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    Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway - Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain–containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inh...
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    Identification of a regeneration-organizing cell in the Xenopus tail - Unlike mammals, Xenopus laevis tadpoles have a high regenerative potential. To characterize this regenerative response, we performed single-cell RNA sequencing after tail amputation. By comparing naturally occurring regeneration-competent and -incompetent tadpoles, we identified a previously unrecognized cell type, which we term the regeneration-organizing cell (ROC). ROCs are present in the epidermis during normal tail development and specifica...
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    De novo design of tunable, pH-driven conformational changes - The ability of naturally occurring proteins to change conformation in response to environmental changes is critical to biological function. Although there have been advances in the de novo design of stable proteins with a single, deep free-energy minimum, the design of conformational switches remains challenging. We present a general strategy to design pH-responsive protein conformational changes by precisely preorganizing histidine residues in ...
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    Quantum gas microscopy of Rydberg macrodimers - The subnanoscale size of typical diatomic molecules hinders direct optical access to their constituents. Rydberg macrodimers—bound states of two highly excited Rydberg atoms—feature interatomic distances easily exceeding optical wavelengths. We report the direct microscopic observation and detailed characterization of such molecules in a gas of ultracold rubidium atoms in an optical lattice. The bond length of about 0.7 micrometers, ...
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    Electron diffraction determines molecular absolute configuration in a pharmaceutical nanocrystal - Determination of the absolute configuration of organic molecules is essential in drug development and the subsequent approval process. We show that this determination is possible through electron diffraction using nanocrystalline material. Ab initio structure determination by electron diffraction has so far been limited to compounds that maintain their crystallinity after a dose of one electron per square angstrom or more. We present a complete ...
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    Probing and imaging spin interactions with a magnetic single-molecule sensor - Magnetic single atoms and molecules are receiving intensifying research focus because of their potential as the smallest possible memory, spintronic, and qubit elements. Scanning probe microscopes used to study these systems have benefited greatly from new techniques that use molecule-functionalized tips to enhance spatial and spectroscopic resolutions and enable new sensing capabilities. We demonstrate a microscopy technique that uses a magneti...
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    Conformationally supple glucose monomers enable synthesis of the smallest cyclodextrins - Cyclodextrins (CDs) are cyclic oligomers of α-1,4-d-glucopyranoside and are known mainly as hexamers to octamers. The central cavities of CDs can retain small molecules, enabling diverse applications. The smallest members, CD3 and CD4, have ring sizes too small to permit the most stable conformations of glucopyranose and have not been accessible synthetically. In this study, we present methods to chemically synthesize both CD3 and CD4. The...
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    Constrained sialic acid donors enable selective synthesis of {alpha}-glycosides - Sialic acid is a sugar residue present in many biologically significant glycans of mammals, commonly as a terminal α-glycoside. The chemical structure of sialic acid, which features an anomeric center with carboxyl and methylene substituents, poses a challenge for synthesis of the α-glycoside, thus impeding biological and therapeutic studies on sialic acid–containing glycans. We present a robust method for the selective α...
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    Hydrodealkenylative C(sp3)-C(sp2) bond fragmentation - Chemical synthesis typically relies on reactions that generate complexity through elaboration of simple starting materials. Less common are deconstructive strategies toward complexity—particularly those involving carbon-carbon bond scission. Here, we introduce one such transformation: the hydrodealkenylative cleavage of C(sp3)–C(sp2) bonds, conducted below room temperature, using ozone, an iron salt, and a hydrogen atom donor. These ...
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    Single-cell genomics identifies cell type-specific molecular changes in autism - Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in the neocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific c...
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    Mechanism of allosteric modulation of P-glycoprotein by transport substrates and inhibitors - The ATP-binding cassette subfamily B member 1 (ABCB1) multidrug transporter P-glycoprotein plays a central role in clearance of xenobiotics in humans and is implicated in cancer resistance to chemotherapy. We used double electron electron resonance spectroscopy to uncover the basis of stimulation of P-glycoprotein adenosine 5'-triphosphate (ATP) hydrolysis by multiple substrates and illuminate how substrates and inhibitors differentially affect ...
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    Spatiotemporal light control with active metasurfaces - Optical metasurfaces have provided us with extraordinary ways to control light by spatially structuring materials. The space-time duality in Maxwell’s equations suggests that additional structuring of metasurfaces in the time domain can even further expand their impact on the field of optics. Advances toward this goal critically rely on the development of new materials and nanostructures that exhibit very large and fast changes in their op...
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    Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments - There is ample evidence for localization of messenger RNAs (mRNAs) and protein synthesis in neuronal dendrites; however, demonstrations of these processes in presynaptic terminals are limited. We used expansion microscopy to resolve pre- and postsynaptic compartments in rodent neurons. Most presynaptic terminals in the hippocampus and forebrain contained mRNA and ribosomes. We sorted fluorescently labeled mouse brain synaptosomes and then sequen...
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    Hierarchical reasoning by neural circuits in the frontal cortex - Humans process information hierarchically. In the presence of hierarchies, sources of failures are ambiguous. Humans resolve this ambiguity by assessing their confidence after one or more attempts. To understand the neural basis of this reasoning strategy, we recorded from dorsomedial frontal cortex (DMFC) and anterior cingulate cortex (ACC) of monkeys in a task in which negative outcomes were caused either by misjudging the stimulus or by a cov...
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    Initial results from the New Horizons exploration of 2014 MU69, a small Kuiper Belt object - The Kuiper Belt is a distant region of the outer Solar System. On 1 January 2019, the New Horizons spacecraft flew close to (486958) 2014 MU69, a cold classical Kuiper Belt object approximately 30 kilometers in diameter. Such objects have never been substantially heated by the Sun and are therefore well preserved since their formation. We describe initial results from these encounter observations. MU69 is a bilobed contact binary with a flattene...
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