Mammalian SWI/SNF family chromatin remodelers, BRG1/BRM-associated factor (BAF) and polybromo-associated BAF (PBAF), regulate chromatin structure and transcription, and their mutations are linked to cancers. The 3.7-angstrom-resolution cryo-electron microscopy structure of human BAF bound to the nucleosome reveals that the nucleosome is sandwiched by the base and the adenosine triphosphatase (ATPase) modules, which are bridged by the actin-related protein (ARP) module. The ATPase motor is positioned proximal to nucleosomal DNA and, upon ATP hydrolysis, engages with and pumps DNA along the nucleosome. The C-terminal α helix of SMARCB1, enriched in positively charged residues frequently mutated in cancers, mediates interactions with an acidic patch of the nucleosome. AT-rich interactive domain-containing protein 1A (ARID1A) and the SWI/SNF complex subunit SMARCC serve as a structural core and scaffold in the base module organization, respectively. Our study provides structural insights into subunit organization and nucleosome recognition of human BAF complex. Copyright © 2020, American Association for the Advancement of Science.Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Stroke affects millions each year. Post-stroke brain edema predicts the severity of eventual stroke damage, yet our concept of how edema develops is incomplete and treatment options remain limited. In early stages, fluid accumulation occurs owing to a net gain of ions, widely thought to enter from the vascular compartment. Here we used magnetic resonance imaging, radiolabeled tracers, and multiphoton imaging in rodents, to show instead that cerebrospinal fluid surrounding the brain enters the tissue within minutes of an ischemic insult along perivascular flow channels. This process was initiated by ischemic spreading depolarizations along with subsequent vasoconstriction, which in turn enlarged the perivascular spaces and doubled glymphatic inflow speeds. Thus, our understanding of post-stroke edema needs to be revised and these findings could provide a conceptual basis for development of alternative treatment strategies. Copyright © 2020, American Association for the Advancement of Science.For centuries, flow visualization has been the art of making fluid motion visible in physical and biological systems. Although such flow patterns can be, in principle, described by the Navier-Stokes equations, extracting the velocity and pressure fields directly from the images is challenging. We addressed this problem by developing hidden fluid mechanics (HFM), a physics-informed deep-learning framework capable of encoding the Navier-Stokes equations into the neural networks while being agnostic to the geometry or the initial and boundary conditions. We demonstrate HFM for several physical and biomedical problems by extracting quantitative information for which direct measurements may not be possible. HFM is robust to low resolution and substantial noise in the observation data, which is important for potential applications. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Quantum control of complex objects in the regime of large size and mass provides opportunities for sensing applications and tests of fundamental physics. The realization of such extreme quantum states of matter remains a major challenge. We demonstrate a quantum interface that combines optical trapping of solids with cavity-mediated light-matter interaction. Precise control over the frequency and position of the trap laser with respect to the optical cavity allowed us to laser-cool an optically trapped nanoparticle into its quantum ground state of motion from room temperature. The particle comprises 108 atoms, similar to current Bose-Einstein condensates, with the density of a solid object. Our cooling technique, in combination with optical trap manipulation, may enable otherwise unachievable superposition states involving large masses. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo-electron microscopy structures of HIV intasomes bound to the latest generation of INSTIs. https://www.selleckchem.com/products/im156.html These structures highlight how small changes in the integrase active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.