Cholestan-3β,5α,6β-triol, but not 7-ketocholesterol, suppresses taurocholate-induced mucin secretion by cultured dog gallbladder epithelial cells

AbstractIn order to investigate oxysterol-mediated effects on the biliary system, we studied the effects of cholestan-3β,5α,6β-triol (TriolC) and 7-ketocholesterol (7KC) on gallbladder epithelial cells. We compared their cell proliferation effects in cultured dog gallbladder epithelial cells (DGBE) to their effects in cultured human pulmonary artery endothelial cells (HPAE). Oxysterols inhibited cell proliferation in a dose-dependent fashion. Oxysterols inhibited cell growth to 50% of control at a higher dose for DGBE cells than for HPAE cells. TriolC was more cytotoxic than 7KC. We also investigated the effect of oxysterols on bile salt-induced mucin secretion by DGBE cells. TriolC suppressed mucin secretion by DGBE cells, whereas 7KC did not. These findings support the hypothesis that biliary oxysterols affect gallbladder mucosal function

Dysregulation of specialized delay/interference-dependent working memory following loss of dysbindin-1A in schizophrenia-related phenotypes

Dysbindin-1, a protein that regulates aspects of early and late brain development, has been implicated in the pathobiology of schizophrenia. As the functional roles of the three major isoforms of dysbindin-1, (A, B, and C) remain unknown, we generated a novel mutant mouse, dys-1A -/-, with selective loss of dysbindin-1A and investigated schizophrenia-related phenotypes in both males and females. Loss of dysbindin-1A resulted in heightened initial exploration and disruption in subsequent habituation to a novel environment, together with heightened anxiety-related behavior in a stressful environment. Loss of dysbindin-1A was not associated with disruption of either long-term (olfactory) memory or spontaneous alternation behavior. However, dys-1A -/-showed enhancement in delay-dependent working memory under high levels of interference relative to controls, ie, impairment in sensitivity to the disruptive effect of such interference. These findings in dys-1A -/-provide the first evidence for differential functional roles for dysbindin-1A vs dysbindin-1C isoforms among phenotypes relevant to the pathobiology of schizophrenia. Future studies should investigate putative sex differences in these phenotypic effects

Nanoscale Phase Separation in DSPC–Cholesterol Systems

The lipid arrangement of eukaryotic cell membranes has been shown to be heterogeneous, with domains enriched in cholesterol and saturated phospholipids, coexisting with a continuous phase that is enriched in unsaturated phospholipids. While the existence of these domains is well-established, there is still a lack of consensus regarding domain size and the factors influencing it. In this work, we investigate model membranes consisting of 1,2-dioleoyl-<i>sn</i>-glycero-3-phosphocholine (DOPC)–1,2-distearoyl-<i>sn</i>-glycero-3-phosphocholine (DSPC)–cholesterol (Chol) and 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine (POPC, 18:1–16:0)–DSPC–Chol with a steady-state fluorescence assay and report the influence of phospholipid chain saturation and chain length on domain size. The spectral shifts of 1-myristoyl-2-[12-[(5-dimethylamino-1-naphthalenesulfonyl)­amino]­dodecanoyl]-<i>sn</i>-glycero-3-phosphocholine (DAN-PC) and a Förster resonance energy transfer (FRET) assay were used, along with an analytical model, to estimate domain sizes. A region of nanoscale domain existence was observed in both ternary systems; however, the domains formed in the system containing the asymmetric lipid (POPC, 18:1–16:0) were larger than those formed in the diunsaturated lipid (DOPC, 18:1–18:1). This is a new finding, as domains were not previously known to exist in similar POPC-based systems

Bursting Bubbles and Bilayers

<p>This paper discusses various interactions between ultrasound, phospholipid monolayer-coated gas bubbles, phospholipid bilayer vesicles, and cells. The paper begins with a review of microbubble physics models, developed to describe microbubble dynamic behavior in the presence of ultrasound, and follows this with a discussion of how such models can be used to predict inertial cavitation profiles. Predicted sensitivities of inertial cavitation to changes in the values of membrane properties, including surface tension, surface dilatational viscosity, and area expansion modulus, indicate that area expansion modulus exerts the greatest relative influence on inertial cavitation. Accordingly, the theoretical dependence of area expansion modulus on chemical composition - in particular, poly (ethylene glyclol) (PEG) - is reviewed, and predictions of inertial cavitation for different PEG molecular weights and compositions are compared with experiment. Noteworthy is the predicted dependence, or lack thereof, of inertial cavitation on PEG molecular weight and mole fraction. Specifically, inertial cavitation is predicted to be independent of PEG molecular weight and mole fraction in the so-called mushroom regime. In the &#8220;brush&#8221; regime, however, inertial cavitation is predicted to increase with PEG mole fraction but to decrease (to the inverse 3/5 power) with PEG molecular weight. While excellent agreement between experiment and theory can be achieved, it is shown that the calculated inertial cavitation profiles depend strongly on the criterion used to predict inertial cavitation. This is followed by a discussion of nesting microbubbles inside the aqueous core of microcapsules and how this significantly increases the inertial cavitation threshold. Nesting thus offers a means for avoiding unwanted inertial cavitation and cell death during imaging and other applications such as sonoporation. A review of putative sonoporation mechanisms is then presented, including those involving microbubbles to deliver cargo <i>into a cell</i>, and those - not necessarily involving microubbles - to release cargo <i>from a phospholipid vesicle</i> (or reverse sonoporation). It is shown that the rate of (reverse) sonoporation from liposomes correlates with phospholipid bilayer phase behavior, liquid-disordered phases giving appreciably faster release than liquid-ordered phases. Moreover, liquid-disordered phases exhibit evidence of two release mechanisms, which are described well mathematically by enhanced diffusion (possibly via dilation of membrane phospholipids) and irreversible membrane disruption, whereas liquid-ordered phases are described by a single mechanism, which has yet to be positively identified. The ability to tune release kinetics with bilayer composition makes reverse sonoporation of phospholipid vesicles a promising methodology for controlled drug delivery. Moreover, nesting of microbubbles inside vesicles constitutes a truly &#8220;theranostic&#8221; vehicle, one that can be used for both long-lasting, safe imaging and for controlled drug delivery.</p

Integrated Taphonomy of an Avian Death Assemblage in Marine Sediments From the Late Pliocene of Florida

We integrate taphonomic data on vertebrate and invertebrate paleontology, micropaleontology and palynology to explain the formation of a late Pliocene death assemblage of marine birds and fish in the “Pinecrest Sand”, Gulf Coastal Florida. Stereonet plots of orientation data on over 1500 cormorant (Phalacrocoracidae: Phalacrocorax) bones indicate that this fossil assemblage formed first from gradual accumulation of bone, shell and sediments on a barrier island beach, and second by rapid sedimentation in a quiet, back-beach setting associated with multiple episodes of breaching of the barrier. This latter event resulted in the preservation of 137 partial and complete cormorant skeletons and thousands of isolated bones that show a high angle of dip and a preferred orientation to the northeast. Invertebrate fossils exhibit taphonomic signatures characteristic of high-energy reworking with a large percentage of abraded shell fragments similar to beach deposits. Moreover, these data indicate that more than a single depositional episode caused the formation of the deposits referred to as the bird layers. Palynological evidence supports this conclusion. The pollen recovered from the deposits is highly abraded and broken and does not represent an in situ vegetational environment as compared to other deposits of this age in Florida and Georgia. The large number of cormorant and other seabird and fish remains in the bird layers appears to have been caused by a series of toxic red tides that occurred on the Gulf Coast of Florida. These events today cause die offs of large flocks of cormorants and bottom-dwelling fish similar to those recovered from the site. Palynological analysis of the sediments revealed abundant cysts of a dinoflagellate species known to produce toxic red tides. The most likely cause of the death of the cormorants and other vertebrates at this site is a toxic bloom of a variety of Pyrodinium bahamense, the thecate form of the dinoflagellate cyst Polysphaeridium zoharyi, which has a stratigraphic range from the lower Eocene to the Holocene

Replication of Eskine, K. J., Kacinik, N. A., &amp; Prinz, J. J. (2011) at the University of Kentucky

We are a group of students at the University of Kentucky intending to replicate the study originally published by Eskine, K. J., Kacinik, N. A., &amp; Prinz, J. J. in regards to the link between physical disgust and moral disgust