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Supplementary Figures S1-S4 from mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor

Purpose: Comparison of the antiangiogenic/vascular properties of the oral mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) and the vascular endothelial growth factor receptor (VEGFR) inhibitor vatalanib (PTK/ZK).Experimental Design: Antiproliferative activity against various tumor histotypes and downstream effects on the mTOR pathway were measured in vitro. In vivo, antitumor activity, plasma, and tumor RAD001 levels were measured. Activity in several different angiogenic/vascular assays in vitro and in vivo was assessed and compared with PTK/ZK.Results: RAD001 inhibited proliferation in vitro (IC50 values 1 μmol/L), and in sensitive and insensitive tumor cells, pS6 kinase and 4E-BP1 were inhibited. Activity in vitro did not correlate with activity in vivo and significant responses were seen in tumors with IC50 values >10-fold higher than tumor RAD001 concentrations. In vitro, RAD001 inhibited the proliferation of VEGF-stimulated and fibroblast growth factor-stimulated human endothelial cells but not dermal fibroblasts and impaired VEGF release from both sensitive and insensitive tumor cells but did not inhibit migration of human endothelial cells. In vivo, in tumor models derived from either sensitive or insensitive cells, RAD001 reduced Tie-2 levels, the amount of mature and immature vessels, total plasma, and tumor VEGF. RAD001 did not affect blood vessel leakiness in normal vasculature acutely exposed to VEGF nor did it affect tumor vascular permeability (Ktrans) as measured by dynamic contrast-enhanced magnetic resonance imaging. However, the pan-VEGFR inhibitor PTK/ZK inhibited endothelial cell migration and vascular permeability but had less effect on mature vessels compared with RAD001.Conclusions: VEGFR and mTOR inhibitors show similar but also distinct effects on tumor vascular biology, which has implications for their clinical activity alone or in combination.

Supplementary Figure Legends 1-3 from Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging

Supplementary Figures 1-3 from Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging

A low-noise low-pressure ultra-high-bypass-ratio fan stage to be implemented in the next generation of aircraft engines is described and evaluated acoustically with semi-empirical and analytical methods suited for preliminary design. As expected, good reduction potentials are observed for the jet noise and fan tonal noise components when the UHBR design is compared to current fans in service. However, concerns are identified for fan broadband noise, which are attributed to the off-design operation of the UHBR fan too close from its stability limit. By unloading the fan and thus reducing the size of the rotor wakes, the variable-area nozzle provides a substantial fan broadband noise reduction with a nozzle opened by around 15% from its design value. Alternatively, with the variable-pitch fan, closing the rotor blades by roughly 5° turns out to be an even more effective method to reduce fan noise, as the unloading mechanism is combined with a stronger tilting of the rotor wakes and a lower intra-stage flow Mach number. Opening the nozzle or closing the blades beyond the setting that provides the best fan efficiency is not recommended as the acoustic benefit progressively vanishes, whereas technical feasibility becomes more challenging. Finally, the presence of one of these systems may allow for the design of a low-solidity rotor, with a smaller contribution from the rotor wakes and thus a weaker fan noise emission.

The matagi are traditional hunters in the mountainous beech forests of northeastern Japan. They are distinguishable from recreational hunters in their veneration of the yama no kami, a female spirit or god who dwells in the mountains. This article will focus on their kuma matsuri, a set of rituals associated with bear hunting. It will argue that the rituals reinforce a sense of connectedness and interdependence with the forested mountains, as personified by the yama no kami, and that the bear epitomizes the gifts they bestow. From this perspective, the mountains are central to people’s lives and livelihoods, a recognition that is somewhat at odds with the “mainstream” culture of the lowland plains and urban areas. For their part, the matagi routinely move back and forth across boundaries, both physical and conceptual. They therefore play a vital role as intermediaries between the cultivated human realm and that of untamed nature.

NIRPS (Near Infra-Red Planet Searcher) is an AO-assisted and fiber-fed spectrograph for high precision radial velocity measurements in the YJH-bands. NIRPS also has the specificity to be an SCAO assisted instrument, enabling the use of few-mode fibers for the first time. This choice offers an excellent trade-off by allowing to design a compact cryogenic spectrograph, while maintaining a high coupling efficiency under bad seeing conditions and for faint stars. The main drawback resides in a much more important modal-noise, a problem that has to be tackled for allowing 1m/s precision radial velocity measurements. In this paper, we present the NIRPS Front-End: an overview of its design (opto-mechanics, control), its performance on-sky, as well as a few lessons learned along the way., Comment: Proceeding of SPIE Telescopes+Instrumentation 2022

PANDA (anti-proton annihiliation at Darmstadt) is planned to be one of the four main experiments at the future international accelerator complex FAIR (Facility for Antiproton and Ion Research) in Darmstadt, Germany. It is going to address fundamental questions of hadron physics and quantum chromodynamics using cooled antiproton beams with a high intensity and and momenta between 1.5 and 15 GeV/c. PANDA is designed to reach a maximum luminosity of 2 × 1032 cm−2 s. Most of the physics programs require an excellent particle identification (PID). The PID of hadronic states at the forward endcap of the target spectrometer will be done by a fast and compact Cherenkov detector that uses the detection of internally reflected Cherenkov light (DIRC) principle. It is designed to cover the polar angle range from 5° to 22° and to provide a separation power for the separation of charged pions and kaons up to 3 standard deviations (s.d.) for particle momenta up to 4 GeV/c in order to cover the important particle phase space. This document describes the technical design and the expected performance of the novel PANDA disc DIRC detector that has not been used in any other high energy physics experiment before. The performance has been studied with Monte-Carlo simulations and various beam tests at DESY and CERN. The final design meets all PANDA requirements and guarantees sufficient safety margins.

A central role for the influenza matrix protein 1 (M1) is to form a polymeric coat on the inner leaflet of the host membrane that ultimately provides shape and stability to the virion. M1 polymerizes upon binding membranes, but triggers for conversion of M1 from a water-soluble component of the nucleus and cytosol into an oligomer at the membrane surface are unknown. While full-length M1 is required for virus viability, the N-terminal domain (M1NT) retains membrane binding and pH-dependent oligomerization. We studied the structural plasticity and oligomerization of M1NT in solution using NMR spectroscopy. We show that the isolated domain can be induced by sterol-containing compounds to undergo a conformational change and self-associate in a pH-dependent manner consistent with the stacked dimer oligomeric interface. Surface-exposed residues at one of the stacked dimer interfaces are most sensitive to sterols. Several perturbed residues are at the interface between the N-terminal subdomains and are also perturbed by changes in pH. The effects of sterols appear to be indirect and most likely mediated by reduction in water activity. The local changes are centered on strictly conserved residues and consistent with a priming of the N-terminal domain for polymerization. We hypothesize that M1NT is sensitive to changes in the aqueous environment and that this sensitivity is part of a mechanism for restricting polymerization to the membrane surface. Structural models combined with information from chemical shift perturbations indicate mechanisms by which conformational changes can be transmitted from one polymerization interface to the other.

Civil aviation is aiming at fuel efficient aircraft concepts. Propulsion systems using boundary layer ingestion (BLI) are promising to reach this goal. The focus of this study is on the DLR UHBR fan stage of a tube and wing aircraft with rear-integrated engines. In this integration scenario the propulsion system and especially the fan stage receives distorted inflow in steady-state flight conditions. The distortion pattern and distortion intensity are dependent on the operating conditions. Consequently, the interaction of the fan and the distortion changes over the flight envelope. The first part of the paper aims at gaining knowledge of the BLI fan performance in the operating points end of field, approach, cruise (CR) and top of climb (TOC) using high-fidelity, unsteady RANS approaches. The analysis includes fan map performance metrics and a deeper insight into the flow field at CR and TOC. The preliminary design of a fan stage requires fast turn-around times, which are not fulfilled by high-fidelity approaches. Therefore, a fast, throughflow-based methodology is developed, which enables aerodynamicists to design distortion-tolerant fans. The main characteristics of the methodology is outlined in the second part. Consequently, the methodology is taken advantage of to investigate parameter sensitivities in terms of tip speed, blade thickness, solidity, the annulus geometry and a non-axisymmetric stator. This study suggests that distortion-tolerant fans should be designed at higher tip speeds than conventional design experience recommends to limit the local operating point excursion.

Lipid availability within transmembrane nano-pockets of ion channels is linked with mechanosensation. However, the effect of hindering lipid-chain penetration into nano-pockets on channel structure has not been demonstrated. Here we identify nano-pockets on the large conductance mechanosensitive channel MscL, the high-pressure threshold channel. We restrict lipid-chain access to the nano-pockets by mutagenesis and sulfhydryl modification, and monitor channel conformation by PELDOR/DEER spectroscopy. For a single site located at the entrance of the nano-pockets and distal to the channel pore we generate an allosteric response in the absence of tension. Single-channel recordings reveal a significant decrease in the pressure activation threshold of the modified channel and a sub-conducting state in the absence of applied tension. Threshold is restored to wild-type levels upon reduction of the sulfhydryl modification. The modification associated with the conformational change restricts lipid access to the nano-pocket, interrupting the contact between the membrane and the channel that mediates mechanosensitivity., How mechanosensitive ion channels, such as MscL, are activated by lipids and physical properties of the membrane remains unclear. Here authors use PELDOR/DEER spectroscopy and identify a single site which generated an allosteric structural response in the absence of membrane tension.

The cytoplasmic C-terminal tail of the matrix protein 2 (M2) from influenza A virus has a well conserved sequence and is involved in interactions with several host proteins as well as the influenza matrix protein 1 (M1). Whereas the transmembrane domain of M2 has been well characterised structurally and functionally, high resolution information about the distal cytoplasmic tail is lacking. Here we report the chemical shifts of the cytoplasmic tail of M2 and the chemical shift perturbations at low pH and in the presence of membrane mimetics. The cytoplasmic tail residues are mostly disordered but an extended backbone conformation is adopted by the LC3 binding motif and the putative M1 interaction site has partial helical content with a small pH-dependence. The chemical shift assignments provide a basis for further investigations into interactions of the M2 cytoplasmic tail with viral and host cell factors.

The hepatitis C virus (HCV) viroporin p7 oligomerizes to form ion channels, which are required for the assembly and secretion of infectious viruses. The 63-amino acid p7 monomer has two putative transmembrane domains connected by a cytosolic loop, and has both N- and C- termini exposed to the endoplasmic reticulum (ER) lumen. NMR studies have indicated differences between p7 structures of distantly related HCV genotypes. A critical question is whether these differences arise from the high sequence variation between the different isolates and if so, how the divergent structures can support similar biological functions. Here, we present a side-by-side characterization of p7 derived from genotype 1b (isolate J4) in the detergent 6-cyclohexyl-1-hexylphosphocholine (Cyclofos-6) and p7 derived from genotype 5a (isolate EUH1480) in n-dodecylphosphocholine (DPC). The 5a isolate p7 in conditions previously associated with a disputed oligomeric form exhibits secondary structure, dynamics, and solvent accessibility broadly like those of the monomeric 1b isolate p7. The largest differences occur at the start of the second transmembrane domain, which is destabilized in the 5a isolate. The results show a broad consensus among the p7 variants that have been studied under a range of different conditions and indicate that distantly related HCVs preserve key features of structure and dynamics.

The Cotton osteotomy or opening wedge medial cuneiform osteotomy is a useful adjunctive flatfoot reconstructive procedure that is commonly performed; however, the outcomes are rarely reported owing to the adjunctive nature of the procedure. The Cotton procedure is relatively quick to perform and effectively corrects forefoot varus deformity after rearfoot fusion or osteotomy to achieve a rectus forefoot to rearfoot relationship. Proper patient selection is critical because the preoperative findings of medial column joint instability, concomitant hallux valgus deformity, or degenerative joint disease of the medial column might be better treated by arthrodesis of the naviculocuneiform or first tarsometatarsal joints. Procedure indications also include elevatus of the first ray, which can be a primary deformity in hallux limitus or an iatrogenic deformity after base wedge osteotomy for hallux valgus. We undertook an institutional review board-approved retrospective review of 32 consecutive patients (37 feet) who had undergone Cotton osteotomy as a part of flatfoot reconstruction. All but 1 case (2.7%) had radiographic evidence of graft incorporation at 10 weeks. No patient experienced graft shifting. Three complications (8.1%) were identified, including 2 cases with neuritis (5.4%) and 1 case of delayed union (2.7%) that healed with a bone stimulator at 6 months postoperatively. Meary's angle improved an average of 17.75°, from -17.24°± 8.00° to 0.51°± 3.81°, and this change was statistically significant (p .01). The present retrospective series highlights our experience with the use of the Cotton osteotomy as an adjunctive procedure in flatfoot reconstructive surgery.

The Cotton osteotomy or opening wedge medial cuneiform osteotomy is a useful adjunctive flatfoot reconstructive procedure that is rarely performed in isolation. The Cotton procedure is relatively quick to perform and effectively corrects forefoot varus deformity after rearfoot fusion or osteotomy to achieve a rectus forefoot to rearfoot relationship. Proper patient selection is critical, because preoperative findings of medial column joint instability, concomitant hallux valgus deformity, or degenerative joint disease of the medial column might be better treated with arthrodesis of the naviculocuneiform or first tarsometatarsal joints. Procedure indications also include elevatus of the first ray, which can be a primary deformity in hallux limitus, or iatrogenic deformity after base wedge osteotomy in hallux valgus. We present the case of an adolescent patient who underwent flatfoot reconstruction, including Cotton osteotomy for correction of forefoot varus that was accentuated after double heel osteotomy. This case highlights our preferred procedure technique, including the use of a nerve-centric incision design. The use of an oblique dorsal medial incision is primarily intended to minimize the risk of trauma to the medial dorsal cutaneous nerve. At 20 months postoperatively for the right extremity and 12 months postoperatively for the left extremity, sensation remained intact, and the patient had not experienced any postoperative nerve symptoms. The patient had returned to playing sports without pain or restrictions.

Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable.Rationalin silicodesign andin vitroscreens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic “swine” H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance.

Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic recovery following induction chemotherapy remain mysterious. Platelet recovery may vary between incomplete and excess recovery among patients achieving remission. We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients. We defined excess platelet rebound (EPR) as platelet increase above 500 G/L. We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 vs 41 months; p = 0.04), as was disease-free survival. By multivariate analysis, EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p

Aircraft concepts using boundary layer ingestion (BLI) are promising future flight systems aiming at reduced mission fuel burn. In this scenario the fan operates at inhomogeneous inflow conditions around the circumference. The accurate calculation of the resulting flow phenomena using uRANS approaches is highly time-consuming and therefore not suitable for fan design at early stages of the design process. In this paper, we introduce a throughflow based design methodology for BLI. The methodology includes the detailed design of the annulus geometry, the design of rotor and stator blades as well as the performance assessment in the BLI scenario. The throughflow approach is extended and calibrated to cover major BLI flow physics. The calibration data set consists of 12 fans with different fan pressure ratios (FPR) and meridional Mach numbers. The new design methodology is applied to design three specific fans and the effect of radial FPR is investigated. All designs are verified using 3D CFD uRANS approaches and the results indicate that either ascending or constant radial FPR should be favored. In addition an exploration study is conducted using the design methodology. This study covers 72 fan stages in the parameter space tip speed and meridional Mach number. The results suggest that there is a favorable tuple of design parameters to design a distortion tolerant fan by trading tip speed and meridional Mach number. In the end the newly gained knowledge is transferred to the DLR UHBR fan in order to improve the tolerance to BLI.

The $\overline{{\rm{P}}}\mathrm{ANDA}$ (anti-Proton ANnihiliation at DArmstadt) experiment will be one of the four flagship experiments at the new international accelerator complex FAIR (Facility for Antiproton and Ion Research) in Darmstadt, Germany. $\overline{{\rm{P}}}\mathrm{ANDA}$ will address fundamental questions of hadron physics and quantum chromodynamics using high-intensity cooled antiproton beams with momenta between 1.5 and 15 GeV/c and a design luminosity of up to 2 × 1032 cm−2 s−1. Excellent particle identification (PID) is crucial to the success of the $\overline{{\rm{P}}}\mathrm{ANDA}$ physics program. Hadronic PID in the barrel region of the target spectrometer will be performed by a fast and compact Cherenkov counter using the detection of internally reflected Cherenkov light (DIRC) technology. It is designed to cover the polar angle range from 22° to 140° and will provide at least 3 standard deviations (s.d.) π/K separation up to 3.5 GeV/c, matching the expected upper limit of the final state kaon momentum distribution from simulation. This documents describes the technical design and the expected performance of the $\overline{{\rm{P}}}\mathrm{ANDA}$ Barrel DIRC detector. The design is based on the successful BaBar DIRC with several key improvements. The performance and system cost were optimized in detailed detector simulations and validated with full system prototypes using particle beams at GSI and CERN. The final design meets or exceeds the PID goal of clean π/K separation with at least 3 s.d. over the entire phase space of charged kaons in the Barrel DIRC.

Bound nuclear systems with two units of strangeness are still poorly known despite their importance for many strong interaction phenomena. Stored antiprotons beams in the GeV range represent an unparalleled factory for various hyperon-antihyperon pairs. Their outstanding large production probability in antiproton collisions will open the floodgates for a series of new studies of systems which contain two or even more units of strangeness at the PANDA experiment at FAIR. For the first time, high resolution gamma-spectroscopy of doubly strange Lambda Lambda-hypernuclei will be performed, thus complementing measurements of ground state decays of Lambda Lambda-hypernuclei at J-PARC or possible decays of particle unstable hypernuclei in heavy ion reactions. High resolution spectroscopy of multistrange Xi(-) -atoms will be feasible and even the production of Omega(-) -atoms will be within reach. The latter might open the door to the vertical bar S vertical bar = 3 world in strangeness nuclear physics, by the study of the hadronic Omega(-) -nucleus interaction. For the first time it will be possible to study the behavior of Xi(+) in nuclear systems under well controlled conditions. (C) 2016 Elsevier B.V. All rights reserved.

Pandemic influenza A virus (IAV) remains a significant threat to global health. Preparedness relies primarily upon a single class of neuraminidase (NA) targeted antivirals, against which resistance is steadily growing. The M2 proton channel is an alternative clinically proven antiviral target, yet a near-ubiquitous S31N polymorphism in M2 evokes resistance to licensed adamantane drugs. Hence, inhibitors capable of targeting N31 containing M2 (M2-N31) are highly desirable. Rational in silico design and in vitro screens delineated compounds favouring either lumenal or peripheral M2 binding, yielding effective M2-N31 inhibitors in both cases. Hits included adamantanes as well as novel compounds, with some showing low micromolar potency versus pandemic “swine” H1N1 influenza (Eng195) in culture. Interestingly, a published adamantane-based M2-N31 inhibitor rapidly selected a resistant V27A polymorphism (M2-A27/N31), whereas this was not the case for non-adamantane compounds. Nevertheless, combinations of adamantanes and novel compounds achieved synergistic antiviral effects, and the latter synergised with the neuraminidase inhibitor (NAi), Zanamivir. Thus, site-directed drug combinations show potential to rejuvenate M2 as an antiviral target whilst reducing the risk of drug resistance., Author summary "Swine flu" illustrated that the spread of influenza pandemics in the modern era is rapid, making antiviral drugs the best way of limiting disease. One proven influenza drug target is the M2 proton channel, which plays an essential role during virus entry. However, resistance against licensed drugs targeting this protein is now ubiquitous, largely due to an S31N change in the M2 sequence. Understandably, considerable effort has focused on developing M2-N31 inhibitors, yet this has been hampered by controversy surrounding two potential drug binding sites. Here, we show that both sites can in fact be targeted by new M2-N31 inhibitors, generating synergistic antiviral effects. Developing such drug combinations should improve patient outcomes and minimise the emergence of future drug resistance.

The Sigma-1 Receptor (S1R) is a small, ligand-regulated integral membrane protein involved in cell homeostasis and the cellular stress response. The receptor has a multitude of protein and small molecule interaction partners with therapeutic potential. Newly reported structures of the human S1R in ligand-bound states provides essential insights into small molecule binding in the context of the overall protein structure. The structure also raises many interesting questions and provides an excellent starting point for understanding the molecular tricks employed by this small membrane receptor to modulate a large number of signaling events. Here, we review insights from the structures of ligand-bound S1R in the context of previous biochemical studies and propose, from a structural viewpoint, a set of important future directions.

The Hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations1-4. We are curious as to what structural solution has the viroporin adopted to afford selective cation conduction because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The p7 activity can be inhibited by amantadine and rimantadine2,5, which also happen to be potent blockers of the influenza M2 channel6 and licensed drugs against influenza infections7. The adamantane derivatives were subjects of HCV clinical trials8, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here, we determined the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbors, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also alludes to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter while an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording showed that these residues are indeed critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives.

International audience; Membrane proteins perform a host of vital cellular functions. Deciphering the molecular mechanisms whereby they fulfill these functions requires detailed biophysical and structural investigations. Detergents have proven pivotal to extract the protein from its native surroundings. Yet, they provide a milieu that departs significantly from that of the biological membrane, to the extent that the structure, the dynamics, and the interactions of membrane proteins in detergents may considerably vary, as compared to the native environment. Understanding the impact of detergents on membrane proteins is, therefore, crucial to assess the biological relevance of results obtained in detergents. Here, we review the strengths and weaknesses of alkyl phosphocholines (or foscholines), the most widely used detergent in solution-NMR studies of membrane proteins. While this class of detergents is often successful for membrane protein solubilization, a growing list of examples points to destabilizing and denaturing properties, in particular for α-helical membrane proteins. Our comprehensive analysis stresses the importance of stringent controls when working with this class of detergents and when analyzing the structure and dynamics of membrane proteins in alkyl phosphocholine detergents.

Nowadays, global warming is one of the biggest issues for human being. A huge part of this warming is due to pollution from the transport industry and more particularly the aeronautical field. A lot of efforts are made in the turbofan engines design with the aim of improving the overall performance as well as respecting the environment (ACARE restrictions). To reduce fuel consumption, new aircraft concepts such as boundary layer ingesting (BLI) configurations are emerging [1]. BLI is a concept in which the engine ingests and reaccelerates the boundary layer from the aircraft fuselage in order to increase propulsive efficiency. It becomes then necessary to investigate the fan/BLI interactions and understand their detrimental influences on the fan performance. In this context, measurements are planned for 2019 at the Institute of Propulsion Technology of DLR in Cologne in which a generic and several real fuselage boundary layers are generated within a duct upstream of a contra rotating fan [2]. The aim of the present study is to provide results about the aerodynamic effects induced by BLI/fan interaction at given measurement locations [3]. This will be done by means of uRANS and Harmonic Balance based CFD computations involving different numerical setups and boundary conditions in order to quantify and isolate the different influential parameters. This is to understand the flow physics on the one hand as well as in order to prepare the cost intensive measurement campaign. In order to assess the dominant effects and most important influential parameters on the fan aerodynamic performance, relevant metrics such as the fan total pressure ratio, isentropic efficiency and the mass flow rate will be considered. In order to better understand the physical detailed interaction mechanisms, the results will also be analyzed based on local flow features as being observed in the CFD results.

This paper describes the current status of the design, implementation, and test of a data acquisition (DAQ) system for the prototypes of the front-end electronics of the Antiproton Annihilation at Darmstadt ($\mathrm{\bar{P}ANDA}$) Micro Vertex Detector (MVD). The features of this DAQ, called Juelich Digital Readout System (JDRS), are driven by the requirements imposed by the physics program of the experiment, such as continuous data collection without external triggering. Flexibility and modularity are thus key points for this system, which is meant to operate during a test beam, as well as in a laboratory environment. The implementation of the system is based on an off-theshelf field-programmable gate array (FPGA) board. So far, two different application-specific integrated circuits (ASICs) have been successfully connected to the JDRS. Tests to establish the performance of the JDRS in terms of processing speed and reliability have been carried out and are still ongoing.

Lisfranc fracture-dislocations can be devastating injuries with significant long-term sequelae with or without surgical intervention. The main goal of treatment is to minimize the common long-term complications including pain, progressive arch collapse, degenerative joint disease, hardware failure, and reoperation. Partial primary fusion involving the first, second, and third tarsometatarsal joints has become a common approach for primarily dislocation injuries, with open reduction and internal fixation (ORIF) favored for Lisfranc injuries involving fracture. ORIF commonly requires revision surgery for hardware removal or delayed fusion. Major revision creates hardship for the patient due to the prolonged recovery required, and even “simple” hardware removal can be traumatic to local nerve, artery, and tendon structures. A common injury pattern includes the findings of primary dislocation and instability of the first tarsometatarsal joint with oftentimes comminuted fracture to the second and third tarsometatarsal joints, which does not fit the standard surgical approach. We report a review of our preferred surgical approach consisting of medial column primary arthrodesis combined with central column ORIF and lateral column temporary pinning. We undertook an institutional review board-approved review of 35 consecutive Lisfranc injuries treated with this hybrid approach. Mean follow-up time was 22.14 ± 22.39 (range 2.5 to 84) months. All but 2 (5.71%) patients had radiographic evidence of union at 10 weeks. Complications included 3 with neuritis, 1 with medial column nonunion that was treated with a bone stimulator, and 1 with revision of second metatarsal nonunion. The present retrospective series highlights our experience with isolated primary fusion of the medial column in both subtle and obvious Lisfranc injuries.

The exclusive charmonium production process in (P) over barp annihilation with an associated pi 0 meson (p) over barp -> J/psi pi(0) is studied in the framework of QCD collinear factorization. The feasibility of measuring this reaction through the J/psi -> e(+) e(-) decay channel with the AntiProton ANnihilation at DArmstadt ((P) over bar ANDA) experiment is investigated. Simulations on signal reconstruction efficiency as well as the background rejection from various sources including the (P) over barp -> pi(+)pi(-)pi(0) and (p) over barp -> J/psi pi(0)pi(0) reactions are performed with PANDAROOT, the simulation and analysis software framework of the (P) over bar ANDA experiment. It is shown that the measurement can be done at (P) over bar ANDA with significant constraining power under the assumption of an integrated luminosity attainable in four to five months of data taking at the maximum design luminosity.

Background: Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic suppression and recovery following induction chemotherapy remain enigmatic. In addition, thrombocytopenia at diagnosis is related to deregulated cytokine expression in specific leukemia subtypes rather than on the degree of bone marrow infiltration per se. Similarly, recovery of platelets after the first induction cycle among individual patients can vary from incomplete to excess recovery even if morphologic remission is achieved. In particular, excess platelet rebound (EPR) with values exceeding 500 G/L can be observed in some patients. However, this clinical observation of EPR is poorly understood so far, and its prognostic relevance is unknown. Methods: We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients receiving at least one cycle of intensive "3+7" based induction treatment. We defined excess platelet rebound (EPR) as a platelet increase above 500 G/L during hematologic recovery after the first induction cycle. Results: We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 versus 41 months; P=0.04), as was disease-free survival (Figure 1). By multivariate analysis, achievement of EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p Conclusion: This study suggests that excess platelet rebound (EPR+) defined as platelets exceeding 500 G/L is a common event identified in AML patients after the first induction cycle. EPR+ was predominantly observed in ELN favorable risk AML, and it was associated with significantly better overall and disease-free survival as compared to EPR- patients. In addition, achievement of EPR+ represented an independent prognostic parameter for improved survival in a multivariate analysis, and may contribute to prognostic assessment in AML patients undergoing intensive treatment with intention to cure. Disclosures No relevant conflicts of interest to declare.

Hybrid pixel and double sided silicon microstrip devices will equip the Micro Vertex Detector of the P ¯ ANDA experiment. The most challenging request of the experiment is the continuous readout at the rate of 2 × 10 7 interactions/s. The detector is in an advanced R&D phase and pixel assemblies, composed of thinned epitaxial sensor read out by the custom chip prototype ToPix, developed in the 130 nm CMOS technology, were produced. The triggerless ASIC implements readout channels that are able to detect signals and transmit the information with a precise timestamp. It performs the energy loss measurement using the Time over Threshold technique, in the input range to about 50 fC. A dedicated testing bench allows the control and the readout of each single chip assembly. Two experimental setups were assembled for testing these first single chip prototypes with pions at CERN, T9, in August 2012. The first one is based on a pixel assembly positioned in the middle of a telescope composed of double sided silicon strips sensors. A 50 MHz clock signal synchronizes these two systems, the triggerless pixels and the strip detectors triggered by scintillation detectors. The second experimental setup is a tracking station housing four pixel assemblies. First results will be reported.

Background: Sigma-1 receptor is a ligand-regulated membrane protein chaperone involved in BiP regulation and the ER stress response. Results: The chaperone domain of human sigma-1 receptor is mostly helical with short extended regions. Conclusion: Regions of the sigma-1 receptor chaperone domain implicated in ligand and cholesterol binding can be mapped to separate helices. Significance: A structural framework for delineating sigma-1 receptor BiP and ligand interactions is presented., The sigma-1 receptor (S1R) is a ligand-regulated membrane protein chaperone involved in the ER stress response. S1R activity is implicated in diseases of the central nervous system including amnesia, schizophrenia, depression, Alzheimer disease, and addiction. S1R has been shown previously to regulate the Hsp70 binding immunoglobulin protein (BiP) and the inositol triphosphate receptor calcium channel through a C-terminal domain. We have developed methods for bacterial expression and reconstitution of the chaperone domain of human S1R into detergent micelles that enable its study by solution NMR spectroscopy. The chaperone domain is found to contain a helix at the N terminus followed by a largely dynamic region and a structured, helical C-terminal region that encompasses a membrane associated domain containing four helices. The helical region at residues ∼198–206 is strongly amphipathic and proposed to anchor the chaperone domain to micelles and membranes. Three of the helices in the C-terminal region closely correspond to previously identified cholesterol and drug recognition sites. In addition, it is shown that the chaperone domain interacts with full-length BiP or the isolated nucleotide binding domain of BiP, but not the substrate binding domain, suggesting that the nucleotide binding domain is sufficient for S1R interactions.

The design process of modern aircraft engines extensively makes use of computational fluid dynamics (CFD). During the design process fan, compressor and turbine stages are typically evaluated using single passage CFD-simulations. For the design of an inlet distortion tolerant fan, the inhomogeneity of the inflow in circumferential direction does not allow the application of periodic boundary conditions and hence single passage simulations. Accordingly transient full annulus simulations have to be applied to correctly resolve the underlying physical interactions. The associated computation time for such a high fidelity simulation prohibit its application in today’s design procedures. This paper compares the simulation results of the ingestion of a mild and generic fuselage boundary layer of a blended wing body aircraft into an UHBR engine on the basis of four different simulation methods. The four different simulations include: transient full annulus CFD, Harmonic Balance frequency domain based CFD, steady full annulus CFD (Frozen Rotor) and steady single passage CFD for each blade passage. The results of the simulations are assessed using a newly developed stream tube based post-processing procedure. For the ingestion of the fuselage boundary layer the four numerical setups result in different aerodynamic conditions in the fan stage. For different aerodynamic measures different discrepancies are encountered for the different simulation methods. While the Harmonic Balance method can reproduce most features well, the simpler models overestimate the variations in the different flow features.Copyright © 2016 by ASME

Background: The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. Methods: Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. Results: Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31% P

Differential counts of bone marrow smears and aspirated material from the spleen were compared in 17 cases of chronic myeloid leukaemia (CML). With increasing signs of relapse i.e. increasing WBC, an increasing proportion of granulopoietic precursor cells were found in the bone marrow. The proportion of granulopoietic precursor cells did not, however, change significantly in the spleen. It is suggested that the differences observed may reflect differences in granulopoiesis between bone marrow and extramedullary tissue in CML.

The integral membrane protein M2 of influenza virus forms pH-gated proton channels in the viral lipid envelope. The low pH of an endosome activates the M2 channel before haemagglutinin-mediated fusion. Conductance of protons acidifies the viral interior and thereby facilitates dissociation of the matrix protein from the viral nucleoproteins--a required process for unpacking of the viral genome. In addition to its role in release of viral nucleoproteins, M2 in the trans-Golgi network (TGN) membrane prevents premature conformational rearrangement of newly synthesized haemagglutinin during transport to the cell surface by equilibrating the pH of the TGN with that of the host cell cytoplasm. Inhibiting the proton conductance of M2 using the anti-viral drug amantadine or rimantadine inhibits viral replication. Here we present the structure of the tetrameric M2 channel in complex with rimantadine, determined by NMR. In the closed state, four tightly packed transmembrane helices define a narrow channel, in which a 'tryptophan gate' is locked by intermolecular interactions with aspartic acid. A carboxy-terminal, amphipathic helix oriented nearly perpendicular to the transmembrane helix forms an inward-facing base. Lowering the pH destabilizes the transmembrane helical packing and unlocks the gate, admitting water to conduct protons, whereas the C-terminal base remains intact, preventing dissociation of the tetramer. Rimantadine binds at four equivalent sites near the gate on the lipid-facing side of the channel and stabilizes the closed conformation of the pore. Drug-resistance mutations are predicted to counter the effect of drug binding by either increasing the hydrophilicity of the pore or weakening helix-helix packing, thus facilitating channel opening.

This article underscores the importance of folk religious concepts in understanding the way in which people interact with the environment that envelops and sustains them. Images of rural Japan have drawn almost exclusively on the tradition of irrigated rice cultivation combined with ancestor worship. Alternative concepts have been overlooked or ignored, fostering the sense of a uniform heritage. The author highlights one such alternative, which derives from the tradition of hunting, gathering, and slash-and-burn cultivation within a spirit-imbued landscape. The contrast between perspectives is illustrated by a historical encounter between a British mountaineer and the residents of two communities located at different elevations within the same watershed. Resume L'auteur souligne l'importance des concepts religieux populaires dans la comprehension des interactions entre les gens et l'environnement qui les entoure et assure leur subsistance. Les images du Japon rural ont tourne presque exclusivement autour de la tradition de la culture irriguee du riz et du culte des ancetres. Les concepts alternatifs ont ete meconnus ou ignores, favorisant ainsi la perception d'un patrimoine culturel uniforme. L'auteur met en evidence une de ces alternatives, issue de la tradition de la chasse, de la cueillette et de la culture sur brulis, dans un paysage habite par les esprits. Le contraste entre les points de vue est illustre par une rencontre historique entre un alpiniste britannique et les habitants de deux villages situes a des altitudes differentes dans un meme bassin versant.