Determination of biomembrane bending moduli in fully atomistic simulations.

The bilayer bending modulus (Kc) is one of the most important physical constants characterizing lipid membranes, but precisely measuring it is a challenge, both experimentally and computationally. Experimental measurements on chemically identical bilayers often differ depending upon the techniques employed, and robust simulation results have previously been limited to coarse-grained models (at varying levels of resolution). This Communication demonstrates the extraction of Kc from fully atomistic molecular dynamics simulations for three different single-component lipid bilayers (DPPC, DOPC, and DOPE). The results agree quantitatively with experiments that measure thermal shape fluctuations in giant unilamellar vesicles. Lipid tilt, twist, and compression moduli are also reported

Concise Total Synthesis of (+)-Asperazine, (+)-Pestalazine A, and (+)-iso-Pestalazine A. Structure Revision of (+)-Pestalazine A

The concise, enantioselective total syntheses of (+)-asperazine (1), (+)-iso-pestalazine A (2), and (+)-pestalazine A (3) have been achieved by the development of a late-stage C3–C8′ Friedel–Crafts union of polycyclic diketopiperazines. Our modular strategy enables the union of complex polycyclic diketopiperazines in virtually their final forms, thus providing rapid and highly convergent assembly at the challenging quaternary stereocenter of these dimeric alkaloids. The significance of this carbon–carbon bond formation can be gauged by the manifold constraints that were efficiently overcome, namely the substantial steric crowding at both reactive sites, the nucleophilic addition of C8′ over N1′ to the C3 carbocation, and the multitude of reactivity posed by the use of complex diketopiperazine fragments in the coupling event. The success of the indoline π-nucleophile that evolved through our studies is notable given the paucity of competing reaction pathways observed in the presence of the highly reactive C3 carbocation generated. This first total synthesis of (+)-pestalazine A also allowed us to revise the molecular structure for this natural alkaloid.National Institute of General Medical Sciences (U.S.) (Grant GM089732)Amgen Inc.Fonds de Recherche du Québe

The Portfolio Pension Plan: An Alternative Model for Retirement Security

This chapter describes a proposed new defined benefit (DB) pension design known as a portfolio pension plan. This design falls within a larger category of so-called ‘shared risk’ pension plans. In the United States, shared risk pension plans address a need created by the limitations of existing retirement plan designs. An alternative to existing designs is needed because DB plans to date have concentrated risk on plan sponsors in a way that makes them financially unsustainable in many, if not most, circumstances. Moreover, existing defined contribution (DC) retirement plans impose risk on employees in a way that is challenging for most individuals to manage. In the past, many employers shared risk with employees by providing both a DB and a DC plan. Nevertheless, this chapter argues that a new model can provide an alternative that better serves employers and employees in the United States

Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis.

Background A major cause of disability in secondary progressive multiple sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS. Methods We used surface-enhanced laser desorption-ionization time-of-flight mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS. Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry. Results There was a significant (p<0.004) correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta-haemoglobin, respectively.  The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001). The serum lactate dehydrogenase activity was also highly significantly raised (p<10-12) in patients with secondary progressive multiple sclerosis. Conclusions An underlying low-grade chronic intravascular haemolysis is a potential source of the iron whose deposition along blood vessels in multiple sclerosis plaques contributes to the neurodegeneration and consequent brain atrophy seen in progressive disease. Chelators of free serum iron will be ineffective in preventing this neurodegeneration, because the iron (Fe2+) is chelated by haemoglobin

How Do Collegiate Sport Clubs Achieve Organizational Effectiveness?

A greater understanding of the organizational processes of sport clubs can inform strategies to improve clubs’ organizational effectiveness. This study examined whether sport club capacity and activities influence the organizational effectiveness of collegiate sport clubs. Sport club members (n = 201) completed a questionnaire, with secondary data collected from the university. Regression analysis found club operations, club fiscal responsibility, frequency of club practice, and frequency of competitions significantly, positively predict organizational effectiveness. Comparatively, club human capital and facility quality significantly, negatively predict organizational effectiveness. These results have implications relating to club training, mentorship, resource allocation, and club activities

Evaluation of encapsulating and microporous nondegradable hydrogel scaffold designs on islet engraftment in rodent models of diabetes

Islet transplantation is a promising therapeutic option for type 1 diabetes mellitus, yet the current delivery into the hepatic portal vasculature is limited by poor engraftment. Biomaterials have been used as a means to promote engraftment and function at extrahepatic sites, with strategies being categorized as encapsulation or microporous scaffolds that can either isolate or integrate islets with the host tissue, respectively. Although these approaches are typically studied separately using distinct material platforms, herein, we developed nondegradable polyethylene glycol (PEG)‐based hydrogels for islet encapsulation or as microporous scaffolds for islet seeding to compare the initial engraftment and function of islets in syngeneic diabetic mice. Normoglycemia was restored with transplantation of islets within either encapsulating or microporous hydrogels containing 700 islet equivalents (IEQ), with transplantation on microporous hydrogels producing lower blood glucose levels at earlier times. A glucose challenge test at 1 month after transplant indicated that encapsulated islets had a delay in glucose‐stimulated insulin secretion, whereas microporous hydrogels restored normoglycemia in times consistent with native pancreata. Encapsulated islets remained isolated from the host tissue, whereas the microporous scaffolds allowed for revascularization of the islets after transplant. Finally, we compared the inflammatory response after transplantation for the two systems and noted that microporous hydrogels had a substantially increased presence of neutrophils. Collectively, these findings suggest that both encapsulation and microporous PEG scaffold designs allow for stable engraftment of syngeneic islets and the ability to restore normoglycemia, yet the architecture influences islet function and responsiveness after transplantation.Non‐degradable PEG hydrogels were developed for islet encapsulation or islet seeding to compare engraftment. Using a syngeneic rodent model of diabetes, normoglycemia was restored using either encapsulating or microporous scaffolds containing 700 islet equivalent, with microporous hydrogels achieving lower blood glucose levels at earlier time points. Characterization of the inflammatory response demonstrated microporous scaffolds had a substantially increased presence of neutrophils. These studies confirm both scaffold designs allow for engraftment, yet the architecture influences islet function and responsiveness post‐transplantation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146483/1/bit26741.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146483/2/bit26741_am.pd