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At least 1,423 records · Page 79

Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer

Neurofibromin is a tumor suppressor encoded by the NF1 gene, which is mutated in Rasopathy disease neurofibromatosis type I. Defects in NF1 lead to aberrant signaling through the RAS–mitogen-activated protein kinase pathway due to disruption of the neurofibromin GTPase-activating function on RAS family small GTPases. Very little is known about the function of most of the neurofibromin protein; to date, biochemical and structural data exist only for its GAP domain and a region containing a Sec-PH motif. To better understand the role of this large protein, here we carried out a series of biochemical and biophysical experiments, including size-exclusion chromatography–multiangle light scattering (SEC-MALS), small-angle X-ray and neutron scattering, and analytical ultracentrifugation, indicating that full-length neurofibromin forms a high-affinity dimer. We observed that neurofibromin dimerization also occurs in human cells and likely has biological and clinical implications. Analysis of purified full-length and truncated neurofibromin variants by negative-stain EM revealed the overall architecture of the dimer and predicted the potential interactions that contribute to the dimer interface. We could reconstitute structures resembling high-affinity full-length dimers by mixing N- and C-terminal protein domains in vitro. The reconstituted neurofibromin was capable of GTPase activation in vitro, and co-expression of the two domains in human cells effectively recapitulated the activity of full-length neurofibromin. Taken together, these results suggest how neurofibromin dimers might form and be stabilized within the cell.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Conformation-specific inhibitors of activated Ras GTPases reveal limited Ras dependency of patient-derived cancer organoids

The small GTPases H, K, and NRAS are molecular switches indispensable for proper regulation of cellular proliferation and growth. Several mutations in the genes encoding members of this protein family are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered variants of the Ras-binding domain (RBD) of the C-Raf proto-oncogene, Ser/Thr kinase (CRAF). These variants bound with high affinity with the effector-binding site of Ras in an active conformation. Structural characterization disclosed how the newly identified RBD mutations cooperate and thereby enhance affinity with the effector-binding site in Ras compared with WT RBD. The engineered RBD variants closely mimicked the interaction mode of naturally occurring Ras effectors and acted as dominant-negative affinity reagents that block Ras signal transduction. We report experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling, reducing cell growth and inducing apoptosis. Using these optimized RBD variants, we stratified patient-derived colorectal cancer organoids with known Ras mutational status according to their response to Ras inhibition. These results revealed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition, suggesting that not all of these tumors required Ras signaling for proliferation. In summary, by engineering the Ras/Raf interface of the CRAF-RBD, we identified potent and selective inhibitors of Ras in its active conformation that outcompete binding of Ras-signaling effectors.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Design and evaluation of an open-source, conformable skin-cooling system for body magnetic resonance guided focused ultrasound treatments

Magnetic resonance guided focused ultrasound (MRgFUS) treatment of tumors uses inter-sonication delays to allow heat to dissipate from the skin and other near-field tissues. Despite inter-sonication delays, treatment of tumors close to the skin risks skin burns. This work has designed and evaluated an open-source, conformable, skin-cooling system for body MRgFUS treatments to reduce skin burns and enable ablation closer to the skin. A MR-compatible skin cooling system is described that features a conformable skin-cooling pad assembly with feedback control allowing continuous flow and pressure maintenance during the procedure. System performance was evaluated with hydrophone, phantom and in vivo porcine studies. Sonications were performed 10 and 5 mm from the skin surface under both control and forced convective skin-cooling conditions. 3D MR temperature imaging was acquired in real time and the accumulated thermal dose volume was measured. Gross analysis of the skin post-sonication was further performed. Device conformability was demonstrated at several body locations. Hydrophone studies demonstrated no beam aberration, but a 5–12% reduction of the peak pressure due to the presence of the skin-cooling pad assembly in the acoustic near field. Phantom evaluation demonstrated there is no MR temperature imaging precision reduction or any other artifacts present due to the coolant flow during MRgFUS sonication. The porcine studies demonstrated skin burns were reduced in size or eliminated when compared to the control condition. An open-source design of an MRgFUS active skin cooling system demonstrates device conformability with a reduction of skin burns while ablating superficial tissues.

60 APPLIED LIFE SCIENCES↗

A review of the metastable omega phase in beta titanium alloys: the phase transformation mechanisms and its effect on mechanical properties

Since its discovery in 1954, the omega (ω) phase in titanium and its alloys has attracted substantial attention from researchers. The β-to-ω and ω-to-α phase transformations are central to β-titanium alloy design, but the transformation mechanisms have been a subject of debate. With new generations of aberration-corrected transmission electron microscopy and atom probe tomography, both the spatial resolution and compositional sensitivity of phase transformation analysis have been rapidly improving. Furthermore, this review provides a detailed assessment of the new understanding gained and related debates in this field enabled by advanced characterization methods. Specifically, new insights into the possibility of a coupled diffusional-displacive component in the β-to-ω transformation and key nucleation driving forces for the ω-assisted α phase formation are discussed. Additionally, the influence of ω phase on the mechanical properties of β-titanium alloys is also reviewed. Lastly, a perspective on open questions and future direction for research is discussed.

36 MATERIALS SCIENCE↗

Quantifying stoichiometry-induced variations in structure and energy of a SrTiO 3 symmetric Σ13 {510}/<100> grain boundary

Grain boundaries (GBs) in complex oxides such as perovskites have been shown to readily accommodate nonstoichiometry changing the electrostatic potential at the boundary plane and effectively controlling material properties such as capacitance, magnetoresistance and superconductivity. Understanding and quantifying exactly how variations in atomic scale nonstoichiometry at the boundary plane extend to the practical mesoscale operating length of the system is therefore critical for improving the overall properties. Bicrystals of SrTiO 3 were fabricated to provide the model GB model structures that are analysed in this paper. We show that statistical analysis of aberration-corrected scanning transmission electron microscope images acquired from a large area of GB is an effective routine to understanding the variation in boundary structure that occurs to accommodate nonstoichiometry. In the case of the SrTiO 3 22.6° Σ13 (510)/[100] GB analysed here, the symmetric atomic structures observed from a micron-long GB can be categorized as two different competing structural arrangements, with and without a rigid-body translation along the boundary plane. How this quantified experimental approach can provide direct insights into the GB energetics is further confirmed from the first principles density functional theory, and the effect of nonstoichiometry in determining the GB energies is quantified.

atomic structure↗

Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure

Self-propagation of aberrant protein folds is the defining characteristic of prions. Knowing the structural basis of self-propagation is essential to understanding prions and their related diseases. Prion rods are amyloid fibrils, but not all amyloids are prions. Prions have been remarkably intractable to structural studies, so many investigators have preferred to work with peptide fragments, particularly in the case of the mammalian prion protein PrP. We compared the structures of a number of fragments of PrP by X-ray fiber diffraction, and found that although all of the peptides adopted amyloid conformations, only the larger fragments adopted conformations that modeled the complexity of self-propagating prions, and even these fragments did not always adopt the PrP structure. It appears that the relatively complex structure of the prion form of PrP is not accessible to short model peptides, and that self-propagation may be tied to a level of structural complexity unobtainable in simple model systems. The larger fragments of PrP, however, are useful to illustrate the phenomenon of deformed templating (heterogeneous seeding), which has important biological consequences.

59 BASIC BIOLOGICAL SCIENCES↗

Chromosome compartmentalization alterations in prostate cancer cell lines model disease progression

Prostate cancer aggressiveness and metastatic potential are influenced by gene expression and genomic aberrations, features that can be influenced by the 3D structure of chromosomes inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, from normal epithelium to bone metastasis. We describe spatial compartment identity (A-open versus B-closed) changes with progression in these cell lines and their relation to gene expression changes in both cell lines and patient samples. In particular, 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches are accompanied by changes in the structure, size, and boundaries of topologically associating domains (TADs). Further, compartment changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation. These results suggest that discrete 3D genome structure changes play a deleterious role in prostate cancer progression.

59 BASIC BIOLOGICAL SCIENCES↗

WIDE-FIELD ASTRONOMICAL MULTISCALE CAMERAS

In order to produce sufficiently low aberrations with a large aperture, telescopes have a limited field of view. Because of this narrow field, large areas of the sky at a given time are unobserved. We propose several telescopes based on monocentric reflective, catadioptric, and refractive objectives that may be scaled to wide fields of view and achieve 1.''1 resolution, which in most locations is the practical seeing limit of the atmosphere. The reflective and Schmidt catadioptric objectives have relatively simple configurations and enable large fields to be captured at the expense of the obscuration of the mirror by secondary optics, a defect that may be managed by image plane design. The refractive telescope design does not have an obscuration but the objective has substantial bulk. The refractive design is a 38 gigapixel camera which consists of a single monocentric objective and 4272 microcameras. Monocentric multiscale telescopes, with their wide fields of view, may observe phenomena that might otherwise be unnoticed, such as supernovae, glint from orbital space debris, and near-earth objects.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

SYNCHROTRON RADIATION OF SELF-COLLIMATING RELATIVISTIC MAGNETOHYDRODYNAMIC JETS

The goal of this paper is to derive signatures of synchrotron radiation from state-of-the-art simulation models of collimating relativistic magnetohydrodynamic (MHD) jets featuring a large-scale helical magnetic field. We perform axisymmetric special relativistic MHD simulations of the jet acceleration region using the PLUTO code. The computational domain extends from the slow-magnetosonic launching surface of the disk up to 6000{sup 2} Schwarzschild radii allowing jets to reach highly relativistic Lorentz factors. The Poynting-dominated disk wind develops into a jet with Lorentz factors of {Gamma} {approx_equal} 8 and is collimated to 1{sup 0}. In addition to the disk jet, we evolve a thermally driven spine jet emanating from a hypothetical black hole corona. Solving the linearly polarized synchrotron radiation transport within the jet, we derive very long baseline interferometry radio and (sub-) millimeter diagnostics such as core shift, polarization structure, intensity maps, spectra, and Faraday rotation measure (RM) directly from the Stokes parameters. We also investigate depolarization and the detectability of a {lambda}{sup 2}-law RM depending on beam resolution and observing frequency. We find non-monotonic intrinsic RM profiles that could be detected at a resolution of 100 Schwarzschild radii. In our collimating jet geometry, the strict bimodality in the polarization direction (as predicted by Pariev et al.) can be circumvented. Due to relativistic aberration, asymmetries in the polarization vectors across the jet can hint at the spin direction of the central engine.

79 ASTRONOMY AND ASTROPHYSICS↗

HIGH-CONTRAST IMAGING VIA MODAL CONVERGENCE OF DEFORMABLE MIRROR

For extremely high contrast imaging, such as direct observation of faint stellar companions, an adaptive optics system is required to produce low-halo and low-speckle regions in the focal plane. A method for deformable mirror control is proposed to achieve this goal. The method relies on a modal convergence of the deformable mirror driven by a focal-plane metric. The modal sets are derived from the Walsh functions. The Walsh-function modes serve two purposes: the expansion of the actuator displacements and the expansion of the phase functions. Taking advantage of the unique properties of the modal functions, a universal control algorithm is devised for the realization of high-contrast focal planes with and without the help of conventional coronagraphy. Numerical modeling is conducted to simulate complete imaging systems under various scenarios. It is shown that the proposed method reliably produces high-contrast focal planes using either a segmented or a membrane mirror. In the presence of random aberration the method is shown to be able to maintain high-contrast focal planes. Requiring neither retrieval of electric fields nor detailed knowledge of the deformable mirrors, this technique may allow high-contrast imaging in real time.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

INFLUENCE OF THE POLAR CAP CURRENT ON PULSAR POLARIZATION

We have developed a model for the polarization of curvature radiation by taking into account the polar-cap-current-induced perturbation on the dipolar magnetic field. We present the effects of the polar cap current on the pulsar radio emission in an artificial case when the rotation effects, such as aberration and retardation, are absent. Our model indicates that the intensity components and the polarization angle inflection point can be shifted to either the leading or the trailing side depending upon the prevailing conditions in the viewing geometry, the non-uniformity in source distribution (modulation), and the polar-cap-current-induced perturbation. Also, we find evidence for the origin of symmetric-type circular polarization in addition to the antisymmetric type. Our model predicts a stronger trailing component compared to that on the leading side of a given cone under some specific conditions.

79 ASTRONOMY AND ASTROPHYSICS↗

FOCAL PLANE WAVEFRONT SENSING USING RESIDUAL ADAPTIVE OPTICS SPECKLES

Optical imperfections, misalignments, aberrations, and even dust can significantly limit sensitivity in high-contrast imaging systems such as coronagraphs. An upstream deformable mirror (DM) in the pupil can be used to correct or compensate for these flaws, either to enhance the Strehl ratio or suppress the residual coronagraphic halo. Measurement of the phase and amplitude of the starlight halo at the science camera is essential for determining the DM shape that compensates for any non-common-path (NCP) wavefront errors. Using DM displacement ripples to create a series of probe and anti-halo speckles in the focal plane has been proposed for space-based coronagraphs and successfully demonstrated in the lab. We present the theory and first on-sky demonstration of a technique to measure the complex halo using the rapidly changing residual atmospheric speckles at the 6.5 m MMT telescope using the Clio mid-IR camera. The AO system's wavefront sensor measurements are used to estimate the residual wavefront, allowing us to approximately compute the rapidly evolving phase and amplitude of speckle halo. When combined with relatively short, synchronized science camera images, the complex speckle estimates can be used to interferometrically analyze the images, leading to an estimate of the static diffraction halo with NCP effects included. In an operational system, this information could be collected continuously and used to iteratively correct quasi-static NCP errors or suppress imperfect coronagraphic halos.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Magnetic pair creation transparency in gamma-ray pulsars

Magnetic pair creation, γ → e {sup +} e {sup –}, has been at the core of radio pulsar paradigms and central to polar cap models of gamma-ray pulsars for over three decades. The Fermi gamma-ray pulsar population now exceeds 140 sources and has defined an important part of Fermi's science legacy, providing rich information for the interpretation of young energetic pulsars and old millisecond pulsars. Among the population characteristics well established is the common occurrence of exponential turnovers in their spectra in the 1-10 GeV range. These turnovers are too gradual to arise from magnetic pair creation in the strong magnetic fields of pulsar inner magnetospheres. By demanding insignificant photon attenuation precipitated by such single-photon pair creation, the energies of these turnovers for Fermi pulsars can be used to compute lower bounds for the typical altitude of GeV band emission. This paper explores such pair transparency constraints below the turnover energy and updates earlier altitude bound determinations that have been deployed in various Fermi pulsar papers. For low altitude emission locales, general relativistic influences are found to be important, increasing cumulative opacity, shortening the photon attenuation lengths, and also reducing the maximum energy that permits escape of photons from a neutron star magnetosphere. Rotational aberration influences are also explored, and are found to be small at low altitudes, except near the magnetic pole. The analysis presented in this paper clearly demonstrates that including near-threshold physics in the pair creation rate is essential to deriving accurate attenuation lengths and escape energies. The altitude bounds are typically in the range of 2-7 stellar radii for the young Fermi pulsar population, and provide key information on the emission altitude in radio quiet pulsars that do not possess double-peaked pulse profiles. The bound for the Crab pulsar is at a much higher altitude, with the putative detection by MAGIC out to 350-400 GeV implying a lower bound of 310 km to the emission region, i.e., approximately 20% of the light cylinder radius. These results are also extended to the super-critical field domain, where it is found that emission in neurton stars originating below around 10 stellar radii will not appear in the Fermi-LAT band.

79 ASTRONOMY AND ASTROPHYSICS↗

Pulse profiles from spinning neutron stars in the Hartle-Thorne approximation

We present a new numerical algorithm for the calculation of pulse profiles from spinning neutron stars in the Hartle-Thorne approximation. Our approach allows us to formally take into account the effects of Doppler shifts and aberration, of frame dragging, as well as of the oblateness of the stellar surface and of its quadrupole moment. We confirm an earlier result that neglecting the oblateness of the neutron-star surface leads to ≅ 5%-30% errors in the calculated profiles and further show that neglecting the quadrupole moment of its spacetime leads to ≅ 1%-5% errors at a spin frequency of ≅ 600 Hz. We discuss the implications of our results for the measurements of neutron-star masses and radii with upcoming X-ray missions, such as NASA's NICER and ESA's LOFT.

79 ASTRONOMY AND ASTROPHYSICS↗

THE COSMIC BATTERY IN ASTROPHYSICAL ACCRETION DISKS

The aberrated radiation pressure at the inner edge of the accretion disk around an astrophysical black hole imparts a relative azimuthal velocity on the electrons with respect to the ions which gives rise to a ring electric current that generates large-scale poloidal magnetic field loops. This is the Cosmic Battery established by Contopoulos and Kazanas in 1998. In the present work we perform realistic numerical simulations of this important astrophysical mechanism in advection-dominated accretion flows, ADAFs. We confirm the original prediction that the inner parts of the loops are continuously advected toward the central black hole and contribute to the growth of the large-scale magnetic field, whereas the outer parts of the loops are continuously diffusing outward through the turbulent accretion flow. This process of inward advection of the axial field and outward diffusion of the return field proceeds all the way to equipartition, thus generating astrophysically significant magnetic fields on astrophysically relevant timescales. We confirm that there exists a critical value of the magnetic Prandtl number between unity and 10 in the outer disk above which the Cosmic Battery mechanism is suppressed.

79 ASTRONOMY AND ASTROPHYSICS↗

Kinematics of and emission from helically orbiting blobs in a relativistic magnetized jet

We present a general relativistic (GR) model of jet variability in active galactic nuclei due to orbiting blobs in helical motion along a funnel or cone-shaped magnetic surface anchored to the accretion disk near the black hole. Considering a radiation pressure driven flow in the inner region, we find that it stabilizes the flow, yielding Lorentz factors ranging between 1.1 and 7 at small radii for reasonable initial conditions. Assuming these as inputs, simulated light curves (LCs) for the funnel model include Doppler and gravitational shifts, aberration, light bending, and time delay. These LCs are studied for quasi-periodic oscillations (QPOs) and the power spectral density (PSD) shape, and yield an increased amplitude (∼12%), a beamed portion and a systematic phase shift with respect to that from a previous special relativistic model. The results strongly justify implementing a realistic magnetic surface geometry in Schwarzschild geometry to describe effects on emission from orbital features in the jet close to the horizon radius. A power-law-shaped PSD with a typical slope of −2 and QPOs with timescales in the range of (1.37–130.7) days consistent with optical variability in blazars, emerges from the simulations for black hole masses M{sub ∙}=(0.5−5)×10{sup 8} M{sub ⊙} and initial Lorentz factors γ{sub jet,i}=2−10. The models presented here can be applied to explain radio, optical, and X-ray variability from a range of jetted sources including active galactic nuclei, X-ray binaries, and neutron stars.

79 ASTRONOMY AND ASTROPHYSICS↗

TECHNIQUES FOR HIGH-CONTRAST IMAGING IN MULTI-STAR SYSTEMS. I. SUPER-NYQUIST WAVEFRONT CONTROL

Direct imaging of extra-solar planets is now a reality with the deployment and commissioning of the first generation of specialized ground-based instruments (GPI, SPHERE, P1640, and SCExAO). These systems allow of planets 10{sup 7} times fainter than their host star. For space-based missions (EXCEDE, EXO-C, EXO-S, WFIRST), various teams have demonstrated laboratory contrasts reaching 10{sup −10} within a few diffraction limits from the star. However, all of these current and future systems are designed to detect faint planets around a single host star, while most non-M-dwarf stars such as Alpha Centauri belong to multi-star systems. Direct imaging around binaries/multiple systems at a level of contrast allowing detection of Earth-like planets is challenging because the region of interest is contaminated by the host star's companion in addition to the host itself. Generally, the light leakage is caused by both diffraction and aberrations in the system. Moreover, the region of interest usually falls outside the correcting zone of the deformable mirror (DM) with respect to the companion. Until now, it has been thought that removing the light of a companion star is too challenging, leading to the exclusion of many binary systems from target lists of direct imaging coronographic missions. In this paper, we will show new techniques for high-contrast imaging of planets around multi-star systems and detail the Super-Nyquist Wavefront Control (SNWC) method, which allows wavefront errors to be controlled beyond the nominal control region of the DM. Our simulations have demonstrated that, with SNWC, raw contrasts of at least 5 × 10{sup −9} in a 10% bandwidth are possible.

79 ASTRONOMY AND ASTROPHYSICS↗

The extreme ultraviolet deficit: Jet connection in the quasar 1442+101

In previous studies, it has been shown that the long-term time-averaged jet power, Q-bar , is correlated with spectral index in the extreme ultraviolet (EUV), α{sub EUV} (defined by F{sub ν}∼ν{sup −α{sub E}{sub U}{sub V}} computed between 700 and 1100 Å ). Larger Q-bar tends to decrease the EUV emission. This is a curious relationship because it connects a long-term average over ∼10{sup 6} years with an instantaneous measurement of the EUV. The EUV appears to emit adjacent to the central supermassive black hole and the most straightforward explanation of this correlation is that the EUV-emitting region interacts in real time with the jet-launching mechanism. Alternatively stated, the Q-bar –α{sub EUV} correlation is a manifestation of a contemporaneous (real time) jet power, Q(t), correlation with α{sub EUV}. In order to explore this possibility, this paper considers the time variability of the strong radio jet of quasar 1442+101, which is not aberrated by strong Doppler enhancement. This high-redshift (z = 3.55) quasar is uniquely suited for this endeavor as the EUV is redshifted into the optical observing window allowing for convenient monitoring. More importantly, it is bright enough to be seen through the Lyman forest and its radio flux is strong enough that it has been monitored frequently. Quasi-simultaneous monitoring (five epochs spanning ∼40 years) shows that increases in Q(t) correspond to decreases in the EUV as expected.

79 ASTRONOMY AND ASTROPHYSICS↗