Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time levels of insulin decrease. In contrast, circulating levels of osteocalcin plummet early ...during adulthood in mice, monkeys, and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15-month-old mice the exercise capacity of 3-month-old mice. This study uncovers a bone-to-muscle feedforward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.
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•Bone via the hormone osteocalcin improves muscle function during exercise•Circulating osteocalcin levels decrease in aging mice, monkeys, and humans•Osteocalcin promotes muscle uptake and utilization of glucose and fatty acids•Osteocalcin promotes muscle IL-6 secretion during exercise
Mera et al. show that the bone-derived hormone osteocalcin is necessary for optimum exercise capacity and that this hormone decreases with aging in mice, monkeys, and humans of both genders. Osteocalcin promotes muscle uptake and utilization of glucose and lipids during exercise and greatly improves the exercise capacity of old mice.
Computational methods have made substantial progress in improving the accuracy and throughput of pathology workflows for diagnostic, prognostic, and genomic prediction. Still, lack of ...interpretability remains a significant barrier to clinical integration. We present an approach for predicting clinically-relevant molecular phenotypes from whole-slide histopathology images using human-interpretable image features (HIFs). Our method leverages >1.6 million annotations from board-certified pathologists across >5700 samples to train deep learning models for cell and tissue classification that can exhaustively map whole-slide images at two and four micron-resolution. Cell- and tissue-type model outputs are combined into 607 HIFs that quantify specific and biologically-relevant characteristics across five cancer types. We demonstrate that these HIFs correlate with well-known markers of the tumor microenvironment and can predict diverse molecular signatures (AUROC 0.601-0.864), including expression of four immune checkpoint proteins and homologous recombination deficiency, with performance comparable to 'black-box' methods. Our HIF-based approach provides a comprehensive, quantitative, and interpretable window into the composition and spatial architecture of the tumor microenvironment.
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal ...atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.
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•Tissue-resident macrophages abound in the mouse and human AV nodes•Connexin 43 connects macrophages with cardiomyocytes•Macrophages modulate the electrical activity of cardiomyocytes•Macrophages assist normal AV nodal conduction
Heart-resident macrophages directly modulate the electrical properties of cardiomyocytes.
Little is known about how human Y-Chromosome gene expression directly contributes to differences between XX (female) and XY (male) individuals in nonreproductive tissues. Here, we analyzed ...quantitative profiles of Y-Chromosome gene expression across 36 human tissues from hundreds of individuals. Although it is often said that Y-Chromosome genes are lowly expressed outside the testis, we report many instances of elevated Y-Chromosome gene expression in a nonreproductive tissue. A notable example is
, which encodes eukaryotic translation initiation factor 1A Y-linked, together with its X-linked homolog
Evolutionary loss of a Y-linked microRNA target site enabled up-regulation of
, but not of
, in the heart. Consequently, this essential translation initiation factor is nearly twice as abundant in male as in female heart tissue at the protein level. Divergence between the X and Y Chromosomes in regulatory sequence can therefore lead to tissue-specific Y-Chromosome-driven sex biases in expression of critical, dosage-sensitive regulatory genes.
Expansion and rupture of abdominal aortic aneurysms (AAA) result in high morbidity and mortality rates. Like stenotic atherosclerotic lesions, AAA accumulate inflammatory cells, but usually exhibit ...much more extensive medial damage. Leukocyte recruitment and expression of pro-inflammatory Th1 cytokines typically characterize early atherogenesis of any kind, and modulation of inflammatory mediators mutes atheroma formation in mice. However, the mechanistic differences between stenotic and aneurysmal manifestations of atherosclerosis remain unexplained. We recently showed that aortic allografts deficient in interferon-γ (IFN-γ) signaling developed AAA correlating with skewed Th2 cytokine environments, suggesting important regulatory roles for Th1/Th2 cytokine balance in modulating matrix remodeling and important implications for the pathophysiology of aortic aneurysm and atherosclerosis. Further probing of their distinct aspects of immune and inflammatory responses in vascular diseases should continue to shed new light on the pathophysiologic mechanisms that give rise to aneurysmal versus occlusive manifestations and atherosclerosis.
Data on the molecular mechanisms that regulate platelet-pulmonary endothelial adhesion under conditions of hypoxia are lacking, but may have important therapeutic implications.
To identify a ...hypoxia-sensitive, modifiable mediator of platelet-pulmonary artery endothelial cell adhesion and thrombotic remodeling.
Network medicine was used to profile protein-protein interactions in hypoxia-treated human pulmonary artery endothelial cells. Data from liquid chromatography-mass spectrometry and microscale thermophoresis informed the development of a novel antibody (Ab) to inhibit platelet-endothelial adhesion, which was tested in cells from patients with chronic thromboembolic pulmonary hypertension (CTEPH) and three animal models
.
The protein NEDD9 was identified in the hypoxia thrombosome network
. Compared with normoxia, hypoxia (0.2% O
) for 24 hours increased HIF-1α (hypoxia-inducible factor-1α)-dependent NEDD9 upregulation
. Increased NEDD9 was localized to the plasma-membrane surface of cells from control donors and patients with CTEPH. In endarterectomy specimens, NEDD9 colocalized with the platelet surface adhesion molecule P-selectin. Our custom-made anti-NEDD9 Ab targeted the NEDD9-P-selectin interaction and inhibited the adhesion of activated platelets to pulmonary artery endothelial cells from control donors
and from patients with CTEPH
. Compared with control mice, platelet-pulmonary endothelial aggregates and pulmonary hypertension induced by ADP were decreased in NEDD9
mice or wild-type mice treated with the anti-NEDD9 Ab, which also decreased chronic pulmonary thromboembolic remodeling
.
The NEDD9-P-selectin protein-protein interaction is a modifiable target with which to inhibit platelet-pulmonary endothelial adhesion and thromboembolic vascular remodeling, with potential therapeutic implications for patients with disorders of increased hypoxia signaling pathways, including CTEPH.
Graft vascular disease (GVD) is the single most important long-term limitation to solid-organ transplantation. It is a concentric vascular intimal hyperplastic lesion composed of smooth muscle-like ...cells and associated matrix. GVD diffusely involves allograft vessels, eventually compromising perfusion and resulting in graft ischemia and failure. Animal models and an increasing sophistication in analyzing human GVD have provided important new insights into GVD pathogenesis. Innate and specific immune responses both participate in the initial vascular injury; GVD develops as a consequence of downstream chemokine- and cytokine-effector pathways. Other significant developments in the field include recognition of the central pathogenic role played by interferon-gamma as well as the contribution of host cell precursors to the intimal lesions. Because GVD shares many features with more common vascular pathologies, insights gleaned from our understanding of allograft vasculopathy may well impact our treatment for "traditional" atherosclerosis or restenosis lesions.
As therapeutic strategies to prevent acute rejection progressively improve, transplant vasculopathy (TV) constitutes the single most important limitation for long-term functioning of solid organ ...allografts. In TV, allograft arteries characteristically develop severe, diffuse intimal hyperplastic lesions that eventually compromise luminal flow and cause ischemic graft failure. Traditional immunosuppressive strategies that check acute allograft rejection do not prevent TV; indeed 50% of transplant recipients will have significant disease within five years of organ transplantation, and 90% will have significant TV a decade after their surgery. TV can involve the entire length of the transplanted arterial bed, including penetrating intraorgan arterioles. Indeed, the luminal narrowing of such penetrating vessels may be the most functionally significant because arterioles represent the major contributors to tissue vascular resistance. Because of the diffuseness of TV involvement in the allograft vascular bed, the only currently definitive therapy requires re-transplantation. Nevertheless, as we better understand the pathogenesis and critical mediators of these lesions, pharmacological advances can be anticipated. Other articles in this thematic review series focus on the specifics of the inciting injury, the cytokines and chemokines that drive TV development, and the nature of the recruited cells in TV lesions, as well as the pathogenic similarities between TV and other vascular lesions such as atherosclerosis. This review focuses on the mechanisms of vascular wall remodeling in TV, including the intimal accumulation of smooth muscle–like cells and associated extracellular matrix, medial smooth muscle cell degeneration, and adventitial fibrosis. A brief overview highlights the aneurysmal changes that can accrue when vessel wall inflammation has a cytokine profile distinct from the typical proinflammatory interferon-γ–dominated milieu.
Archaeological excavations close to St Louis' castle in Sidon, Lebanon have revealed two mass grave deposits containing partially articulated and disarticulated human skeletal remains. A minimum of ...25 male individuals have been recovered, with no females or young children. Radiocarbon dating of the human remains, a crusader coin, and the design of Frankish belt buckles strongly indicate they belong to a single event in the mid-13th century CE. The skeletal remains demonstrate a high prevalence of unhealed sharp force, penetrating force and blunt force trauma consistent with medieval weaponry. Higher numbers of wounds on the back of individuals than the front suggests some were attacked from behind, possibly as they fled. The concentration of blade wounds to the back of the neck of others would be compatible with execution by decapitation following their capture. Taphonomic changes indicate the skeletal remains were left exposed for some weeks prior to being collected together and re-deposited in the defensive ditch by a fortified gateway within the town wall. Charring on some bones provides evidence of burning of the bodies. The findings imply the systematic clearance of partially decomposed corpses following an attack on the city, where adult and teenage males died as a result of weapon related trauma. The skeletons date from the second half of the Crusader period, when Christian-held Sidon came under direct assault from both the Mamluk Sultanate (1253 CE) and the Ilkhanate Mongols (1260 CE). It is likely that those in the mass graves died during one of these assaults.
Sex differences abound in human health and disease, as they do in other mammals used as models. The extent to which sex differences are conserved at the molecular level across species and tissues is ...unknown. We surveyed sex differences in gene expression in human, macaque, mouse, rat, and dog, across 12 tissues. In each tissue, we identified hundreds of genes with conserved sex-biased expression-findings that, combined with genomic analyses of human height, explain ~12% of the difference in height between females and males. We surmise that conserved sex biases in expression of genes otherwise operating equivalently in females and males contribute to sex differences in traits. However, most sex-biased expression arose during the mammalian radiation, which suggests that careful attention to interspecies divergence is needed when modeling human sex differences.
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