Donor cell engineering with GSK3 inhibitor–loaded nanoparticles enhances engraftment after in utero transplantation

Host cell competition is a major barrier to engraftment after in utero hematopoietic cell transplantation (IUHCT). Here we describe a cell-engineering strategy using glycogen synthase kinase-3 (GSK3) inhibitor–loaded nanoparticles conjugated to the surface of donor hematopoietic cells to enhance their proliferation kinetics and ability to compete against their fetal host equivalents. With this approach, we achieved remarkable levels of stable, long-term hematopoietic engraftment for up to 24 weeks post-IUHCT. We also show that the salutary effects of the nanoparticle-released GSK3 inhibitor are specific to donor progenitor/stem cells and achieved by a pseudoautocrine mechanism. These results establish that IUHCT of hematopoietic cells decorated with GSK3 inhibitor–loaded nanoparticles can produce therapeutic levels of long-term engraftment and could therefore allow single-step prenatal treatment of congenital hematological disorders

Localized Fetomaternal Hyperglycemia: Spatial and Kinetic Definition by Positron Emission Tomography

to isolated hyperglycemia in the pregnant rat. mg/dL) localized to the left uterine artery was sustained for at least 48 hours while maternal euglycemia was maintained. fetal effects of isolated hyperglycemia. Broadly, this approach can be extended to study a variety of maternal-sided perturbations suspected to directly affect fetal health

Mining and state-space modeling and verification of sub-networks from large-scale biomolecular networks

<p>Abstract</p> <p>Background</p> <p>Biomolecular networks dynamically respond to stimuli and implement cellular function. Understanding these dynamic changes is the key challenge for cell biologists. As biomolecular networks grow in size and complexity, the model of a biomolecular network must become more rigorous to keep track of all the components and their interactions. In general this presents the need for computer simulation to manipulate and understand the biomolecular network model.</p> <p>Results</p> <p>In this paper, we present a novel method to model the regulatory system which executes a cellular function and can be represented as a biomolecular network. Our method consists of two steps. First, a novel scale-free network clustering approach is applied to the large-scale biomolecular network to obtain various sub-networks. Second, a state-space model is generated for the sub-networks and simulated to predict their behavior in the cellular context. The modeling results represent <it>hypotheses </it>that are tested against high-throughput data sets (microarrays and/or genetic screens) for both the natural system and perturbations. Notably, the dynamic modeling component of this method depends on the automated network structure generation of the first component and the sub-network clustering, which are both essential to make the solution tractable.</p> <p>Conclusion</p> <p>Experimental results on time series gene expression data for the human cell cycle indicate our approach is promising for sub-network mining and simulation from large-scale biomolecular network.</p

Mechanisms of Risk and Resilience in Military Families: Theoretical and Empirical Basis of a Family-Focused Resilience Enhancement Program

Recent studies have confirmed that repeated wartime deployment of a parent exacts a toll on military children and families and that the quality and functionality of familial relations is linked to force preservation and readiness. As a result, family-centered care has increasingly become a priority across the military health system. FOCUS (Families OverComing Under Stress), a family-centered, resilience-enhancing program developed by a team at UCLA and Harvard Schools of Medicine, is a primary initiative in this movement. In a large-scale implementation project initiated by the Bureau of Navy Medicine, FOCUS has been delivered to thousands of Navy, Marine, Navy Special Warfare, Army, and Air Force families since 2008. This article describes the theoretical and empirical foundation and rationale for FOCUS, which is rooted in a broad conception of family resilience. We review the literature on family resilience, noting that an important next step in building a clinically useful theory of family resilience is to move beyond developing broad “shopping lists” of risk indicators by proposing specific mechanisms of risk and resilience. Based on the literature, we propose five primary risk mechanisms for military families and common negative “chain reaction” pathways through which they undermine the resilience of families contending with wartime deployments and parental injury. In addition, we propose specific mechanisms that mobilize and enhance resilience in military families and that comprise central features of the FOCUS Program. We describe these resilience-enhancing mechanisms in detail, followed by a discussion of the ways in which evaluation data from the program’s first 2 years of operation supports the proposed model and the specified mechanisms of action