The secondary structure of apolipoprotein A-I on 9.6-nm reconstituted high-density lipoprotein determined by EPR spectroscopy.

Apolipoprotein A-I (ApoA-I) is the major protein component of high-density lipoprotein (HDL), and is critical for maintenance of cholesterol homeostasis. During reverse cholesterol transport, HDL transitions between an array of subclasses, differing in size and composition. This process requires ApoA-I to adapt to changes in the shape of the HDL particle, transiting from an apolipoprotein to a myriad of HDL subclass-specific conformations. Changes in ApoA-I structure cause alterations in HDL-specific enzyme and receptor-binding properties, and thereby direct the HDL particle through the reverse cholesterol transport pathway. In this study, we used site-directed spin label spectroscopy to examine the conformational details of the ApoA-I central domain on HDL. The motional dynamics and accessibility to hydrophobic/hydrophilic relaxation agents of ApoA-I residues 99-163 on 9.6-nm reconstituted HDL was analyzed by EPR. In previous analyses, we examined residues 6-98 and 164-238 (of ApoA-I's 243 residues), and combining these findings with the current results, we have generated a full-length map of the backbone structure of reconstituted HDL-associated ApoA-I. Remarkably, given that the majority of ApoA-I's length is composed of amphipathic helices, we have identified nonhelical residues, specifically the presence of a β-strand (residues 149-157). The significance of these nonhelical residues is discussed, along with the other features, in the context of ApoA-I function in contrast to recent models derived by other methods

Orbifold Resolution by D-Branes

We study topological properties of the D-brane resolution of three-dimensional orbifold singularities, C^3/Gamma, for finite abelian groups Gamma. The D-brane vacuum moduli space is shown to fill out the background spacetime with Fayet--Iliopoulos parameters controlling the size of the blow-ups. This D-brane vacuum moduli space can be classically described by a gauged linear sigma model, which is shown to be non-generic in a manner that projects out non-geometric regions in its phase diagram, as anticipated from a number of perspectives.Comment: 26 pages, 2 figures (TeX, harvmac big, epsf

Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen

OBJECTIVE: Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. APPROACH AND RESULTS: By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbβ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. CONCLUSIONS: These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbβ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis

Cosmology of Brane Models with Radion Stabilization

We analyze the cosmology of the Randall-Sundrum model and that of compact brane models in general in the presence of a radius stabilization mechanism. We find that the expansion of our universe is generically in agreement with the expected effective four dimensional description. The constraint (which is responsible for the appearance of non-conventional cosmologies in these models) that must be imposed on the matter densities on the two branes in the theory without a stabilized radius is a consequence of requiring a static solution even in the absence of stabilization. Such constraints disappear in the presence of a stablizing potential, and the ordinary FRW (Friedmann-Robertson-Walker) equations are reproduced, with the expansion driven by the sum of the physical values of the energy densities on the two branes and in the bulk. For the case of the Randall-Sundrum model we examine the kinematics of the radion field, and find that corrections to the standard FRW equations are small for temperatures below the weak scale. We find that the radion field has renormalizable and unsuppressed couplings to Standard Model particles after electroweak symmetry breaking. These couplings may have important implications for collider searches. We comment on the possibility that matter off the TeV brane could serve as a dark matter candidate.Comment: 35 pages, Late

Die Werkmeisterfamilie Bernhard, Peter und Franz Niuron

Bernhard, Peter und Franz Niuron wirkten als Werkmeister in einem Territorium, welches sich von Schlesien über Brandenburg und Sachsen bis in das Fürstentum Anhalt erstreckt. Die recherchierte Lebenszeit von ca. 1550 bis 1618 zeigt sie als typische Vertreter der neuen Bauorganisation des späten 16. und beginnenden 17. Jahrhunderts, eingebunden in den Amtsapparat der jeweiligen fürstlichen Residenz. Außerdem hatten sie häufig synchron unterschiedliche Baustellen verschiedener Auftraggeber zu betreuen. Dies bedeutete auf der einen Seite eine ständige Reisetätigkeit, die Notwendigkeit einer fast täglichen Korrespondenz mit dem Hof, meist dem Schlosshauptmann oder dem Fürsten selbst, und den Aufbau eines Bauteams aus verschiedenen Spezialisten, Handwerkern und Arbeitern. Hinzu kam die oft problematische Beschaffung der notwendigen Baumaterialien. Die Menge und der Transport verursachten in der Regel Probleme. Auch dieser Aspekt soll untersucht und am Beispiel aufgezeigt werden. Die Niurons wirkten wie frühe Bauunternehmer, die gleichzeitig als Architekten nicht nur für den Entwurf allein, sondern für alle Phasen der Realisierung des Bauauftrages verantwortlich waren. Um eine derartige Stellung zu erreichen, mussten auch die Niurons ihre Fähigkeiten unter Beweis stellen. Vom Stadium des Befehlsempfängers als Unterbaumeisters bis hin zu besoldeten höfischen Baubeamten auf der einen und freiem Architekten- Unternehmer auf der anderen Seite, durchliefen auch sie alle diese Stadien. Wegbereiter für die Niurons in Brandenburg, Dresden und Anhalt war ohne Zweifel der Festungsbaumeister Graf Rochus zu Lynar, dessen Schaffen bereits eingehend untersucht worden ist, während die Niurons unberechtigt bisher beinahe unbekannt geblieben sind. Die Zusammenarbeit zwischen den Niurons und Lynar wird am Rande ebenfalls beleuchtet und es ließen sich einige neue Aspekte aufdecken, welche die Dissertation zu Lynar von Richard Korn von 1905 leider nicht erfasst hat. Die vorliegende Arbeit fasst erstmals alle recherchierten Fakten zum Leben und Schaffen der Niurons zusammen und überprüft sie eingehend an dem verfügbaren Quellenmaterial. Dabei konnten über Jahrzehnte transportierte Lücken und Fehler beseitigt werden. Bei der Archivrecherche tauchte auch das Testament Peter Niurons auf, was genaue Angaben zur Lebenszeit ermöglicht und bisher bestehende Auffassungen korrigiert. Außerdem wurden die Erkenntnisse aus der polnischen Literaur zu Bernhard Niuron eingearbeitet und damit gezeigt, dass die Niurons stets zusammen arbeiteten und nicht als Einzelpersonen in ihrem Schaffensprozess betrachtet werden können.Bernhard, Peter and Franz Niuron worked as architects in a territory which extends over Brandenburg and Saxony from Silesia to the principality of Anhalt. The investigated lifetime of ca 1550 to 1618 it shows as typical representatives of the new construction organization of the late 16th and beginning 17th century, integrated into the office apparatus of the respective princely residence. In addition they had to be in charge of frequently synchronously different construction sites of different customers. On the one hand this meant a continuous travel activity, the necessity of an almost daily correspondence with the yard, mostly the castle captain or the prince himself, and the construction of a construction team from different specialists, craftsmen and workers. In addition to problematic often came procurement of the necessary building materials. The amount and the transportation normally caused problems. Also this aspect is supposed to be examined and to be shown at the example. The Niurons worked as early building contractors who simultaneously were responsible as architects not only for the draft alone, but for all phases of the realization of the building order. In order to reach a such position, also the Niurons had to put under evidence. Of the stage of the recipient of an order as a foundation master up to paid courtly construction officials on one and free architect entrepreneur on the other hand, also they all ran through these stages. Pioneer for the Niurons in Brandenburg, Dresden and Anhalt was count Rochus zu Lynar too without doubts of the fortress master builders Lynar, that tubs has been examined already coming in, while the Niurons were remaining without authorization up to now almost unknown. The cooperation between the Niurons and Lynar is also illuminated on the fringe and some new aspects, were not let to the dissertation to Lynar of Richard Korn from 1905 has captured. The present work summarizes for the first time all investigated facts to the life and tubs of the Niurons and checks it coming in at the available source material. In this case gaps transported over decades and mistakes could be removed. During the archive research also the last will Peter Niurons emerged, what facilitates precise information to the lifetime and corrects up to now existing opinions. In addition the findings were incorporated from the Polish Literaur to Bernhard Niuron and shown in this way, that the Niurons worked always together and are considered not as individuals in their work process.von Oda Michae

The Central-Bank Balance Sheet as an Instrument of Monetary Policy

While many analyses of monetary policy consider only a target for a short-term nominal interest rate, other dimensions of policy have recently been of greater importance: changes in the supply of bank reserves, changes in the assets acquired by central banks, and changes in the interest rate paid on reserves. We extend a standard New Keynesian model to allow a role for the central bank's balance sheet in equilibrium determination, and consider the connections between these alternative dimensions of policy and traditional interest-rate policy. We distinguish between "quantitative easing" in the strict sense and targeted asset purchases by a central bank, and argue that while the former is likely be ineffective at all times, the latter dimension of policy can be effective when financial markets are sufficiently disrupted. Neither is a perfect substitute for conventional interest-rate policy, but purchases of illiquid assets are particularly likely to improve welfare when the zero lower bound on the policy rate is reached. We also consider optimal policy with regard to the payment of interest on reserves; in our model, this requires that the interest rate on reserves be kept near the target for the policy rate at all times

Comparison of Therapeutic Effects between Pulsed and Continuous Wave 810-nm Wavelength Laser Irradiation for Traumatic Brain Injury in Mice

Background and Objective Transcranial low-level laser therapy (LLLT) using near-infrared light can efficiently penetrate through the scalp and skull and could allow non-invasive treatment for traumatic brain injury (TBI). In the present study, we compared the therapeutic effect using 810-nm wavelength laser light in continuous and pulsed wave modes in a mouse model of TBI. Study Design/Materials and Methods TBI was induced by a controlled cortical-impact device and 4-hours post-TBI 1-group received a sham treatment and 3-groups received a single exposure to transcranial LLLT, either continuous wave or pulsed at 10-Hz or 100-Hz with a 50% duty cycle. An 810-nm Ga-Al-As diode laser delivered a spot with diameter of 1-cm onto the injured head with a power density of 50-mW/cm2 for 12-minutes giving a fluence of 36-J/cm2. Neurological severity score (NSS) and body weight were measured up to 4 weeks. Mice were sacrificed at 2, 15 and 28 days post-TBI and the lesion size was histologically analyzed. The quantity of ATP production in the brain tissue was determined immediately after laser irradiation. We examined the role of LLLT on the psychological state of the mice at 1 day and 4 weeks after TBI using tail suspension test and forced swim test. Results The 810-nm laser pulsed at 10-Hz was the most effective judged by improvement in NSS and body weight although the other laser regimens were also effective. The brain lesion volume of mice treated with 10-Hz pulsed-laser irradiation was significantly lower than control group at 15-days and 4-weeks post-TBI. Moreover, we found an antidepressant effect of LLLT at 4-weeks as shown by forced swim and tail suspension tests. Conclusion The therapeutic effect of LLLT for TBI with an 810-nm laser was more effective at 10-Hz pulse frequency than at CW and 100-Hz. This finding may provide a new insight into biological mechanisms of LLLT.National Institutes of Health (U.S.) (NIH grant R01AI050875)Center for Integration of Medicine and Innovative Technology (DAMD17-02-2-0006)United States. Dept. of Defense. Congressionally Directed Medical Research Programs (W81XWH-09-1-0514)United States. Air Force Office of Scientific Research (Military Photomedicine Program (FA9950-04-1-0079))Japan. Ministry of Education, Culture, Sports, Science and TechnologyJapan Society for the Promotion of Scienc

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Apoptosis signaling proteins as prognostic biomarkers in colorectal cancer: a review.

Colorectal cancer is a leading cause of cancer related mortality in the Western world. In recent years, combination 5-fluorouracil based adjuvant chemotherapy as first line treatment of this disease has led to improved disease free and overall survival. However drug resistance, both innate and acquired, remains an obstacle in the effective treatment of this disease. Apoptotic pathways are frequently altered in both tumor progression and drug resistance; therefore proteins associated with this pathway may have potential as prognostic biomarkers for this disease. Identification of clinical biomarkers that are able to identify patients who are more likely to respond to specific chemotherapy will lead to more personalized, effective, and less toxic therapy. This review focuses on the current status of apoptosis related proteins as biomarkers for colorectal cancer and discusses the possible application of systems approaches in this context