Exploring the Racial Gap in Infant Mortality Rates, 1920-1970

This paper examines the racial gap in infant mortality rates from 1920 to 1970. Using state-level panel data with information on income, urbanization, women's education, and physicians per capita, we can account for a large portion of the racial gap in infant mortality rates between 1920 and 1945, but a smaller portion thereafter. We re-examine the post-war period in light of trends in birth weight, smoking, air pollution, breast-feeding, insurance, and hospital births.

Loss of Rb Cooperates with Ras to Drive Oncogenic Growth in Mammalian Cells

Background The p53, Rb, and Ras/PI3K pathways are implicated in the development of the majority of human cancers. A number of studies have established that these pathways cooperate at the level of the cell cycle leading to loss of normal proliferative controls. Here we have investigated how these signals influence a second critical component of tumor formation—cell growth. Results We find that oncogenic Ras is sufficient to drive growth via the canonical growth pathway, PI3K-AKT-TOR; however, it does so relatively weakly and p53 loss does not drive cell growth at all. Importantly, we identify a novel role for the Rb family of tumor suppressors in directing cell growth via a signaling pathway distinct from PI3K-AKT-TOR and via an E2F-independent mechanism. However, we find that strong, sustained growth requires Rb loss together with Ras signaling, identifying an additional mechanism by which these oncogenic pathways cooperate and a critical role for Ras in preserving the uptake of extracellular nutrients required for biogenesis. Conclusions We have identified a new role for the Rb family in cell biogenesis and show that, as for other processes associated with tumor development, oncogenic cell growth is dependent on cooperating oncogenes

Loss of Rb Cooperates with Ras to Drive Oncogenic Growth in Mammalian Cells

SummaryBackgroundThe p53, Rb, and Ras/PI3K pathways are implicated in the development of the majority of human cancers. A number of studies have established that these pathways cooperate at the level of the cell cycle leading to loss of normal proliferative controls. Here we have investigated how these signals influence a second critical component of tumor formation—cell growth.ResultsWe find that oncogenic Ras is sufficient to drive growth via the canonical growth pathway, PI3K-AKT-TOR; however, it does so relatively weakly and p53 loss does not drive cell growth at all. Importantly, we identify a novel role for the Rb family of tumor suppressors in directing cell growth via a signaling pathway distinct from PI3K-AKT-TOR and via an E2F-independent mechanism. However, we find that strong, sustained growth requires Rb loss together with Ras signaling, identifying an additional mechanism by which these oncogenic pathways cooperate and a critical role for Ras in preserving the uptake of extracellular nutrients required for biogenesis.ConclusionsWe have identified a new role for the Rb family in cell biogenesis and show that, as for other processes associated with tumor development, oncogenic cell growth is dependent on cooperating oncogenes

Translating Evidence-Based Policy to Practice: A Multilevel Partnership Using the Interactive Systems Framework

This is the published version, made available with the permission of the publisher.Despite increases in federal allocations, little is known about how to ensure successful implementation of evidence-based programs. This descriptive case study using the Interactive Systems Framework for Dissemination and Implementation illustrates the Prevention Support System (PSS) implemented for one federal evidence-based policy initiative. Exploring perspectives of intermediary organizations, the article describes the impetus for promoting evidence-based programming, multilevel systemic change, and the collaborations to develop strategic partnerships between national and state entities. Two early adopters, Kansas and Nebraska, illustrate the general capacity-building technical assistance activities conducted to build a multilevel PSS. The article concludes with outcomes, lessons learned, and recommendations for building stronger implementation capacity

A Central Role for the ERK-Signaling Pathway in Controlling Schwann Cell Plasticity and Peripheral Nerve Regeneration In Vivo

SummaryFollowing damage to peripheral nerves, a remarkable process of clearance and regeneration takes place. Axons downstream of the injury degenerate, while the nerve is remodeled to direct axonal regrowth. Schwann cells are important for this regenerative process. “Sensing” damaged axons, they dedifferentiate to a progenitor-like state, in which they aid nerve regeneration. Here, we demonstrate that activation of an inducible Raf-kinase transgene in myelinated Schwann cells is sufficient to control this plasticity by inducing severe demyelination in the absence of axonal damage, with the period of demyelination/ataxia determined by the duration of Raf activation. Remarkably, activation of Raf-kinase also induces much of the inflammatory response important for nerve repair, including breakdown of the blood-nerve barrier and the influx of inflammatory cells. This reversible in vivo model identifies a central role for ERK signaling in Schwann cells in orchestrating nerve repair and is a powerful system for studying peripheral neuropathies and cancer

Functionally Conserved Noncoding Regulators of Cardiomyocyte Proliferation and Regeneration in Mouse and Human

BACKGROUND: The adult mammalian heart has little regenerative capacity after myocardial infarction (MI), whereas neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI. METHODS AND RESULTS: Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA (miRNA) expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and noncoding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two-thirds of each of the messenger RNAs, long noncoding RNAs, and miRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these miRNAs, miR-144-3p, miR-195a-5p, miR- 451a, and miR-6240 showed evidence of functional conservation in human cardiomyocytes. CONCLUSIONS: The sets of messenger RNAs, miRNAs, and long noncoding RNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.Leducq Foundation funding via the Transatlantic Network of Excellence (Grant 11CVD01), the British Heart Foundation funding via the Imperial College Centre of Research Excellence and the Imperial Cardiovascular Regenerative Medicine Centre RM/13/1/30157

Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated HckF/F “knock-in” mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y499-residue in the Hck protein. Unlike their Hck−/− “loss-of-function” counterparts, HckF/F “gain-of-function” mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from HckF/F mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), HckF/F mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)α. Similarly, HckF/F mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from HckF/F mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFα production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in HckF/F mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage

Rapid, Low-Cost Detection of Zika Virus Using Programmable Biomolecular Components

The recent Zika virus outbreak highlights the need for low-cost diagnostics that can be rapidly developed for distribution and use in pandemic regions. Here, we report a pipeline for the rapid design, assembly, and validation of cell-free, paper-based sensors for the detection of the Zika virus RNA genome. By linking isothermal RNA amplification to toehold switch RNA sensors, we detect clinically relevant concentrations of Zika virus sequences and demonstrate specificity against closely related Dengue virus sequences. When coupled with a novel CRISPR/Cas9-based module, our sensors can discriminate between viral strains with single-base resolution. We successfully demonstrate a simple, field-ready sample-processing workflow and detect Zika virus from the plasma of a viremic macaque. Our freeze-dried biomolecular platform resolves important practical limitations to the deployment of molecular diagnostics in the field and demonstrates how synthetic biology can be used to develop diagnostic tools for confronting global health crises.Defense Threat Reduction Agency (DTRA) (HDTRA1-14-1-0006)United States. National Institutes of Health (NIH AI100190

Development of a Rabbit Human Glioblastoma Model for Testing of Endovascular Selective Intra-Arterial Infusion (ESIA) of Novel Stem Cell-Based Therapeutics

BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24). METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on magnetic resonance imaging, histologic, and immunohistochemistry analysis. Selective microcatheter infusion of MSC-D24 was performed via the ipsilateral internal carotid artery to assess model utility and the efficacy and safety of this approach. RESULTS: Twenty-five rabbits were implanted (18 with U87, 2 MDA-GSC-17, and 5 MDA-GSC-8-11). Tumors formed in 68% of rabbits (77.8% for U87, 50.0% for MDA-GSC-17, and 40.0% for MDA-GSC-8-11). On MRI, the tumors were hyperintense on T2-weighted image with variable enhancement (evidence of blood brain barrier breakdown). Histologically, tumors showed phenotypic traits of human GBM including varying levels of vascularity. ESIA infusion into the distal internal carotid artery of 2 ml of MSCs-D24 (107 cells) was safe in the model. Examination of post infusion specimens documented that MSCs-D24 homed to the implanted tumor at 24 hours. CONCLUSIONS: The intracranial immunosuppressed rabbit human GBM model allows testing of ESIA infusion of novel therapeutics (eg, MSC-D24) in a clinically relevant fashion