Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives

The retinal pigment epithelium (RPE) is a monolayer of cells underlying and supporting the neural retina. It begins as a plastic tissue, capable, in some species, of generating lens and retina, but differentiates early in development and remains normally nonproliferative throughout life. Here we show that a subpopulation of adult human RPE cells can be activated in vitro to a self-renewing cell, the retinal pigment epithelial stem cell (RPESC) that loses RPE markers, proliferates extensively, and can redifferentiate into stable cobblestone RPE monolayers. Clonal studies demonstrate that RPESCs are multipotent and in defined conditions can generate both neural and mesenchymal progeny. This plasticity may explain human pathologies in which mesenchymal fates are seen in the eye, for example in proliferative vitroretinopathy (PVR) and phthisis bulbi. This study establishes the RPESC as an accessible, human CNS-derived multipotent stem cell, useful for the study of fate choice, replacement therapy, and disease modeling.     

Subsistence Exposure Scenarios for Tribal Applications

The article provides an overview of methods that can be used to develop exposure scenarios for unique tribal natural resource usage patterns. Exposure scenarios are used to evaluate the degree of environmental contact experienced by people with different patterns of lifestyle activities, such as residence, recreation, or work. In 1994, U.S. President Bill Clinton's Executive Order 12898 recognized that disproportionately high exposures could be incurred by people with traditional subsistence lifestyles because of their more intensive contact with natural resources. Since then, we have developed several tribal exposure scenarios that reflect tribal-specific traditional lifeways. These scenarios are not necessarily intended to capture contemporary resource patterns, but to describe how the resources were used before contamination or degradation, and will be used once again in fully traditional ways after cleanup and restoration. The direct exposure factors for inhalation and soil ingestion rates are the same in each tribal scenario, but the diets are unique to each tribe and its local ecology, natural foods, and traditional practices. Scenarios, in part or in whole, also have other applications, such as developing environmental standards, evaluating disproportionate exposures, developing sampling plans, planning for climate change, or evaluating service flows as part of natural resource damage assessments.     

High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor

The nuclear protein high mobility group box protein 1 (HMGB1) promotes inflammation upon extracellular release. HMGB1 induces proinflammatory cytokine production in macrophages via Toll-like receptor (TLR)-4 signaling in a redox-dependent fashion. Independent of its redox state and endogenous cytokine-inducing ability, HMGB1 can form highly immunostimulatory complexes by interaction with certain proinflammatory mediators. Such complexes have the ability to enhance the induced immune response up to 100-fold, compared with induction by the ligand alone. To clarify the mechanisms for these strong synergistic effects, we studied receptor requirements. Interleukin (IL)-6 production was assessed in supernatants from cultured peritoneal macrophages from mice each deficient in one of the HMGB1 receptors (receptor for advanced glycation end products [RAGE], TLR2 or TLR4) or from wild-type controls. The cultures were stimulated with the TLR4 ligand lipopolysaccaride (LPS), the TLR2 ligand Pam₃CysSerLys₄ (Pam₃CSK₄), noninflammatory HMGB1 or each TLR ligand in complex with noninflammatory HMGB1. The activity of the HMGB1-TLR ligand complexes relied on engagement of the same receptor as for the noncomplexed TLR ligand, since HMGB1-LPS complexes used TLR4 and HMGB1-Pam₃CSK₄ complexes used TLR2. Deletion of any of the intracellular adaptor molecules used by TLR2 (myeloid differentiation factor-88 [MyD88], TIR domain–containing adaptor protein [TIRAP]) or TLR4 (MyD88, TIRAP, TIR domain–containing adaptor-inducing interferon-β [TRIF], TRIF-related adaptor molecule [TRAM]) had similar effects on HMGB1 complex activation compared with noncomplexed LPS or Pam₃CSK₄. This result implies that the enhancing effects of HMGB1-partner molecule complexes are not regulated by the induction of additional signaling cascades. Elucidating HMGB1 receptor usage in processes where HMGB1 acts alone or in complex with other molecules is essential for the understanding of basic HMGB1 biology and for designing HMGB1-targeted therapies.     

Priming of Social Distance? Failure to Replicate Effects on Social and Food Judgments

Williams and Bargh (2008) reported an experiment in which participants were simply asked to plot a single pair of points on a piece of graph paper, with the coordinates provided by the experimenter specifying a pair of points that lay at one of three different distances (close, intermediate, or far, relative to the range available on the graph paper). The participants who had graphed a more distant pair reported themselves as being significantly less close to members of their own family than did those who had plotted a more closely-situated pair. In another experiment, people's estimates of the caloric content of different foods were reportedly altered by the same type of spatial distance priming. Direct replications of both results were attempted, with precautions to ensure that the experimenter did not know what condition the participant was assigned to. The results showed no hint of the priming effects reported by Williams and Bargh (2008).