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Hypertrophic chondrocytes give rise to osteoblasts during skeletal development; however, the process by which these non-mitotic cells make this transition is not well understood. Prior studies have also suggested that skeletal stem and progenitor cells (SSPCs) localize to the surrounding periosteum and serve as a major source of marrow-associated SSPCs, osteoblasts, osteocytes, and adipocytes during skeletal development. To further understand the cell transition process by which hypertrophic chondrocytes contribute to osteoblasts or other marrow associated cells, we utilized inducible and constitutive hypertrophic chondrocyte lineage tracing and reporter mouse models ( Col10a1CreERT2; Rosa26 fs-tdTomato and Col10a1Cre; Rosa26 fs-tdTomato ) in combination with a PDGFRa H2B-GFP transgenic line, single-cell RNA-sequencing, bulk RNA-sequencing, immunofluorescence staining, and cell transplantation assays. Our data demonstrate that hypertrophic chondrocytes undergo a process of dedifferentiation to generate marrow-associated SSPCs that serve as a primary source of osteoblasts during skeletal development. These hypertrophic chondrocyte-derived SSPCs commit to a CXCL12-abundant reticular (CAR) cell phenotype during skeletal development and demonstrate unique abilities to recruit vasculature and promote bone marrow establishment, while also contributing to the adipogenic lineage.

In two separate studies, Amato Giaccia and Calvin Kuo and colleagues show that targeting of hypoxia-inducible factor-2α to increase its expression results in elevation of a key downstream effector of insulin signaling and thus improved insulin sensitivity in a mouse model of type 2 diabetes. Signaling initiated by hypoxia and insulin powerfully alters cellular metabolism. The protein stability of hypoxia-inducible factor-1 alpha (Hif-1α) and Hif-2α is regulated by three prolyl hydroxylase domain–containing protein isoforms (Phd1, Phd2 and Phd3). Insulin receptor substrate-2 (Irs2) is a critical mediator of the anabolic effects of insulin, and its decreased expression contributes to the pathophysiology of insulin resistance and diabetes 1 . Although Hif regulates many metabolic pathways 2 , it is unknown whether the Phd proteins regulate glucose and lipid metabolism in the liver. Here, we show that acute deletion of hepatic Phd3 , also known as Egln3 , improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2α, which then increases Irs2 transcription and insulin-stimulated Akt activation. Hif-2α and Irs2 are both necessary for the improved insulin sensitivity, as knockdown of either molecule abrogates the beneficial effects of Phd3 knockout on glucose tolerance and insulin-stimulated Akt phosphorylation. Augmenting levels of Hif-2α through various combinations of Phd gene knockouts did not further improve hepatic metabolism and only added toxicity. Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms.

Bone fractures and related complications are a significant concern for older adults, particularly with the growing aging population. Therapeutic interventions that promote bone tissue regeneration are attractive for geriatric fracture repair. Extracellular adenosine plays a key role in bone homeostasis and regeneration. Herein, we examined the changes in extracellular adenosine with aging and the potential of local delivery of adenosine to promote fracture healing using aged mice. Extracellular adenosine level was found to be significantly lower in aged bone tissue compared to young mice. Concomitantly, the ecto-5′-nucleotidase CD73 expression was also lower in aged bone. Local delivery of adenosine using injectable, in situ curing microgel delivery units yielded a pro-regenerative environment and promoted fracture healing in aged mice. This study offers new insights into age-related physiological changes in adenosine levels and demonstrates the therapeutic potential of adenosine supplementation to circumvent the compromised healing of geriatric fractures.

This essay discusses what is at stake when Dickinson's poetry is situated within a social, cultural, or historical context in order to define its distinctive poetic value. The relation between Dickinson's lyric self and external contexts is one with tension and spontaneity, and thus, as I will argue, is close to a dialectical relation defined by Theodor W. Adorno. I will further explain how Adorno and Heidegger put each other's ideas into question and thus delineate a more genuine dialectical relation. Via this dialectical relation, I will interpret Dickinson's poems and show how her lyric self “has overcome himself [or herself] as subject” (Heidegger's term). Dickinson's lyric self challenges both Adorno's and Heidegger's arguments because the lyric self's resistance to social definition results from the possibility of a mediated “I” in poetry. The lyric self's resistance is thus not always socially or politically motivated as Adorno argues. The lyric self overcomes his/her subjectivity not through a prepared ground plan to interpret the world, as Heidegger suggests, but because the self is already a mediated “I” from the very beginning—an “I” mediated by the other composed in poetry as soon as “I” is written. It is an “I” mediated within poetry contending with an “I” mediated by social context.

T. S. Eliot succinctly concludes that “a thought to Donne was an experience.” This statement is paradoxical in nature as a metaphysical thought is expressed through a secular experience. Metaphysical thinking characterizes Donne's poetry as metaphysics is to define an abstract idea through empirical entities, and, as Eliot notes, Donne is good at turning a thought into an experience and giving an illustration or elaboration of a metaphysical idea. For Adorno, “metaphysics, because it attempts to regard the Ideas as something linked to the empirical world but endangered by advancing secularization, was itself threatened from the first in its own development.” As metaphysics purports to grasp what is essential, this purpose is simultaneously questioned and counteracted by its own movement. Nonetheless, the controversy in this movement happens to define the possibility of metaphysics—that is, its possibility lies in its difficulty and impossibility of self-definition. This essay aims to discuss how Donne presents love in his love poems as he relates love to concrete particulars and secular experiences in a metaphysical approach. At the end, in Donne's love poems, love as an abstract idea deconstructs itself in its definition as it is no longer pure or abstract. Nonetheless, love's engagement with objects and subjects in a social context shows how far Donne's presentation of love reaches what it is not (or its opposite) and the empirical world, and thus reveals how much Donne's understanding of love might speak of the truth of love in the world.

Purpose: We provide background information/education for national recommendations to include initial newborn screening dried bloodspot serial numbers in electronic birth registrations. Mutual data linking would provide quality checks for each data source, determinations of percentages of newborns screened, and identification of locations where screening is lacking. Methods: State newborn screening dried bloodspot programs were surveyed to determine the extent of newborn screening dried bloodspot and electronic birth registration linking and the states’ level of interest in such linkages. These data were reviewed with federal and state policy makers and presented to the Secretary of Health and Human Services’ Advisory Committee on Heritable Disorders in Newborns and Children for national policy recommendations. Results: Only 40% of state newborn screening dried bloodspot programs reported comparing births with screens. All states use serially numbered newborn screening dried bloodspot collection cards, and electronic birth registrations exist in almost all states. Newborn screening dried bloodspot serial number data fields currently exist in only 24% of state electronic birth registrations. Conclusion: The Secretary of Health and Human Services’ Advisory Committee on Heritable Disorders in Newborns and Children recommends the universal use of the newborn screening dried bloodspot serial number in a standardized format as part of state birth registration; consideration of including the initial newborn screening dried bloodspot serial number as a required data field; and, once established, using these data linkages to monitor completeness of newborn screening and to validate demographic information in both systems. Genet Med 2013:15(3):229–233

Radiation therapy is an essential cancer treatment, yet collateral damage to normal tissues remains a major clinical challenge. In bone, radiation-induced toxicity is characterized by loss of hematopoietic function, reduced bone volume, and increased marrow adipose tissue (MAT). Importantly, cancer patients who undergo radiotherapy exhibit significantly higher fracture risk compared to those receiving similar treatments without radiation exposure, underscoring the clinical consequences of bone microenvironment (BME) injury. The BME is inherently hypoxic resulting in the activation of by hypoxia-inducible factor (HIF) signaling. Here, we demonstrate that radiation induces a rapid and persistent accumulation of MAT, with adipocytes localizing preferentially to hypoxic regions of the marrow. To investigate the role of hypoxia/HIF signaling in this process, we generated conditional knockout mice. Surprisingly, these mice exhibited increased MAT expansion following radiation compared to controls, suggesting that HIF deletion in aP2-expressing cells exacerbates radiation-induced adipogenesis. Analysis aP2CreRosa26 mice revealed that most aP2-expressing cells did not give rise to mature adipocytes, macrophages, or endothelial cells, pointing instead to an uncharacterized stromal population that influences MAT formation. In contrast, conditional ablation of HIFα transcription factors in -expressing skeletal stem cells, which contain a subpopulation of skeletal progenitors which directly contribute to marrow adipocytes, had no effect on radiation-induced MAT expansion. Collectively, these findings identify a previously unrecognized population of adipocyte-regulatory cells whose HIF-dependent activity constrains stress-induced marrow adiposity. This work provides new mechanistic insight into how radiation disrupts the marrow microenvironment and expands MAT, advancing our understanding of the cellular and molecular drivers of radiation-induced bone fragility. Loss of HIF signaling in aP2Cre expressing cells enhances radiation induced marrow adiposity.

Despite the clonal origins of tumors, the majority of neoplasms are composed of a heterogeneous population of cells. The origins of this phenotype these cells have the potential to get can be associated with cancer stem cells or tumor initiating cells have the potential to self-renew and to differentiate giving rise to all cell types compromising a heterogeneous malignancy. These cells are clinically important as they preferentially give rise to tumors and are therefore hypothesized to account for the longevity and recurrence of neoplastic lesions. Cancer stem cells have been identified from a broad range of hematopoietic, neural and epithelia tumors; however, their function in mesenchymal neoplasms is less well defined. Using the side population assay, we identified a subpopulation of cells within mesenchymal neoplasms, referred to as side population cells, which are enhanced for tumor initiating potential. Importantly, we show a correlation between the percentage of side population cells and tumor grade suggesting clinical prognostic value as the proportion of side population cells may be a predictor of patient outcome. Interestingly side population cells show distinct molecular features when compared to non-side population cells and manipulation of these molecular mechanisms reduces the ability of side population cells to initiate tumor formation in osteosarcoma cell lines. In conjunction with these experiments, we also sought to determine the cellular origins of the mesenchymal neoplasm, aggressive fibromatosis. Using mouse models we show the influence of a mesenchymal precursor cells in the development of this malignancy. These results identify important biological features of mesenchymal neoplasms from which the development of targeted treatment strategies can begin.