Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and ...release of leukocyte increases after stroke, it is currently unknown whether its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow-derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.
Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. ...The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2−/− cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.
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•HSC proliferation is elevated in mice and humans with atherosclerosis•Increased proliferation accelerates somatic evolution and clonal hematopoiesis (CH)•Measured rates imply several-fold increased risk of CH in atherosclerosis patients•Mutant expansion is accelerated in mice with increased HSC proliferation
Heyde et al. propose that clonal hematopoiesis can be a symptom rather than a cause of atherosclerosis, since this disease increases hematopoietic stem cell division, which results in accelerated somatic evolution.
A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that ...voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creER
; Lepr
mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.
BACKGROUND:Diabetes mellitus is a prevalent public health problem that affects about one-third of the US population and leads to serious vascular complications with increased risk for coronary artery ...disease. How bone marrow hematopoiesis contributes to diabetes mellitus complications is incompletely understood. We investigated the role of bone marrow endothelial cells in diabetic regulation of inflammatory myeloid cell production.
METHODS:In 3 types of mouse diabetes mellitus, including streptozotocin, high-fat diet, and genetic induction using leptin-receptor-deficient db/db mice, we assayed leukocytes, hematopoietic stem and progenitor cells (HSPC). In addition, we investigated bone marrow endothelial cells with flow cytometry and expression profiling.
RESULTS:In diabetes mellitus, we observed enhanced proliferation of HSPC leading to augmented circulating myeloid cell numbers. Analysis of bone marrow niche cells revealed that endothelial cells in diabetic mice expressed less Cxcl12, a retention factor promoting HSPC quiescence. Transcriptome-wide analysis of bone marrow endothelial cells demonstrated enrichment of genes involved in epithelial growth factor receptor (Egfr) signaling in mice with diet-induced diabetes mellitus. To explore whether endothelial Egfr plays a functional role in myelopoiesis, we generated mice with endothelial-specific deletion of Egfr (Cdh5 Egfr). We found enhanced HSPC proliferation and increased myeloid cell production in Cdh5 Egfr mice compared with wild-type mice with diabetes mellitus. Disrupted Egfr signaling in endothelial cells decreased their expression of the HSPC retention factor angiopoietin-1. We tested the functional relevance of these findings for wound healing and atherosclerosis, both implicated in complications of diabetes mellitus. Inflammatory myeloid cells accumulated more in skin wounds of diabetic Cdh5 Egfr mice, significantly delaying wound closure. Atherosclerosis was accelerated in Cdh5 Egfr mice, leading to larger and more inflamed atherosclerotic lesions in the aorta.
CONCLUSIONS:In diabetes mellitus, bone marrow endothelial cells participate in the dysregulation of bone marrow hematopoiesis. Diabetes mellitus reduces endothelial production of Cxcl12, a quiescence-promoting niche factor that reduces stem cell proliferation. We describe a previously unknown counterregulatory pathway, in which protective endothelial Egfr signaling curbs HSPC proliferation and myeloid cell production.
This article focuses on the theory of Conditional Party Government (CPG). It seeks to recapitulate the development of the argument for CPG, pulling together various strands articulated during work on ...the theory over the last four decades in order to explain why the theory took the form it did. The discussion focuses on some of the most important evidence that relates to the predictions of CPG, in order to account for the evolution of the theory over time in interaction with that evidence. It also offers some reflections at various points on the implications of this theoretical and empirical effort for the study of Congress.
RATIONALE:After a stroke, patients frequently experience altered systemic immunity resulting in peripheral immunosuppression and higher susceptibility to infections, which is at least partly ...attributed to lymphopenia. The mechanisms that profoundly change the systemic leukocyte repertoire after stroke are incompletely understood. Emerging evidence indicates that stroke alters hematopoietic output of the bone marrow.
OBJECTIVE:To explore the mechanisms that lead to defects of B lymphopoiesis after ischemic stroke.
METHODS AND RESULTS:We here report that ischemic stroke triggers brain-bone marrow communication via hormonal long-range signals that regulate hematopoietic B lineage decisions. Bone marrow fluorescence-activated cell sorter analyses and serial intravital microscopy indicate that transient middle cerebral artery occlusion in mice arrests B-cell development beginning at the pro-B-cell stage. This phenotype was not rescued in Myd88 and TLR4 mice with disrupted TLR (Toll-like receptor) signaling or after blockage of peripheral sympathetic nerves. Mechanistically, we identified stroke-induced glucocorticoid release as the main instigator of B lymphopoiesis defects. B-cell lineage-specific deletion of the GR (glucocorticoid receptor) in CD19-Cre loxP Nr3c1 mice attenuated lymphocytopenia after transient middle cerebral artery. In 20 patients with acute stroke, increased cortisol levels inversely correlated with blood lymphocyte numbers.
CONCLUSIONS:Our data demonstrate that the hypothalamic-pituitary-adrenal axis mediates B lymphopoiesis defects after ischemic stroke.
This text meticulously and accessibly explains the National Election Studies data and analyzes its importance and impact, covering the most recent presidential and Congressional elections, voter ...turnout, and the social forces, party loyalties, and prominent issues that affect voting behavior.
A continental-scale model of Holocene Australian hunter-gatherer demography and mobility is generated using radiocarbon data and geospatial techniques. Results show a delayed expansion and settlement ...of much of Australia following the termination of the late Pleistocene until after 9,000 years ago (or 9ka). The onset of the Holocene climatic optimum (9-6ka) coincides with rapid expansion, growth and establishment of regional populations across ~75% of Australia, including much of the arid zone. This diffusion from isolated Pleistocene refugia provides a mechanism for the synchronous spread of pan-continental archaeological and linguistic attributes at this time (e.g. Pama-Nyungan language, Panaramitee art style, backed artefacts). We argue longer patch residence times were possible at the end of the optimum, resulting in a shift to more sedentary lifestyles and establishment of low-level food production in some parts of the continent. The onset of El Niño - Southern Oscillation (ENSO; 4.5-2ka) restricted low-level food production, and resulted in population fragmentation, abandonment of marginal areas, and reduction in ranging territory of ~26%. Importantly, climate amelioration brought about by more pervasive La Niña conditions (post-2ka), resulted in an intensification of the mobility strategies and technological innovations that were developed in the early- to mid-Holocene. These changes resulted in population expansion and utilization of the entire continent. We propose that it was under these demographically packed conditions that the complex social and religious societies observed at colonial contact were formed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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