Forever is a Long Time: Reconsidering Universities' Perpetual Endowment Policies in the Twenty - First Century

College and university officials in the United States have long invoked a combination of Anglo-Saxon legal precedents, plus the obligations of responsible philanthropic stewardship, to justify policies of perpetual endowments. Closely related to this general principle has been the practice of not spending more than the annual earnings (in other words, interest and dividends) from an endowment. Our historical analysis provides a counter to this contemporary conventional wisdom that has been accepted with little critical consideration in American higher education. Rediscovery of philosophical arguments, and actual cases of foundations and philanthropists who placed limits on the life span of gifts, demonstrates how historical research can provide an informed base for reconsideration of government and institutional policies and practices that shape giving and spending at colleges and universities in the twenty-first century.The grounding in economics for our study is Howard Bowen's 1980 "revenue theory" of college costs. The historical precedent for our policy analysis comes from eighteenth-century France, as advanced by A.J. Turgot, to shape national economic development. Its implications for higher education in the United States is illustrated by philanthropist John D. Rockefeller's reservations about a perpetual endowment for an educational project: "Forever is a long time . . ." Our historical research addresses the consequences -- pro and con -- of government policies requiring colleges to spend endowments at more than a marginal annual rate and in a fixed period of time; and, secondly, are there good reasons for donors to colleges to voluntarily opt to increase spending and place time limits on gifts

Time Is Of The Essence: Foundations And The Policies Of Limited Life And Endowment Spend-Down

In contrast to congressional hearings and proposed punitive legislation, we consider the present and past proposition that institutions, especially nonprofit foundations, opt voluntarily and by decision to spend down endowments. And, by extension, for many cases, it includes consideration that boards and donors may wish to plan for deliberate dissolution of funds or foundations to coincide with a fixed, finite target date for addressing solutions to specific foundation programs and agenda items

The regulation of CFTR by protein-protein interactions

Cystic fibrosis (CF) is an autosomal recessive disease resulting from the misregulation of epithelial ion transport. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an apical membrane chloride channel expressed in polarized epithelial cells. To identify factors that regulate CFTR activity, we utilized biochemical and proteomics approaches to identify novel CFTR binding proteins. We find that the C-terminus of CFTR directly interacts with the serine/threonine phosphatase PP2A. PP2A is a heterotrimeric phosphatase composed of a catalytic subunit and two divergent regulatory subunits (A and B), which mediate the cellular localization and substrate specificity of the enzyme. By mass spectrometry, we identified the exact PP2A regulatory subunits associated with CFTR as Aα and B’ε, and find that the B’ε subunit binds CFTR directly. PP2A subunits localize to the apical surface of airway epithelia and PP2A phosphatase activity co-purifies with CFTR in Calu-3 cells. In functional assays, PP2A inhibition blocks the rundown of basal CFTR currents and increases channel activity in excised patches of airway epithelia and in intact mouse jejunum. Moreover, PP2A inhibition increases the pericilliary liquid in cultures of well differentiated human bronchial epithelial cells by a CFTR-dependent mechanism. Thus, PP2A is a relevant CFTR phosphatase in epithelial tissues and may be a clinically relevant drug target for CF. Additionally, the N-terminus of CFTR directly interacts with two actin binding proteins, filamin A and filamin B. In polarized epithelial cells, filamins are highly localized to the sub-apical compartment where they likely interact with CFTR at or near the plasma membrane. We find that CFTR and filamins specifically interact by co-immunoprecipitation and that a disease-causing mutation in CFTR, serine 13 to phenylalanine (S13F), disrupts this interaction. Consistent with the loss of cytoskeletal anchorage, S13F CFTR displays decreased cell surface levels and less confinement at the plasma membrane relative to wildtype CFTR. Furthermore, S13F CFTR is more rapidly degraded compared to wild-type CFTR which correlates with the accumulation of S13F CFTR in the lysosomes. Taken together, these data suggest the filamins regulate the cell surface stability and endocytic trafficking of CFTR

Pressure Dependency of the Membrane Structure Parameter and Implications in Pressure Retarded Osmosis (PRO)

Pressure retarded osmosis (PRO) can be used to exploit the mixing energy e.g. between river water and sea water. A PRO membrane must be highly permeable for water, whereas salt ions should be retained. Furthermore, the structure parameter of the membrane support and backing structure must be low. This paper summarises an assessment of the pressure dependency of the structure parameter for flat sheet membranes, and a transport model for PRO and procedures for determination of the pressure dependency of the structure parameter are presented. The results from laboratory experiments show that that the structure parameter increases significantly with increasing trans-membrane pressure. The increase in the structure parameter was observed to depend on both characteristics of the membrane and the fresh water spacer. Using a finely textured tricot spacer reduced the pressure dependency on the structure parameter, compared to a coarser spacer. Applying a non-woven backing material between the membrane and the fresh water spacer also reduced the impact of pressure. The results show that membranes suitable for river water/sea water PRO must have a sufficiently low structure parameter and additionally resist severe deformation at relevant operating pressures

Transient anchorage of cross-linked glycosyl-phosphatidylinositol–anchored proteins depends on cholesterol, Src family kinases, caveolin, and phosphoinositides

How outer leaflet plasma membrane components, including glycosyl-phosphatidylinositol–anchored proteins (GPIAPs), transmit signals to the cell interior is an open question in membrane biology. By deliberately cross-linking several GPIAPs under antibody-conjugated 40-nm gold particles, transient anchorage of the gold particle–induced clusters of both Thy-1 and CD73, a 5′ exonucleotidase, occurred for periods ranging from 300 ms to 10 s in fibroblasts. Transient anchorage was abolished by cholesterol depletion, addition of the Src family kinase (SFK) inhibitor PP2, or in Src-Yes-Fyn knockout cells. Caveolin-1 knockout cells exhibited a reduced transient anchorage time, suggesting the partial participation of caveolin-1. In contrast, a transmembrane protein, the cystic fibrosis transmembrane conductance regulator, exhibited transient anchorage that occurred without deliberately enhanced cross-linking; moreover, it was only slightly inhibited by cholesterol depletion or SFK inhibition and depended completely on the interaction of its PDZ-binding domain with the cytoskeletal adaptor EBP50. We propose that cross-linked GPIAPs become transiently anchored via a cholesterol-dependent SFK-regulatable linkage between a transmembrane cluster sensor and the cytoskeleton

A Novel PDZ Protein Regulates the Activity of Guanylyl Cyclase C, the Heat-stable Enterotoxin Receptor

Secretory diarrhea is the leading cause of infectious diarrhea in humans. Secretory diarrhea may be caused by binding of heat-stable enterotoxins to the intestinal receptor guanylyl cyclase C (GCC). Activation of GCC catalyzes the formation of cGMP, initiating a signaling cascade that opens the cystic fibrosis transmembrane conductance regulator chloride channel at the apical cell surface. To identify proteins that regulate the trafficking or function of GCC, we used the unique COOH terminus of GCC as the "bait" to screen a human intestinal yeast two-hybrid library. We identified a novel protein, IKEPP (intestinal and kidney-enriched PDZ protein) that associates with the COOH terminus of GCC in biochemical assays and by co-immunoprecipitation. IKEPP is expressed in the intestinal epithelium, where it is preferentially accumulated at the apical surface. The GCC-IKEPP interaction is not required for the efficient targeting of GCC to the apical cell surface. Rather, the association with IKEPP significantly inhibits heat-stable enterotoxin-mediated activation of GCC. Our findings are the first to identify a regulatory protein that associates with GCC to modulate the catalytic activity of the enzyme and provides new insights in mechanisms that regulate GCC activity in response to bacterial toxin

Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury.

BACKGROUND: Neuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development; however, how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition. METHODS: TBI patients recruited to a previous randomised controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n = 10 treatment arm, n = 10 control arm). Cytokine concentrations were measured in arterial and jugular venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 h. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used. RESULTS: Jugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen. No substantial delayed temporal associations between blood and brain compartments were detected. The development of a systemic clinical infection resulted in a significant decrease of IL1-ra, G-CSF, PDGF-ABBB, MIP-1b and RANTES (p < 0.05, respectively) in brain-ECF, even if adjusting for injury severity and demographic factors, while an increase in several cytokines could be seen in arterial blood. CONCLUSIONS: Systemic inflammation, and infection in particular, alters cytokine levels with different patterns seen in brain and in blood. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, but novel prospective trials are warranted to confirm these associations