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Computer program computes system reliability for very general class of reliability block diagrams. Four factors are considered in calculating probability of system success: active block redundancy, standby block redundancy, partial redundancy, and presence of equivalent blocks in the diagram.
Recent International Ultraviolet Explorer (IUE) observations of two interacting binaries, R Arae and HD 207739 are reported. The ultraviolet spectra indicate the presence of optically-thick, variable hot plasma in those binary systems. These two binaries may belong to a class of binaries that are currently undergoing a rarely observed and probably short-lived phase in their evolution. Their properties are compared with those of two other interacting binaries, U Cephei and Beta Lyrae.
New turbulence modeling options recently implemented for the 3D version of Proteus, a Reynolds-averaged compressible Navier-Stokes code, are described. The implemented turbulence models include: the Baldwin-Lomax algebraic model, the Baldwin-Barth one-equation model, the Chien k-epsilon model, and the Launder-Sharma k-epsilon model. Features of this turbulence modeling package include: well documented and easy to use turbulence modeling options, uniform integration of turbulence models from different classes, automatic initialization of turbulence variables for calculations using one- or two-equation turbulence models, multiple solid boundaries treatment, and fully vectorized L-U solver for one- and two-equation models. Good agreements are obtained between the computational results and experimental data. Sensitivity of the compressible turbulent solutions with the method of y(+) computation, the turbulent length scale correction, and some compressibility corrections are examined in detail. Test cases show that the highly optimized one- and two-equation turbulence models can be used in routine 3D Navier-Stokes computations with no significant increase in CPU time as compared with the Baldwin-Lomax algebraic model.
Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.
Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd remains poorly understood. Here we report the structure of an unliganded human Fzd5 determined by single-particle cryo-EM at 3.7 Å resolution, with the aid of an antibody chaperone acting as a fiducial marker. We also analyzed the topology of low-resolution XWnt8/Fzd5 complex particles, which revealed extreme flexibility between the Wnt/Fzd-CRD and the Fzd-TM regions. Analysis of Wnt/β-catenin signaling in response to Wnt3a versus a ‘surrogate agonist’ that cross-links Fzd to LRP6, revealed identical structure-activity relationships. Thus, canonical Wnt/β-catenin signaling appears to be principally reliant on ligand-induced Fzd/LRP6 heterodimerization, versus the allosteric mechanisms seen in structurally analogous class A G protein-coupled receptors, and Smoothened. These findings deepen our mechanistic understanding of Wnt signal transduction, and have implications for harnessing Wnt agonism in regenerative medicine.
The test results of small LOX/LH2 engines for two propulsion systems, a pump fed system and a pressure fed system are reported. The pump fed system has the advantages of higher performances and higher mass fraction. The pressure fed system has the advantages of higher reliability and relative simplicity. Adoption of these cryogenic propulsion systems for upper stage of launch vehicle increases the payload capability with low cost. The 1,000 kg thrust class engine was selected for this cryogenic stage. A thrust chamber assembly for the pressure fed propulsion system was tested. It is indicated that it has good performance to meet system requirements.
Published data from bulk chemical analyses of 94 ordinary chondrites are compiled in a table of normative mineralogy and discussed in detail. Significant variations in olivine, pyroxene, and metal abundance ratios are found within each chondrite class and attributed to redox processes superimposed on initial differences in metal/silicate ratios. The use of the diagrams constructed here to predict the mineralogic characteristics of asteroids on the basis of spectrophotometric observations is suggested.
Engineered reverse hairpin constructs containing a partial C-heptad repeat (CHR) sequence followed by a short loop and full-length N-heptad repeat (NHR) were previously shown to form trimers in solution and to be nanomolar inhibitors of HIV-1 Env mediated fusion. Their target is the in situ gp41 fusion intermediate, and they have similar potency to other previously reported NHR trimers. However, their design implies that the NHR is partially covered by CHR, which would be expected to limit potency. An exposed hydrophobic pocket in the folded structure may be sufficient to confer the observed potency, or they may exist in a partially unfolded state exposing full length NHR. Here, in this study, we examined their structure by crystallography, CD and fluorescence, establishing that the proteins are folded hairpins both in crystal form and in solution. We examined unfolding in the milieu of the fusion reaction by conducting experiments in the presence of a membrane mimetic solvent and by engineering a disulfide bond into the structure to prevent partial unfolding. We further examined the role of the hydrophobic pocket, using a hairpin-small molecule adduct that occluded the pocket, as confirmed by X-ray footprinting. The results demonstrated that the NHR region nominally covered by CHR in the engineered constructs and the hydrophobic pocket region that is exposed by design were both essential for nanomolar potency and that interaction with membrane is likely to play a role in promoting the required inhibitor structure. The design concepts can be applied to other Class 1 viral fusion proteins.
An account is given of the types of carbonaceous meteorites available in the Antarctic collections of the U.S. and Japan. In the case of the collection for Victoria Land and Queen Maud Land, all known classes for meteorites except C1 are present; available pairing data, though limited, are indicative of the presence of many different falls. Thus far, attention has been focused on the largest meteorites. Most samples, however, are small.
This panel will discuss the implications of atrial arrhythmias in astronauts from a variety of perspectives; including historical data, current practices, and future challenges for exploration class missions. The panelists will present case histories, outline the evolution of current NASA medical standards for atrial arrhythmias, discuss the use of predictive tools, and consider potential challenges for current and future missions.
The inclusive production of the J/ ψ and ψ (2S) charmonium states is studied as a function of centrality in p-Pb collisions at a centre-of-mass energy per nucleon pair \( \sqrt{s_{\mathrm{NN}}} \) = 8 . 16 TeV at the LHC. The measurement is performed in the dimuon decay channel with the ALICE apparatus in the centre-of-mass rapidity intervals – 4 . 46 < y cms < – 2 . 96 (Pb-going direction) and 2 . 03 < y cms < 3 . 53 (p-going direction), down to zero transverse momentum ( p T ). The J/ ψ and ψ (2S) production cross sections are evaluated as a function of the collision centrality, estimated through the energy deposited in the zero degree calorimeter located in the Pb-going direction. The p T -differential J/ ψ production cross section is measured at backward and forward rapidity for several centrality classes, together with the corresponding average \( \left\langle {p}_{\mathrm{T}}\right\rangle \) and \( \left\langle {p}_{\mathrm{T}}^2\right\rangle \) values. The nuclear effects affecting the production of both charmonium states are studied using the nuclear modification factor. In the p-going direction, a suppression of the production of both charmonium states is observed, which seems to increase from peripheral to central collisions. In the Pb-going direction, however, the centrality dependence is different for the two states: the nuclear modification factor of the J/ ψ increases from below unity in peripheral collisions to above unity in central collisions, while for the ψ (2S) it stays below or consistent with unity for all centralities with no significant centrality dependence. The results are compared with measurements in p-Pb collisions at \( \sqrt{s_{\mathrm{NN}}} \) = 5 . 02 TeV and no significant dependence on the energy of the collision is observed. Finally, the results are compared with theoretical models implementing various nuclear matter effects.
The influence of the optical Stark effect on spectral line shapes in four-wave-mixing Raman spectroscopy (FWMRS) and stimulated Raman spectroscopy (SRS) is investigated experimentally and theoretically. Using an experimental setup capable of rapid alternation between the simultaneous measurement of coherent Stokes Raman spectroscopy and inverse Raman spectroscopy at low and high intensities, together with a sophisticated frequency reference scheme, it was possible to perform a rather direct comparison between Stark-broadened and non-Stark-broadened spectra of both classes of Raman spectroscopies. The results demonstrate that SRS spectra show more Stark shift and broadening than their FWMRS counterparts. A discrepancy with theoretical results is pointed out, and an attempt is made to explain it.
The massive amount of wasted heat energy from industry has pushed the development of thermoelectric (TE) materials that directly convert heat into electricity to a new level of concern. Recently, multicomponent alloys such as GeTe-based and PbSe-based high-entropy (HE) chalcogenides have attracted a great deal of attention due to their potential application as TE materials. The nature of the interatomic bonding, lattice distortion (LD), and the electronic structure in this class of materials is not fully understood. Herein, we report a comprehensive computational investigation of nine GeTe-based HE alloys with eight metallic elements (Ag, Pb, Sb, Bi, Cu, Cd, Mn, and Sn) with large supercells of 1080 atoms each; seven PbSe-based HE solid solutions: Pb0.99−ySb0.012SnySe1−2xTexSx (x = 0.1, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, with y = 0) with supercells of 1000 atoms each; and five Pb0.99−ySb0.012SnySe1−2xTexSx (y = 0.05, 0.1, 0.15, 0.2, 0.25 with x = 0.25) solid solutions with supercells of 1000 atoms each. All these HE models are theoretically investigated for the first time. The electronic structure, interatomic bonding, charge transfer, and lattice distortion (LD) are investigated by first-principles calculations based on density functional theory. Multicomponent HE alloys can cause a significant LD, which affects their mechanical, thermal, and TE properties. The calculations for the GeTe-based HE chalcogenides showed that they are semiconductors with a narrow bandgap, except for m8, which has a semi-metallic characteristic, and this makes them good candidates for TE applications. For most of these models, the Fermi level shifts upward and locates deeply in the conduction bands, resulting in the enhancement of the electrical conductivity (σ). The bonding properties showed that most bonds in m5 are more dispersed, indicating highest LD and lower lattice thermal conductivity. For PbSe-based HE solid solutions, the LD calculations showed that the models Pb0.99Sb0.012Se0.5Te0.25S0.25 and Pb0.89Sb0.012Sn0.1Se0.5Te0.25S0.25 have the higher LD, and thus a lower lattice thermal conductivity. Such investigations are in high demand since it enables us to design new HE chalcogenides for TE applications. We use the novel concept of total bond order density as a single quantum mechanical metric to characterize the internal cohesion of these HE alloys and correlate with calculated properties, especially the mechanical properties. This work provides a solid database for HE chalcogenides and a road map for many potential applications. Moreover, the computational procedure we developed can be used to design new HE chalcogenides for specific TE applications.
The author has identified the following significant results. Visual and automatic interpretation of LANDSAT imagery was used to classify the general Pinus and Eucalyptus according to their age and species. A methodology was derived, based on training areas, to define the legend and spectral characteristics of the analyzed classes. Imager analysis of the training areas show that Pinus taeda is separable from the other Pinus species based on JM distance measurement. No difference of JM measurements was observed among Eucalyptus species. Two classes of Eucalyptus were separated according to their ages: those under and those over two years of age. Channel 6 and 7 were suitable for the discrimination of the reforested classes. Channel 5 was efficient to separated reforested areas from nonforested targets in the region. The automatic analysis shows the highest classification precision was obtained for Eucalyptus over two years of age (95.12 percent).
The author has identified the following significant results. The class of reforestation (Pinus, Eucalyptus, Araucaria) was defined using iterative image analysis (1-100) and LANDSAT MSS data. Estimates of class area by 1-100 were compared with data supplied by the forestry institute in Sao Paulo. LANDSAT channels 4 and 5 served to differentiate the Pinus, Eucalyptus, and Araucaria from the other trees. Channels 6 and 7 gave best results for differentiating between the classes. A good representative spectral response was obtained for Auraucaria on these two channels. The small relative differences obtained were +4.24% for Araucaria, -7.51% for Pinus, and -32.07% for Eucalyptus.
One of the results of the EINSTEIN/C.f.A. X-ray stellar survey was a determination of the contribution of the disk stellar population to the galactic component of the diffuse soft (0.28 - 1.0 keV) X-ray background. This analysis employed both binned and unbinned nonparametric statistical methods that have been developed by Avni, et al. (1980). These methods permitted the use of the information contained in both the 22 detections and 4 upper bounds on the luminosities of 26 dM stars in order to derive their luminosity function. Luminosity functions for earlier stellar types are not yet developed. For these earlier stellar types, the median luminosities as determined by Vaiana, et al., are used (1981), which underestimates their contribution to the background. We find that it is the M dwarfs that dominate the disk population stellar contribution to this background. To calculate the contribution of the stellar sources to the background, simple models both for the spatial distribution of the stars and for the properties of the intervening interstellar medium are used. A model is chosen in which all stellar classes have the same functional form for their spatial distribution: an exponentially decreasing distribution above the galactic equatorial plane, and a uniform distribution within the galactic plane for a region of several kiloparsecs centered on the Sun.
Multiprincipal-element alloys are an enabling class of materials owing to their impressive mechanical and oxidation-resistant properties, especially in extreme environments. Here we develop a new oxide-dispersion-strengthened NiCoCr-based alloy using a model-driven alloy design approach and laser-based additive manufacturing. This oxide-dispersion-strengthened alloy, called GRX-810, uses laser powder bed fusion to disperse nanoscale Y 2 O 3 particles throughout the microstructure without the use of resource-intensive processing steps such as mechanical or in situ alloying. We show the successful incorporation and dispersion of nanoscale oxides throughout the GRX-810 build volume via high-resolution characterization of its microstructure. The mechanical results of GRX-810 show a twofold improvement in strength, over 1,000-fold better creep performance and twofold improvement in oxidation resistance compared with the traditional polycrystalline wrought Ni-based alloys used extensively in additive manufacturing at 1,093 °C. The success of this alloy highlights how model-driven alloy designs can provide superior compositions using far fewer resources compared with the ‘trial-and-error’ methods of the past. These results showcase how future alloy development that leverages dispersion strengthening combined with additive manufacturing processing can accelerate the discovery of revolutionary materials.
The sensitivity of reflectance spectra to mean ferrous iron content and olivine and pyroxene proportion enhancements in the course of metamorphic oxidation is presently used to examine whether metamorphically-induced ranges in mineralogy, and corresponding spectral parameters, may explain the observed variations in S-asteroid rotational spectra. The predicted spectral variations within any one chondrite class are, however, insufficient to account for S-asteroid rotational spectra, and predicted spectral-range slopes have a sign opposite to the rotational measurements. Metamorphic oxidation is found unable to account for S-asteroid rotational spectra.