A Microcantilever Device to Assess the Effect of Force on the Lifetime of Selectin-Carbohydrate Bonds

A microcantilever technique was used to apply force to receptor-ligand molecules involved in leukocyte rolling on blood vessel walls. E-selectin was adsorbed onto 3-μm-diameter, 4-mm-long glass fibers, and the selectin ligand, sialyl Lewisx, was coupled to latex microspheres. After binding, the microsphere and bound fiber were retracted using a computerized loading protocol that combines hydrodynamic and Hookean forces on the fiber to produce a range of force loading rates (force/time), rf. From the distribution of forces at failure, the average force was determined and plotted as a function of ln rf. The slope and intercept of the plot yield the unstressed reverse reaction rate, kro , and a parameter that describes the force dependence of reverse reaction rates, ro. The ligand was titrated so adhesion occurred in ~30% of tests, implying that \u3e80% of adhesive events involve single bonds. Monte Carlo simulations show that this level of multiple bonding has little effect on parameter estimation. The estimates are ro = 0.048 and 0.016 nm and kro = 0.72 and 2.2 s-1 for loading rates in the ranges 200–1000 and 1000–5000 pN s-1, respectively. Levenberg-Marquardt fitting across all values of rf gives ro = 0.034 nm and kro = 0.82 s-1. The values of these parameters are in the range required for rolling, as suggested by adhesive dynamics simulations

Reductions of erythrocyte membrane viscoelastic coefficients reflect spectrin deficiencies in hereditary spherocytosis

Hereditary spherocytosis is a common hemolytic anemia associated with deficiencies in spectrin, the principal structural protein of the erythrocyte membrane-skeleton. We have examined 20 different individuals from 10 spherocytosis kindreds and 2 elliptocytosis kindreds to determine the effects of different levels of spectrin deficiency on the viscoelastic properties of the erythrocyte membrane. Micropipettes were used to perform single-cell micromechanical measurements of approximately 1,000 individual cells to determine the membrane elastic shear modulus, the apparent membrane bending stiffness, and whole cell recovery time constant for the different cell populations. The membrane viscosity was calculated by the product of the shear modulus and the recovery time constant. Results show correlation between the fractional reduction in shear modulus and the fractional reduction in spectrin content (determined by spectrin radioimmunoassay) and spectrin density (determined by the ratios of spectrin to band 3 on electrophoresis gels) suggesting that membrane shear elasticity is directly proportional to the surface density of spectrin on the membrane (P less than 0.001). The apparent membrane bending stiffness is also reduced in proportion to the density of spectrin (P less than 0.001). The membrane viscosity is reduced relative to control (P less than 0.001), but the nature of the relationship between spectrin density and membrane viscosity is less clearly defined. These studies document striking relationships between partial deficiencies of erythrocyte spectrin and specific viscoelastic properties of the mutant membranes

Seasonal Variations of Stratospheric Age Spectra in GEOSCCM

There are many pathways for an air parcel to travel from the troposphere to the stratosphere, each of which takes different time. The distribution of all the possible transient times, i.e. the stratospheric age spectrum, contains important information on transport characteristics. However, it is computationally very expensive to compute seasonally varying age spectra, and previous studies have focused mainly on the annual mean properties of the age spectra. To date our knowledge of the seasonality of the stratospheric age spectra is very limited. In this study we investigate the seasonal variations of the stratospheric age spectra in the Goddard Earth Observing System Chemistry Climate Model (GEOSCCM). We introduce a method to significantly reduce the computational cost for calculating seasonally dependent age spectra. Our simulations show that stratospheric age spectra in GEOSCCM have strong seasonal cycles and the seasonal cycles change with latitude and height. In the lower stratosphere extratropics, the average transit times and the most probable transit times in the winter/early spring spectra are more than twice as old as those in the summer/early fall spectra. But the seasonal cycle in the subtropical lower stratosphere is nearly out of phase with that in the extratropics. In the middle and upper stratosphere, significant seasonal variations occur in the sUbtropics. The spectral shapes also show dramatic seasonal change, especially at high latitudes. These seasonal variations reflect the seasonal evolution of the slow Brewer-Dobson circulation (with timescale of years) and the fast isentropic mixing (with timescale of days to months)

Assessment of the Effects of High-Speed Aircraft in the Stratosphere: 1998

This report assesses the potential atmospheric impacts of a proposed fleet of high-speed civil transport (HSCT) aircraft. The purpose of the report is to assess the effects of HSCT's on atmospheric composition and climate in order to provide a scientific basis for making technical, commercial, and environmental policy decisions regarding the HSCT fleet. The work summarized here was carried out as part of NASA's Atmospheric Effects of Aviation Project (a component of the High-Speed Research Program) as well as other NASA, U.S., and international research programs. The principal focus is on change in stratospheric ozone concentrations. The impact on climate change is also a concern. The report describes progress in understanding atmospheric processes, the current state of understanding of HSCT emissions, numerical model predictions of HSCT impacts, the principal uncertainties in atmospheric predictions, and the associated sensitivities in predicted effects of HSCT'S

An Open Label, Adaptive, Phase 1 Trial of High-Dose Oral Nitazoxanide in Healthy Volunteers: An Antiviral Candidate for SARS-CoV-2.

Funder: UnitaidRepurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19

Measurement of inclusive D*+- and associated dijet cross sections in photoproduction at HERA

Inclusive photoproduction of D*+- mesons has been measured for photon-proton centre-of-mass energies in the range 130 < W < 280 GeV and a photon virtuality Q^2 < 1 GeV^2. The data sample used corresponds to an integrated luminosity of 37 pb^-1. Total and differential cross sections as functions of the D* transverse momentum and pseudorapidity are presented in restricted kinematical regions and the data are compared with next-to-leading order (NLO) perturbative QCD calculations using the "massive charm" and "massless charm" schemes. The measured cross sections are generally above the NLO calculations, in particular in the forward (proton) direction. The large data sample also allows the study of dijet production associated with charm. A significant resolved as well as a direct photon component contribute to the cross section. Leading order QCD Monte Carlo calculations indicate that the resolved contribution arises from a significant charm component in the photon. A massive charm NLO parton level calculation yields lower cross sections compared to the measured results in a kinematic region where the resolved photon contribution is significant.Comment: 32 pages including 6 figure

Measurement of Jet Shapes in Photoproduction at HERA

The shape of jets produced in quasi-real photon-proton collisions at centre-of-mass energies in the range $134-277$ GeV has been measured using the hadronic energy flow. The measurement was done with the ZEUS detector at HERA. Jets are identified using a cone algorithm in the $\eta - \phi$ plane with a cone radius of one unit. Measured jet shapes both in inclusive jet and dijet production with transverse energies $E^{jet}_T>14$ GeV are presented. The jet shape broadens as the jet pseudorapidity ($\eta^{jet}$) increases and narrows as $E^{jet}_T$ increases. In dijet photoproduction, the jet shapes have been measured separately for samples dominated by resolved and by direct processes. Leading-logarithm parton-shower Monte Carlo calculations of resolved and direct processes describe well the measured jet shapes except for the inclusive production of jets with high $\eta^{jet}$ and low $E^{jet}_T$. The observed broadening of the jet shape as $\eta^{jet}$ increases is consistent with the predicted increase in the fraction of final state gluon jets.Comment: 29 pages including 9 figure

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

A useful savagery: The invention of violence in nineteenth-century England

‘A Useful Savagery: The Invention of Violence in Nineteenth-Century England’ considers a particular configuration of attitudes toward violence that emerged in the early decades of the nineteenth century. As part of a longer-term process of emerging ‘sensibilities,’ violence was, seemingly paradoxically, ‘invented’ as a social issue while concurrently relocated in the ‘civilised’ imagination as an anti-social feature mainly of ‘savage’ working-class life. The dominant way this discourse evolved was through the creation of a narrative that defined ‘civilisation’ in opposition to the presumed ‘savagery’ of the working classes. Although the refined classes were often distanced from the physical experience of violence, concern with violence and brutality became significant parts of social commentary aimed at a middle-class readership. While stridently redefining themselves in opposition to ‘brutality,’ one of the purposes of this literature was to create a new middle class and justify the expansion of state power. By the closing decades of the nineteenth century, as the working classes adopted tenets of Victorian respectability, a proliferating number of social and psychological ‘others’ were identified against which ‘civilised’ thought could define itself