Rapid rotation is a fundamental characteristic of classical Be stars and a crucial property allowing for the formation of their circumstellar disks. Past evolution in a mass and angular momentum ...transferring binary system offers a plausible solution to how Be stars attained their fast rotation. Although the subdwarf remnants of mass donors in such systems should exist in abundance, only a few have been confirmed due to tight observational constraints. An indirect method of detecting otherwise hidden companions is offered by their effect on the outer parts of Be star disks, which are expected to be disrupted or truncated. In the context of the infrared and radio continuum excess radiation originating in the disk, the disk truncation can be revealed by a turndown in the spectral energy distribution due to reduced radio flux levels. In this work, we search for signs of spectral turndown in a sample of 57 classical Be stars with radio data, which include new data for 23 stars and the longest-wavelength detections so far (λ 10 cm) for two stars. We confidently detect the turndown for all 26 stars with sufficient data coverage (20 of which are not known to have close binary companions). For the remaining 31 stars, the data are inconclusive as to whether the turndown is present or not. The analysis suggests that many if not all Be stars have close companions influencing their outer disks. If confirmed to be subdwarf companions, the mass transfer spin-up scenario might explain the existence of the vast majority of classical Be stars.
Loss-of-function pathogenic variants in BRCA1 confer a predisposition to breast and ovarian cancer. Genetic testing for sequence changes in BRCA1 frequently reveals a missense variant for which the ...impact on cancer risk and on the molecular function of BRCA1 is unknown. Functional BRCA1 is required for the homology-directed repair (HDR) of double-strand DNA breaks, a critical activity for maintaining genome integrity and tumor suppression. Here, we describe a multiplex HDR reporter assay for concurrently measuring the effects of hundreds of variants of BRCA1 for their role in DNA repair. Using this assay, we characterized the effects of 1,056 amino acid substitutions in the first 192 residues of BRCA1. Benchmarking these results against variants with known effects on DNA repair function or on cancer predisposition, we demonstrate accurate discrimination of loss-of-function versus benign missense variants. We anticipate that this assay can be used to functionally characterize BRCA1 missense variants at scale, even before the variants are observed in results from genetic testing.
Interpreting variants of uncertain significance (VUS) is a central challenge in medical genetics. One approach is to experimentally measure the functional consequences of VUS, but to date this ...approach has been post hoc and low throughput. Here we use massively parallel assays to measure the effects of nearly 2000 missense substitutions in the RING domain of BRCA1 on its E3 ubiquitin ligase activity and its binding to the BARD1 RING domain. From the resulting scores, we generate a model to predict the capacities of full-length BRCA1 variants to support homology-directed DNA repair, the essential role of BRCA1 in tumor suppression, and show that it outperforms widely used biological-effect prediction algorithms. We envision that massively parallel functional assays may facilitate the prospective interpretation of variants observed in clinical sequencing.
ABSTRACT
The bright and understudied classical Be star HD 6226 has exhibited multiple outbursts in the last several years during which the star grew a viscous decretion disc. We analyse 659 optical ...spectra of the system collected from 2017 to 2020, along with a ultraviolet spectrum from the Hubble Space Telescope and high cadence photometry from both Transiting Exoplanet Survey Satellite (TESS) and the Kilodegree Extremely Little Telescope (KELT) survey. We find that the star has a spectral type of B2.5IIIe, with a rotation rate of 74 per cent of critical. The star is nearly pole-on with an inclination of 13${_{.}^{\circ}}$4. We confirm the spectroscopic pulsational properties previously reported, and report on three photometric oscillations from KELT photometry. The outbursting behaviour is studied with equivalent width measurements of H α and H β, and the variations in both of these can be quantitatively explained with two frequencies through a Fourier analysis. One of the frequencies for the emission outbursts is equal to the difference between two photometric oscillations, linking these pulsation modes to the mass ejection mechanism for some outbursts. During the TESS observation time period of 2019 October 7 to 2019 November 2, the star was building a disc. With a large data set of H α and H β spectroscopy, we are able to determine the time-scales of dissipation in both of these lines, similar to past work on Be stars that has been done with optical photometry. HD 6226 is an ideal target with which to study the Be disc-evolution given its apparent periodic nature, allowing for targeted observations with other facilities in the future.
The nicotinic acetylcholine receptor is a prototype ligand-gated ion channel that mediates signal transduction in the neuromuscular junctions and other cholinergic synapses. The molecular basis for ...the energetics of ligand binding and unbinding is critical to our understanding of the pharmacology of this class of receptors. Here, we used steered molecular dynamics to investigate the unbinding of acetylcholine from the ligand-binding domain of human alpha7 nicotinic acetylcholine receptor along four different predetermined pathways. Pulling forces were found to correlate well with interactions between acetylcholine and residues in the binding site during the unbinding process. From multiple trajectories along these unbinding pathways, we calculated the potentials of mean force for acetylcholine unbinding. Four available methods based on Jarzynski's equality were used and compared for their efficiencies. The most probable pathway was identified to be along a direction approximately parallel to the membrane. The derived binding energy for acetylcholine was in good agreement with that derived from the experimental binding constant for acetylcholine binding protein, but significantly higher than that for the complete human alpha7 nicotinic acetylcholine receptor. In addition, it is likely that several intermediate states exist along the unbinding pathways.
The mechanosensitive channel of large conductance (MscL) in prokaryotes plays a crucial role in exocytosis as well as in the response to osmotic downshock. The channel can be gated by tension in the ...membrane bilayer. The determination of functionally important residues in MscL, patch-clamp studies of pressure-conductance relationships, and the recently elucidated crystal structure of MscL from
Mycobacterium tuberculosis have guided the search for the mechanism of MscL gating. Here, we present a molecular dynamics study of the MscL protein embedded in a fully hydrated POPC bilayer. Simulations totaling 3
ns in length were carried out under conditions of constant temperature and pressure using periodic boundary conditions and full electrostatics. The protein remained in the closed state corresponding to the crystal structure, as evidenced by its impermeability to water. Analysis of equilibrium fluctuations showed that the protein was least mobile in the narrowest part of the channel. The gating process was investigated through simulations of the bare protein under conditions of constant surface tension. Under a range of conditions, the transmembrane helices flattened as the pore widened. Implications for the gating mechanism in light of these and experimental results are discussed.
Molecular recognition and mechanical properties of proteins govern molecular processes in the cell that can cause disease and can be targeted for drug design. Single molecule measurement techniques ...have greatly advanced knowledge but cannot resolve enough detail to be interpreted in terms of protein structure. We seek to complement the observations through so-called Steered Molecular Dynamics (SMD) simulations that link directly to experiments and provide atomic-level descriptions of the underlying events. Such a research program has been initiated in our group and has involved, for example, studies of elastic properties of immunoglobulin and fibronectin domains as well as the binding of biotin and avidin. In this article we explain the SMD method and suggest how it can be applied to the function of three systems that are the focus of modern molecular biology research: force transduction by the muscle protein titin and extracellular matrix protein fibronectin, recognition of antibody-antigene pairs, and ion selective conductivity of the K
+ channel.
Be stars are rapidly rotating B stars whose spectra contain Balmer emission lines originating from circumstellar decretion disks. The decretion disks also produce in- frared (IR) excesses in their ...spectral energy distributions, and the slope of the excess reveals information about the density of the disk. The decretion disks serve as medi- ums through which mass and angular momentum are transported away from the star. Be stars rotate at or near the critical rotation rate, and the angular momentum lost through the disks prevents them from breaking up. Determinations of the amount mass and angular momentum lost through the decretion disks are model dependent. The best accepted model describing the decretion disk is the Viscous Decretion Disk (VDD) model. However, there is a discrepancy between the current measurements of mass-loss rates and those predicted by stellar evolutionary models. The projects in this thesis were chosen to better constrain the models in an effort to reconcile this discrepancy. First, it has been suggested that Be stars are spun up through previous mass- transfer from a binary companion. Also, binary companions are observed to be common. However, the VDD model assumes an isolated Be star. In this thesis, I investigate the density structure of the disks in the presence of binary companions. The Be disk is truncated by the companion, and while most of the disk material accretes onto the binary companion, we find that a portion flows past the binary in what is likely a wind-like outflow. Second, the radiation from the central Be star can launch a line-driven ablation wind that flows radially outward along the surface of the disk. This disk wind is an additional source of mass and angular momentum loss from the central star. I investigate how the disk wind would be observed in the ultraviolet (UV) wind line profiles. I find that the disk wind can be seen as a low velocity narrow absorption component in the UV wind line when the observing geometry is within a few degrees of edge-on.
Rapid rotation is a fundamental characteristic of classical Be stars and a crucial property allowing for the formation of their circumstellar disks. Past evolution in a mass and angular momentum ...transferring binary system offers a plausible solution to how Be stars attained their fast rotation. Although the subdwarf remnants of mass donors in such systems should exist in abundance, only a few have been confirmed due to tight observational constraints. An indirect method of detecting otherwise hidden companions is offered by their effect on the outer parts of Be star disks, which are expected to be disrupted or truncated. In the context of the IR and radio continuum excess radiation originating in the disk, the disk truncation can be revealed by a turndown in the spectral energy distribution due to reduced radio flux levels. In this work we search for signs of spectral turndown in a sample of 57 classical Be stars with radio data, which include new data for 23 stars and the longest wavelength detections so far (\(\lambda \approx\) 10\,cm) for 2 stars. We confidently detect the turndown for all 26 stars with sufficient data coverage (20 of which are not known to have close binary companions). For the remaining 31 stars, data are inconclusive as to whether the turndown is present or not. The analysis suggests that many if not all Be stars have close companions influencing their outer disks. If confirmed to be subdwarf companions, the mass transfer spin-up scenario might explain the existence of the vast majority of classical Be stars.
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