SR-SCARLET 1: Peregrin

This report presents a reconnaissance aircraft with a lifting body configuration. The aircraft is capable of flying a distance of 6000 nmi at Mach 5 with a payload of 7500 pounds. The aircraft does not require a runway for takeoff for it is air launched from a carrier aircraft. Specifically this report addresses the areas of external aerodynamics, cost, thermal protection systems, propulsion, stability and control, and materials. Each area is represented by a separate section. This allows for selective reading

Membrane effects of aminoglycoside antibiotics measured in liposomes containing the fluorescent probe, 1-anilino-8-naphthalene sulfonate

The mechanism of membrane disturbance by aminoglycoside antibiotics was investigated in liposomes containing the fluorescent probe, 1-anilino-8-naphthalene sulfonate (ANS). Liposomes of PC and different anionic phospholipids (1:1 to 15:1 molar ratios) were challenged with aminoglycosides in the presence of low (1 [mu]M) and high (3 mM) concentrations of calcium. Liposomes containing PIP2 showed the greatest drug-induced changes in ANS fluorescence in the presence of high and low concentrations of calcium and at all PC:PIP2 molar ratios tested. Liposomes containing other anionic phospholipids (PS, PI and PIP2) were not reactive toward aminoglycosides in the presence of 3 mM calcium or when the ratio of PC to anionic lipid was increased to 10:1. The aminoglycoside-induced changes of ANS flouorescence were not due to any changes in the emission spectrum of ANS, nor to changes in quantum yield, nor to a change in the binding affinity of ANS. It is concluded that a specific aminoglycoside-PIP2 interaction results in phase separation of PC and PIP2 and thus increases the number of available ANS binding sites in PC:PIP2 liposomes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25983/1/0000049.pd

Interactions of neomycin and calcium in synaptosomal membranes and polyphosphoinositide monolayers

Neomycin and related aminoglycosidic antibiotics displace calcium from synaptosomes of guinea pig cerebral cortex and from preparations of phosphatidylinositol diphosphate. At low drug concentrations, inhibition of synaptosomal calcium binding is competitive (Ki = 3[middle dot]10-5M), at high concentrations it is non-competitive (Ki = 4[middle dot]10-4M). Monomolecular films of phosphatidylinositol diphosphate are contracted by low concentrations of neomycin in the subphase, and are expanded at high concentrations. This expansion persists even at the collapse pressure indicating a strong interaction between the drug and the lipid.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21792/1/0000187.pd

Aminoglycoside antibiotics preferentially increase permeability in phosphoinositide-containing membranes: a study with carboxyfluorescein in liposomes

The rate of release from multilamellar liposomes of the fluoroscent probe carboxyfluorescein was determined as a measure of membrane permeability. Liposomes of phosphatidylcholine and different anionic phospholipids were incubated with low (1 [mu]M) and high (3 mM) concentrations of calcium in the absence or presence of aminoglycoside antibiotics. The leakage of carboxyfluorescein into the medium was not caused by liposomal fusion as no vesicle fusion was observed in experiments with terbium and dipicolinic acid-loaded liposomes. The basal rate of carboxyfluorescein release (in the absence or presence of 1 [mu]M calcium) from all types of liposomes ranged from 0.1 to 0.3% of trapped carboxyfluorescein per hour. The presence of 3 mM calcium caused the greatest increase in the rate of carboxyfluorescein release (about 9-fold) in liposomes containing phosphatidylinositol 4,5-bisphosphate (PIP2) whereas liposomes containing the other anionic phospholipids (phosphatidylserine, phosphatidylinositol and phosphatidylinositol 4-phosphate) showed an approximate 5-fold increase. In the presence of 1 [mu]M calcium, the aminoglycosides neomycin and gentamicin also increased the rate of carboxyfluorescein release, with PIP2-containing liposomes showing a 3-5-times greater response than the other liposomes, releasing up to 4.6% of trapped carboxyfluorescein per hour. This drug-induced release was dose-dependent and antagonized by calcium. In the presence of 3 mM calcium, 0.1 mM gentamicin or neomycin were ineffective while the drug at 1 mM affected carboxyfluorescein release from PIP2-liposomes only. The aminoglycoside antibiotics, neomycin, gentamicin, tobramycin, kanamycin, amikacin, netilmicin, as well as neamine and spectinomycin (all at 0.1 mM) showed a graded effect on the rate of carboxyfluorescein release from PIP2-containing vesicles in the presence of 0.1 mM calcium. The magnitude of the effect correlated well with the ototoxicity of the drugs previously determined directly in cochlear perfusions in the guinea pig. The study demonstrates that aminoglycoside antibiotics are capable of altering membrane permeabilities and that this effect is most pronounced if PIP2 is present in the bilayers. The excellent correlation between this membrane action and the in-situ toxicity of the drugs further establishes the specific role of PIP2 in the molecular mechanism of aminoglycoside-induced hearing loss. Moreover, it confirms the usefulness of such physicochemical models for the screening and prediction of aminoglycoside toxicity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26611/1/0000152.pd

Gentamicin alters membrane structure as shown by freeze-fracture of liposomes

Freeze-fracture has been used to examine the effects of gentamicin on membrane structure in liposomes of different anionic phospholipids combined with a neutral phospholipid, phosphatidylcholine. The molar ratios of neutral: anionic lipid were 1:1 (high anionic lipid ratio) and 4:1 (low anionic lipid) and the liposomes were incubated with 0.1 mM (low) and 1 mM (high) gentamicin. With the anionic phospholipid phosphatidylinositol bisphosphate, an identifiable disruption of the membrane bilayer was observed as well as aggregation of liposomes leading to membrane fusion. These effects occurred both at low gentamicin concentration and low anionic lipid content of the liposomes; these responses were not inhibited by 1 mM Ca2+. With the other anionic lipids tested (phosphatidylserine, phosphatidylinositol and phosphatidylinositol monophosphate), only aggregation and fusion of liposomes was observed and this effect only occurred at high gentamicin concentration and high anionic lipid content. Further, 1 mM Ca2+ inhibited the responses of these other anionic lipids to gentamicin. The results demonstrate the unique character of the interaction between gentamicin and phosphatidylinositol bisphosphate and provide further support for the hypothesis that a specific binding to this lipid is a key step in the ototoxic action of aminoglycoside antibiotics. They also suggest that such an interaction in vivo might cause alterations to the structure and properties of cell membranes in the inner ear.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28139/1/0000591.pd

Electroencephalographic signatures of the binge drinking pattern during adolescence and young adulthood: A PRISMA-driven systematic review

Research on neurophysiological impairments associated with binge drinking (BD), an excessive but episodic alcohol use pattern, has significantly increased over the last decade. This work is the first to systematically review -following PRISMA guidelines- the empirical evidence regarding the effects of BD on neural activity -assessed by electroencephalography- of adolescents and young adults. A systematic review was conducted in 34 studies (N = 1723). Results indicated that binge drinkers (BDs) showed similar behavioral performance as non/low drinkers. The most solid electrophysiological finding was an augmented P3 amplitude during attention, working memory and inhibition tasks. This increased neural activity suggests the recruitment of additional resources to perform the task at adequate/successful levels, which supports the neurocompensation hypothesis. Similar to alcoholics, BDs also displayed increased reactivity to alcohol-related cues, augmented resting-state electrophysiological signal and reduced activity during error detection -which gives support to the continuum hypothesis. Evidence does not seem to support greater vulnerability to BD in females. Replication and longitudinal studies are required to account for mixed results and to elucidate the extent/direction of the neural impairments associated with BD.Foundation for Science and Technology (FCT) through the Portuguese State Budget [Ref.: UIDB/PSI/01662/2020]. This study was also supported by the project POCI-01-0145-FEDER-028672, funded by FCT and the European Regional Development Fund (FEDER). Eduardo López-Caneda and Alberto Crego were supported by the FCT and the Portuguese Ministry of Science, Technology and Higher Education, within the scope of the Individual Call to Scientific Employment Stimulus (CEECIND/02979/2018), and within the scope of the Transitory Disposition of the Decrete No. 57/2016, of 29th of August, amended by Law No. 57/2017 of 19 July, respectively. Natália Antunes was supported by a fellowship from the FCT (SFRH/BD/146194/2019). Carina Carbia has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement [grant number 754535

Introduction: Nietzsche's Life and Works

An introduction to Nietzsche's life and works

Nietzsche's Ethics of Affirmation

This chapter looks at Nietzsche's notion of the affirmation of life. It begins with the origins of the concept in Schopenhauer and in the Schopenhauerian philosophy known to Nietzsche. It then examines affirmation in three phases of Nietzsche's writing: early, middle and late. It relates affirmation to other key Nietzschean concepts like the Apollonian and the Dionysian, eternal recurrence, amor fati and will to power

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Measurement and interpretation of same-sign W boson pair production in association with two jets in pp collisions at s = 13 TeV with the ATLAS detector

This paper presents the measurement of fducial and diferential cross sections for both the inclusive and electroweak production of a same-sign W-boson pair in association with two jets (W±W±jj) using 139 fb−1 of proton-proton collision data recorded at a centre-of-mass energy of √s = 13 TeV by the ATLAS detector at the Large Hadron Collider. The analysis is performed by selecting two same-charge leptons, electron or muon, and at least two jets with large invariant mass and a large rapidity diference. The measured fducial cross sections for electroweak and inclusive W±W±jj production are 2.92 ± 0.22 (stat.) ± 0.19 (syst.)fb and 3.38±0.22 (stat.)±0.19 (syst.)fb, respectively, in agreement with Standard Model predictions. The measurements are used to constrain anomalous quartic gauge couplings by extracting 95% confdence level intervals on dimension-8 operators. A search for doubly charged Higgs bosons H±± that are produced in vector-boson fusion processes and decay into a same-sign W boson pair is performed. The largest deviation from the Standard Model occurs for an H±± mass near 450 GeV, with a global signifcance of 2.5 standard deviations