdomen was done to rule out other causes of vomiting which showed thickening of stomach wall. MRI suggested asymmetrical circumferential thickening of antropyloric region of stomach. Endoscopic biopsy showed diffuse infiltrative adenocarcinoma (signet ring cell). Her nutritional deficiency was managed. She had preterm vaginal delivery and baby was handed over after 35days of birth. She received neoadjuvant chemotherapy followed by surgery and radiotherapy and chemotherapy. She is living normal day to day life now. Conclusion: Severe, persistent and nonresponsive NVP associated with weight loss should be investigated vigilantly and thoroughly. Apart from other causes one of rarest cause i.e., gastric carcinoma should not be missed. Diagnosis in early stage and management can have better prognosis and prolong the life expectancy.

Single-cell gene expression analyses of mammalian tissues have uncovered profound stage-specific molecular regulatory phenomena that have changed the understanding of unique cell types and signaling pathways critical for lineage determination, morphogenesis, and growth. We discuss here the case for a Pediatric Cell Atlas as part of the Human Cell Atlas consortium to provide single-cell profiles and spatial characterization of gene expression across human tissues and organs. Such data will complement adult and developmentally focused HCA projects to provide a rich cytogenomic framework for understanding not only pediatric health and disease but also environmental and genetic impacts across the human lifespan.

The plasma membrane of eukaryotic cells forms the essential barrier to the extracellular environment, and thus plasma membrane disruptions pose a fatal threat to cells. Here, using invasive breast cancer cells we show that the Ca 2+ - and phospholipid-binding protein annexin A7 is part of the plasma membrane repair response by enabling assembly of the endosomal sorting complex required for transport (ESCRT) III. Following injury to the plasma membrane and Ca 2+ flux into the cytoplasm, annexin A7 forms a complex with apoptosis linked gene-2 (ALG-2) to facilitate proper recruitment and binding of ALG-2 and ALG-2-interacting protein X (ALIX) to the damaged membrane. ALG-2 and ALIX assemble the ESCRT III complex, which helps excise and shed the damaged portion of the plasma membrane during wound healing. Our results reveal a novel function of annexin A7 – enabling plasma membrane repair by regulating ESCRT III-mediated shedding of injured plasma membrane.

Muscle function is regulated by Ca2+, which mediates excitation-contraction coupling, energy metabolism, adaptation to exercise, and sarcolemmal repair. Several of these actions rely on Ca2+ delivery to the mitochondrial matrix via the mitochondrial Ca2+ uniporter, the pore of which is formed by mitochondrial calcium uniporter (MCU). MCU's gatekeeping and cooperative activation are controlled by MICU1. Loss-of-protein mutation in MICU1 causes a neuromuscular disease. To determine the mechanisms underlying the muscle impairments, we used MICU1 patient cells and skeletal muscle-specific MICU1 knockout mice. Both these models show a lower threshold for MCU-mediated Ca2+ uptake. Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake during excitation-contraction, aerobic metabolism impairment, muscle weakness, fatigue, and myofiber damage during physical activity. MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal injury, which causes ineffective repair of the damaged myofibers. Thus, dysregulation of mitochondrial Ca2+ uptake hampers myofiber contractile function, likely through energy metabolism and membrane repair.

The plasma membrane of eukaryotic cells forms the essential barrier to the extracellular environment, and thus plasma membrane disruptions pose a fatal threat to cells. Here, using invasive breast cancer cells we show that the Ca 2+ - and phospholipid-binding protein annexin A7 is part of the plasma membrane repair response by enabling assembly of the endosomal sorting complex required for transport (ESCRT) III. Following injury to the plasma membrane and Ca 2+ flux into the cytoplasm, annexin A7 forms a complex with apoptosis linked gene-2 (ALG-2) to facilitate proper recruitment and binding of ALG-2 and ALG-2-interacting protein X (ALIX) to the damaged membrane. ALG-2 and ALIX assemble the ESCRT III complex, which helps excise and shed the damaged portion of the plasma membrane during wound healing. Our results reveal a novel function of annexin A7 – enabling plasma membrane repair by regulating ESCRT III-mediated shedding of injured plasma membrane.

The plasma membrane of eukaryotic cells forms the essential barrier to the extracellular environment, and thus plasma membrane disruptions pose a fatal threat to cells. Here, using invasive breast cancer cells we show that the Ca2+ - and phospholipid-binding protein annexin A7 is part of the plasma membrane repair response by enabling assembly of the endosomal sorting complex required for transport (ESCRT) III. Following injury to the plasma membrane and Ca2+ flux into the cytoplasm, annexin A7 forms a complex with apoptosis linked gene-2 (ALG-2) to facilitate proper recruitment and binding of ALG-2 and ALG-2-interacting protein X (ALIX) to the damaged membrane. ALG-2 and ALIX assemble the ESCRT III complex, which helps excise and shed the damaged portion of the plasma membrane during wound healing. Our results reveal a novel function of annexin A7 – enabling plasma membrane repair by regulating ESCRT III-mediated shedding of injured plasma membrane.

Exon skipping is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), employing morpholino antisense oligonucleotides (PMO-AO) to exclude disruptive exons from the mutant DMD transcript and elicit production of truncated dystrophin protein. Clinical trials for PMO show variable and sporadic dystrophin rescue. Here, we show that robust PMO uptake and efficient production of dystrophin following PMO administration coincide with areas of myofiber regeneration and inflammation. PMO localization is sustained in inflammatory foci where it enters macrophages, actively differentiating myoblasts and newly forming myotubes. We conclude that efficient PMO delivery into muscle requires two concomitant events: first, accumulation and retention of PMO within inflammatory foci associated with dystrophic lesions, and second, fusion of PMO-loaded myoblasts into repairing myofibers. Identification of these factors accounts for the variability in clinical trials and suggests strategies to improve this therapeutic approach to DMD.

Exon skipping is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), employing morpholino antisense oligonucleotides (PMO-AO) to exclude disruptive exons from the mutant DMD transcript and elicit production of truncated dystrophin protein. Clinical trials for PMO show variable and sporadic dystrophin rescue. Here, we show that robust PMO uptake and efficient production of dystrophin following PMO administration coincide with areas of myofiber regeneration and inflammation. PMO localization is sustained in inflammatory foci where it enters macrophages, actively differentiating myoblasts and newly forming myotubes. We conclude that efficient PMO delivery into muscle requires two concomitant events: first, accumulation and retention of PMO within inflammatory foci associated with dystrophic lesions, and second, fusion of PMO-loaded myoblasts into repairing myofibers. Identification of these factors accounts for the variability in clinical trials and suggests strategies to improve this therapeutic approach to DMD.

In this paper we have studied the some curvature properties of a quarter-symmetric non metric connection of Kenmostu manifolds. We also studied the some properties of projective ricci tensor, pseudo projective curvature tensor and m-projective curvature tensor.

During terminal differentiation of cells, there is typically a transition of the nuclear envelope from the Lamin B protein to Lamin A/C proteins. This is commensurate with exit from the cell cycle, and maintenance of the transcriptional programs associated with the terminally differentiated cells. Dominant missense mutations in Lamin A/C cause a broad spectrum of human genetic disorders, where specific point mutations are associated with defects in specific organs or tissues. We have previously presented a model where Lamin A/C mutations disrupt developmentally appropriate interactions between chromatin and the nuclear envelope and lead to poor coordination of E2F cell cycle pathways and terminal differentiation pathways [1]. One of the phenotypes caused by Lamin A/C mutations is Emery Dreifuss Muscular Dystrophy (EDMD). An X-linked recessive phenocopy of EDMD is caused by loss of function of emerin – a binding partner to Lamin A/C at the nuclear envelope. Here, we tested the hypothesis that emerin plays a role in chromatin remodeling via stabilizing nuclear lamina-heterochromatin interactions necessary for appropriate and time dependent muscle differentiation. We used WT and emerin null mouse myogenic stem cells to study transcriptional and epigenetic changes during in vitro exit from the cell cycle and differentiation to the myogenic lineage. Specific cell cycle (E2F) and myogenic genes were analyzed by qPCR and ChlP-qPCR to determine mRNA timing and H3K9me3 enrichment on gene promoters. Nuclear lamina-chromatin colocalization was determined and quantified by confocal imaging and Matlab. Our results showed that TK1 and other cell cycle genes are inappropriately persistently expressed in emerin null cells during differentiation causing delayed exit from cell cycle. Transcripts marking commitment to the myogenic lineage (myogenin and Mef5A) showed delayed activation on both mRNA and protein level. Epigenetic imprints predicted observed deviations from transcriptiona

Doublecortin (Dcx) defines a growing family of microtubule (MT)-associated proteins (MAPs) involved in neuronal migration and process outgrowth. We show that Dcx is essential for the function of Kif1a, a kinesin-3 motor protein that traffics synaptic vesicles. Neurons lacking Dcx and/or its structurally conserved paralogue, doublecortin-like kinase 1 (Dclk1), show impaired Kif1a-mediated transport of Vamp2, a cargo of Kif1a, with decreased run length. Human disease-associated mutations in Dcx's linker sequence (e.g., W146C, K174E) alter Kif1a/Vamp2 transport by disrupting Dcx/Kif1a interactions without affecting Dcx MT binding. Dcx specifically enhances binding of the ADP-bound Kif1a motor domain to MTs. Cryo-electron microscopy and subnanometer-resolution image reconstruction reveal the kinesin-dependent conformational variability of MT-bound Dcx and suggest a model for MAP-motor crosstalk on MTs. Alteration of kinesin run length by MAPs represents a previously undiscovered mode of control of kinesin transport and provides a mechanism for regulation of MT-based transport by local signals., National Institutes of Health (U.S.) (Grant NIH-P30-HD-18655), National Institutes of Health (U.S.) (Grant 2T32NS007473-11), National Institutes of Health (U.S.) (Grant 2T32NS007484-11), National Institutes of Health (U.S.) (Grant 1F32D070549-01), National Science Foundation (U.S.) (CAREER Award), National Institutes of Health (U.S.) (Grant 5R21NS063185-02)

The plasma membrane of eukaryotic cells forms the essential barrier to the extracellular environment, and thus plasma membrane disruptions pose a fatal threat to cells. Here, using invasive breast cancer cells we show that the Ca2+ - and phospholipid-binding protein annexin A7 is part of the plasma membrane repair response by enabling assembly of the endosomal sorting complex required for transport (ESCRT) III. Following injury to the plasma membrane and Ca2+ flux into the cytoplasm, annexin A7 forms a complex with apoptosis linked gene-2 (ALG-2) to facilitate proper recruitment and binding of ALG-2 and ALG-2-interacting protein X (ALIX) to the damaged membrane. ALG-2 and ALIX assemble the ESCRT III complex, which helps excise and shed the damaged portion of the plasma membrane during wound healing. Our results reveal a novel function of annexin A7 – enabling plasma membrane repair by regulating ESCRT III-mediated shedding of injured plasma membrane.