Tangeretin regulates platelet function through inhibition of phosphoinositide 3-Kinase and cyclic nucleotide signaling

OBJECTIVE: Dietary flavonoids have long been appreciated in reducing cardiovascular disease risk factors, but their mechanisms of action are complex in nature. In this study, the effects of tangeretin, a dietary flavonoid, were explored on platelet function, signaling, and hemostasis. APPROACH AND RESULTS: Tangeretin inhibited agonist-induced human platelet activation in a concentration-dependent manner. It inhibited agonist-induced integrin αIIbβ3 inside-out and outside-in signaling, intracellular calcium mobilization, and granule secretion. Tangeretin also inhibited human platelet adhesion and subsequent thrombus formation on collagen-coated surfaces under arterial flow conditions in vitro and reduced hemostasis in mice. Further characterization to explore the mechanism by which tangeretin inhibits platelet function revealed distinctive effects of platelet signaling. Tangeretin was found to inhibit phosphoinositide 3-kinase-mediated signaling and increase cGMP levels in platelets, although phosphodiesterase activity was unaffected. Consistent with increased cGMP levels, tangeretin increased the phosphorylation of vasodilator-stimulated phosphoprotein at S239. CONCLUSIONS: This study provides support for the ability and mechanisms of action of dietary flavonoids to modulate platelet signaling and function, which may affect the risk of thrombotic disease

RPGR protein complex regulates proteasome activity and mediates store-operated calcium entry

Ciliopathies are a group of genetically heterogeneous disorders, characterized by defects in cilia genesis or maintenance. Mutations in the RPGR gene and its interacting partners, RPGRIP1 and RPGRIP1L, cause ciliopathies, but the function of their proteins remains unclear. Here we show that knockdown (KD) of RPGR, RPGRIP1 or RPGRIP1L in hTERT-RPE1 cells results in abnormal actin cytoskeleton organization. The actin cytoskeleton rearrangement is regulated by the small GTPase RhoA via the planar cell polarity (PCP) pathway. RhoA activity was upregulated in the absence of RPGR, RPGRIP1 or RPGRIP1L proteins. In RPGR, RPGRIP1 or RPGRIP1L KD cells, we observed increased levels of DVl2 and DVl3 proteins, the core components of the PCP pathway, due to impaired proteasomal activity. RPGR, RPGRIP1 or RPGRIP1L KD cells treated with thapsigargin (TG), an inhibitor of sarcoendoplasmic reticulum Ca2+ - ATPases, showed impaired store-operated Ca2+ entry (SOCE), which is mediated by STIM1 and Orai1 proteins. STIM1 was not localized to the ER-PM junction upon ER store depletion in RPGR, RPGRIP1 or RPGRIP1L KD cells. Our results demonstrate that the RPGR protein complex is required for regulating proteasomal activity and for modulating SOCE, which may contribute to the ciliopathy phenotype

Training augmentation using additive sensory noise in a lunar rover navigation task

BackgroundThe uncertain environments of future space missions means that astronauts will need to acquire new skills rapidly; thus, a non-invasive method to enhance learning of complex tasks is desirable. Stochastic resonance (SR) is a phenomenon where adding noise improves the throughput of a weak signal. SR has been shown to improve perception and cognitive performance in certain individuals. However, the learning of operational tasks and behavioral health effects of repeated noise exposure aimed to elicit SR are unknown.ObjectiveWe evaluated the long-term impacts and acceptability of repeated auditory white noise (AWN) and/or noisy galvanic vestibular stimulation (nGVS) on operational learning and behavioral health.MethodsSubjects (n = 24) participated in a time longitudinal experiment to access learning and behavioral health. Subjects were assigned to one of our four treatments: sham, AWN (55 dB SPL), nGVS (0.5 mA), and their combination to create a multi-modal SR (MMSR) condition. To assess the effects of additive noise on learning, these treatments were administered continuously during a lunar rover simulation in virtual reality. To assess behavioral health, subjects completed daily, subjective questionnaires related to their mood, sleep, stress, and their perceived acceptance of noise stimulation.ResultsWe found that subjects learned the lunar rover task over time, as shown by significantly lower power required for the rover to complete traverses (p < 0.005) and increased object identification accuracy in the environment (p = 0.05), but this was not influenced by additive SR noise (p = 0.58). We found no influence of noise on mood or stress following stimulation (p > 0.09). We found marginally significant longitudinal effects of noise on behavioral health (p = 0.06) as measured by strain and sleep. We found slight differences in stimulation acceptability between treatment groups, and notably nGVS was found to be more distracting than sham (p = 0.006).ConclusionOur results suggest that repeatedly administering sensory noise does not improve long-term operational learning performance or affect behavioral health. We also find that repetitive noise administration is acceptable in this context. While additive noise does not improve performance in this paradigm, if it were used for other contexts, it appears acceptable without negative longitudinal effects

Training augmentation using additive sensory noise in a lunar rover navigation task

Background The uncertain environments of future space missions means that astronauts will need to acquire new skills rapidly; thus, a non-invasive method to enhance learning of complex tasks is desirable. Stochastic resonance (SR) is a phenomenon where adding noise improves the throughput of a weak signal. SR has been shown to improve perception and cognitive performance in certain individuals. However, the learning of operational tasks and behavioral health effects of repeated noise exposure aimed to elicit SR are unknown. Objective We evaluated the long-term impacts and acceptability of repeated auditory white noise (AWN) and/or noisy galvanic vestibular stimulation (nGVS) on operational learning and behavioral health.MethodsSubjects (n = 24) participated in a time longitudinal experiment to access learning and behavioral health. Subjects were assigned to one of our four treatments: sham, AWN (55 dB SPL), nGVS (0.5 mA), and their combination to create a multi-modal SR (MMSR) condition. To assess the effects of additive noise on learning, these treatments were administered continuously during a lunar rover simulation in virtual reality. To assess behavioral health, subjects completed daily, subjective questionnaires related to their mood, sleep, stress, and their perceived acceptance of noise stimulation. Results We found that subjects learned the lunar rover task over time, as shown by significantly lower power required for the rover to complete traverses (p 0.09). We found marginally significant longitudinal effects of noise on behavioral health (p = 0.06) as measured by strain and sleep. We found slight differences in stimulation acceptability between treatment groups, and notably nGVS was found to be more distracting than sham (p = 0.006). Conclusion Our results suggest that repeatedly administering sensory noise does not improve long-term operational learning performance or affect behavioral health. We also find that repetitive noise administration is acceptable in this context. While additive noise does not improve performance in this paradigm, if it were used for other contexts, it appears acceptable without negative longitudinal effects

Tobias Smollett and the work of writing

This essay offers an overview of the state of Smollett Studies today. It is also an argument about what makes Tobias Smollett interesting. It therefore seeks to avoid the value judgments about “English literature” that have dogged Smollett's reputation (ever since “English literature” was invented) and restore him to the “work of writing” in which he was engaged. The essay thus provides an account of the wide‐ranging nature of his work in order to balance a previous critical emphasis on his novels. It includes some views of his role as a translator, historian, critic, editor, and, perhaps more provocatively, “hack.” Recent studies in eighteenth‐century print culture and the (Scottish) Enlightenment point the way to a new Smollett, at work within a messier history of writing

Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation

Acute myeloid leukemia (AML) involves a block in terminal differentiation of the myeloid lineage and uncontrolled proliferation of a progenitor state. Using phorbol myristate acetate (PMA), it is possible to overcome this block in THP-1 cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced micro- RNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed cause cell-cycle arrest and partial differentiation and when used in combination induce additional changes not seen by any individual microRNA. We further characterize these prodifferentiative microRNAs and show that mir-155 and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and mir-503 are derived from a polycistronic precursor mir-424-503 that is under repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs directly target cell-cycle regulators and induce G1 cell-cycle arrest when overexpressed in THP-1. We also find that the pro-differentiative mir-424 and mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its primary transcript. Our study highlights the combinatorial effects of multiple microRNAs within cellular systems.Comment: 45 pages 5 figure

Living together in student accommodation: Performances, boundaries and homemaking

Recent discussions of the geographies of students have drawn attention to the trajectories of UK students electing to leave home for university. While such debates recognise these important mobilities, little has been discussed as to how students interact within their term-time accommodation. Through a qualitative study of the living arrangements of UK students, this paper will demonstrate that much can be drawn from focusing on the micro-geographies of non-local students within their term-time homes. Student accommodation is more than simply somewhere to live. Student homes are intensely dynamic places, perhaps more so than family homes as they contain multiple, disconnected identities. This research contributes to research on the geographies of the home by unpacking how house-sharers in transition interact with each other, how they transfer their identities from one home to another, how they delineate their territory and whether they integrate or withdraw within their term-time accommodation. This paper addresses this by exploring (1) how students negotiate their habitualised behaviours in shared spaces and (2) how these behaviours become spatialised through the configuration and maintenance of boundaries

Student Recital (December 12, 2012)

What Good Would the Moon Be / Kurt Weill Jordan Ennis, soprano Concerto / Nikolai Rimsky-Korsakov Andante Cantabile Sage Lewis, trombone Du bist wie eine Blume, Op. 25, No. 24 / Robert Schumann Long Time Ago / Aaron Copland Richard Moran, tenor Estudios Sencillos / Leo Brouwer Five Studies / Fredric Hand Nolan Driscoll, guitar Study No. 7 in A minor / Matteo Carcassi Jeremy Place, guitar Concerto no. 3 in G, K. 216 / Wolfgang Amadeus Mozart Allegro Carla Mason, violin Etude No. 14 in D Major / M. Carcassi Etude No. 1 in E minor / Heitor Villa-Lobos James Davidson, guitar Prelude No. 4 / H. Villa-Lobos Mark Gavin, guitar Bois Epais / Jean-Baptiste Lully The Call / Ralph Vaughan Williams Justine Smigel, mezzo-soprano Allegro, Op. 20 / Joseph Hector Fiocco Gail Colombo, violin Improvisation II et III pour Saxophone Alto Seul / Ryo Noda III Chelsea Fisk, alto saxophonehttps://vc.bridgew.edu/student_concerts/1034/thumbnail.jp

The Recent Stellar Archeology of M31 - The Nearest Red Disk Galaxy

We examine the star-forming history (SFH) of the M31 disk during the past few hundred Myr. The luminosity functions (LFs) of main sequence stars at distances R_GC > 21 kpc (i.e. > 4 disk scale lengths) are matched by models that assume a constant star formation rate (SFR). However, at smaller R_GC the LFs suggest that during the past ~10 Myr the SFR was 2 - 3 times higher than during the preceding ~100 Myr. The rings of cool gas that harbor a significant fraction of the current star-forming activity are traced by stars with ages ~100 Myr, indicating that (1) these structures have ages of at least 100 Myr, and (2) stars in these structures do not follow the same relation between age and random velocity as their counterparts throughout the disks of other spiral galaxies, probably due to the inherently narrow orbital angular momentum distribution of the giant molecular clouds in these structures. The distribution of evolved red stars is not azimuthally symmetric, in the sense that their projected density along the north east segment of the major axis is roughly twice that on the opposite side of the galaxy. The north east arm of the major axis thus appears to be a fossil star-forming area that dates to intermediate epochs. Such a structure may be the consequence of interactions with a companion galaxy.Comment: To appear in The Astrophysical Journa

The Metallicity-Luminosity Relation, Effective Yields, and Metal Loss in Spiral and Irregular Galaxies

I present results on the correlation between galaxy mass, luminosity, and metallicity for a sample of spiral and irregular galaxies having well-measured abundance profiles, distances, and rotation speeds. Additional data for low surface brightness galaxies from the literature are also included for comparison. These data are combined to study the metallicity-luminosity and metallicity-rotation speed correlations for spiral and irregular galaxies. The metallicity luminosity correlation shows its familiar form for these galaxies, a roughly uniform change in the average present-day O/H abundance of about a factor 100 over 11 magnitudes in B luminosity. However, the O/H - V(rot) relation shows a change in slope at a rotation speed of about 125 km/sec. At faster V(rot), there appears to be no relation between average metallicity and rotation speed. At lower V(rot), the metallicity correlates with rotation speed. This change in behavior could be the result of increasing loss of metals from the smaller galaxies in supernova-driven winds. This idea is tested by looking at the variation in effective yield, derived from observed abundances and gas fractions assuming closed box chemical evolution. The effective yields derived for spiral and irregular galaxies increase by a factor of 10-20 from V(rot) approximately 5 km/sec to V(rot) approximately 300 km/sec, asympotically increasing to approximately constant y(eff) for V(rot) > 150 km/sec. The trend suggests that galaxies with V(rot) < 100-150 km/sec may lose a large fraction of their SN ejecta, while galaxies above this value tend to retain metals.Comment: 40 pages total, including 7 encapsulated postscript figures. Accepted for publication in 20 Dec 2002 Ap