The DNA binding CXC domain of MSL2 is required for faithful targeting the Dosage Compensation Complex to the X chromosome

Dosage compensation in Drosophila melanogaster involves the selective targeting of the male X chromosome by the dosage compensation complex (DCC) and the coordinate, ∼2-fold activation of most genes. The principles that allow the DCC to distinguish the X chromosome from the autosomes are not understood. Targeting presumably involves DNA sequence elements whose combination or enrichment mark the X chromosome. DNA sequences that characterize ‘chromosomal entry sites’ or ‘high-affinity sites’ may serve such a function. However, to date no DNA binding domain that could interpret sequence information has been identified within the subunits of the DCC. Early genetic studies suggested that MSL1 and MSL2 serve to recognize high-affinity sites (HAS) in vivo, but a direct interaction of these DCC subunits with DNA has not been studied. We now show that recombinant MSL2, through its CXC domain, directly binds DNA with low nanomolar affinity. The DNA binding of MSL2 or of an MSL2–MSL1 complex does not discriminate between different sequences in vitro, but in a reporter gene assay in vivo, suggesting the existence of an unknown selectivity cofactor. Reporter gene assays and localization of GFP-fusion proteins confirm the important contribution of the CXC domain for DCC targeting in vivo

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The persistent shadow of the supermassive black hole of M 87

In April 2019, the Event Horizon Telescope (EHT) Collaboration reported the first-ever event-horizon-scale images of a black hole, resolving the central compact radio source in the giant elliptical galaxy M 87. These images reveal a ring with a southerly brightness distribution and a diameter of ∼42 μas, consistent with the predicted size and shape of a shadow produced by the gravitationally lensed emission around a supermassive black hole. These results were obtained as part of the April 2017 EHT observation campaign, using a global very long baseline interferometric radio array operating at a wavelength of 1.3 mm. Here, we present results based on the second EHT observing campaign, taking place in April 2018 with an improved array, wider frequency coverage, and increased bandwidth. In particular, the additional baselines provided by the Greenland telescope improved the coverage of the array. Multiyear EHT observations provide independent snapshots of the horizon-scale emission, allowing us to confirm the persistence, size, and shape of the black hole shadow, and constrain the intrinsic structural variability of the accretion flow. We have confirmed the presence of an asymmetric ring structure, brighter in the southwest, with a median diameter of 43.3−3.1+1.5 μas. The diameter of the 2018 ring is remarkably consistent with the diameter obtained from the previous 2017 observations. On the other hand, the position angle of the brightness asymmetry in 2018 is shifted by about 30° relative to 2017. The perennial persistence of the ring and its diameter robustly support the interpretation that the ring is formed by lensed emission surrounding a Kerr black hole with a mass ∼6.5 × 109 M⊙. The significant change in the ring brightness asymmetry implies a spin axis that is more consistent with the position angle of the large-scale jet

First Sagittarius A* Event Horizon Telescope Results. VIII. Physical Interpretation of the Polarized Ring

In a companion paper, we present the first spatially resolved polarized image of Sagittarius A* on event horizon scales, captured using the Event Horizon Telescope, a global very long baseline interferometric array operating at a wavelength of 1.3 mm. Here we interpret this image using both simple analytic models and numerical general relativistic magnetohydrodynamic (GRMHD) simulations. The large spatially resolved linear polarization fraction (24%–28%, peaking at ∼40%) is the most stringent constraint on parameter space, disfavoring models that are too Faraday depolarized. Similar to our studies of M87*, polarimetric constraints reinforce a preference for GRMHD models with dynamically important magnetic fields. Although the spiral morphology of the polarization pattern is known to constrain the spin and inclination angle, the time-variable rotation measure (RM) of Sgr A* (equivalent to ≈46° ± 12° rotation at 228 GHz) limits its present utility as a constraint. If we attribute the RM to internal Faraday rotation, then the motion of accreting material is inferred to be counterclockwise, contrary to inferences based on historical polarized flares, and no model satisfies all polarimetric and total intensity constraints. On the other hand, if we attribute the mean RM to an external Faraday screen, then the motion of accreting material is inferred to be clockwise, and one model passes all applied total intensity and polarimetric constraints: a model with strong magnetic fields, a spin parameter of 0.94, and an inclination of 150°. We discuss how future 345 GHz and dynamical imaging will mitigate our present uncertainties and provide additional constraints on the black hole and its accretion flow

Cinematic metaphor in perspective: reflections on a transdisciplinary framework Cinepoetics ;, v. 5./ edited by Sarah Greifenstein, Dorothea Horst, Thomas Scherer, Christina Schmitt, Hermann Kappelhoff, and Cornelia Müller.

Includes bibliographical references and indexes.Over centuries, scholars have explored how metaphor contributes to thought, language, culture. This collection of essays reflects on Müller, Kappelhoff, and colleagues' transdisciplinary (film studies and linguistics) approach formulated in "Cinematic Metaphor: Experience - Affectivity - Temporality". The key concept of cinematic metaphor opens up reflections on metaphor as a form of embodied meaning-making in human life across disciplines. The book documents collaborative work, reflecting intense, sometimes controversial, discussions across disciplinary boundaries. In this edited volume, renowned authors explore how exposure to the framework of Cinematic Metaphor inspires their views of metaphor in film and of metaphor theory and analysis more generally. Contributions include explorations from the point of view of applied linguistics (Lynne Cameron), cognitive linguistics (Alan Cienki), media studies (Kathrin Fahlenbrach), media history (Michael Wedel), philosophy (Anne Eusterschulte), and psychology (Raymond W. Gibbs, Jr.).Greifenstein, Sarah / Horst, Dorothea / Scherer, Thomas / Schmitt, Christina / Kappelhoff, Hermann / Müller, Cornelia -- Cameron, Lynne -- Wedel, Michael -- Cienki, Alan -- Fahlenbrach, Kathrin -- Eusterschulte, Anne -- Gibbs, Raymond W. -- Frontmatter -- Acknowledgements -- Contents -- Introduction / From Metaphor To Metaphorizing: How Cinematic Metaphor Opens Up Metaphor Studies / Murnau And Metaphor: From Cinematic Expressionism To Cinematic Expressive Movements / Insights For Linguistics And Gesture Studies From Film Studies: A View From Researching Cinematic Metaphor / Moving Metaphors: Affects, Movements, And Embodied Metaphors In Cinema / Actio Per Distans: Blumenberg'S Metaphorology And Hitchcock'S Rear Window / Our Metaphorical Experiences Of Film / Name Index -- Subject Index -- About The Authors -- About The Editors.1 online resource (158 pages

High and Low Rotational Barriers in Metal Tricarbonyl Complexes of 2- and 3‑Indenyl Anthracenes and Triptycenes: Rational Design of Molecular Brakes

Syntheses and X-ray crystal structures are reported for a series of M­(CO)₃ derivatives (M = Cr, Re) of phenyl and also 2- and 3-indenyl anthracenes and triptycenes. In each case, the rotational barrier about the bond linking the two organic fragments was evaluated both experimentally by VT or 2D-EXSY NMR and by calculation at the DFT level. Attachment of the metal tripod to the indenyl moiety in an η⁶ fashion does not markedly change the barrier relative to that for the free ligand but lowers the symmetry so as to facilitate its direct measurement. Interestingly, an η⁶ → η⁵ haptotropic shift of the Cr­(CO)₃ moiety in 9-indenylanthracenes led to a somewhat lowered barrier, probably attributable to an increase in the ground state energy rather than to decreased steric interactions in the transition state. In contrast, in indenyltriptycenes η⁶ → η⁵ migration of the M­(CO)₃ unit along the indenyl skeleton and closer to a paddlewheel leads to a very significant increase in the rotational barrier. These effects can be rationalized in terms of angular steric strain and multiple interactions in the ground state and in the transition state. The results not only provide semiquantitative data on the steric effects of η⁶-phenyl and η⁶- or η⁵-indenyl M­(CO)₃ fragments but are also discussed with relevance to their role in organometallic molecular brakes

Manganese-Cycling Microbial Communities Inside Deep-Sea Manganese Nodules

Polymetallic nodules (manganese nodules) have been formed on deep sea sediments over millions of years and are currently explored for their economic potential, particularly for cobalt, nickel, copper, and manganese. Here we explored microbial communities inside nodules from the northeastern equatorial Pacific. The nodules have a large connected pore space with a huge inner surface of 120 m²/g as analyzed by computer tomography and BET measurements. X-ray photoelectron spectroscopy (XPS) and electron microprobe analysis revealed a complex chemical fine structure. This consisted of layers with highly variable Mn/Fe ratios (<1 to >500) and mainly of turbostratic phyllomanganates such as 7 and 10 Å vernadites alternating with layers of Fe-bearing vernadite (δ-MnO₂) epitaxially intergrown with amorphous feroxyhyte (δ-FeOOH). Using molecular 16S rRNA gene techniques (clone libraries, pyrosequencing, and real-time PCR), we show that polymetallic nodules provide a suitable habitat for prokaryotes with an abundant and diverse prokaryotic community dominated by nodule-specific Mn­(IV)-reducing and Mn­(II)-oxidizing bacteria. These bacteria were not detected in the nodule-surrounding sediment. The high abundance and dominance of Mn-cycling bacteria in the manganese nodules argue for a biologically driven closed manganese cycle inside the nodules relevant for their formation and potential degradation