Mutational tipping points for switching protein folds and functions

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Highlights? Switching between 3α and 4β+α folds can occur in multiple ways ? Single-residue mutations at diverse positions can induce fold switching ? Mutations lead to a near-complete shift in equilibrium between the two folds ? New function can be gained before the relevant fold is significantly populated     

A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition

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Highlights? Splice-isoform switching favors prosurvival BCL2 family expression in human BC ? BC LSCs are quiescent and TKI-resistant in the marrow niche ? Sabutoclax, a pan-BCL2 inhibitor, enhances TKI sensitivity of bone marrow BC LSCs     

Incoming RNA Virus Nucleocapsids Containing a 5′-Triphosphorylated Genome Activate RIG-I and Antiviral Signaling

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Highlights? RIG-I is activated by the incoming RNA virus nucleocapsids during infection ? RIG-I activation requires a 5′triphosphate dsRNA structure on the nucleocapsids ? Viral nucleocapsids trigger conformational switching and oligomerization of RIG-I ? RIG-I directly binds to viral nucleocapsids containing a 5′triphosphate dsRNA structure     

Direct Conversion of Fibroblasts to Neurons by Reprogramming PTB-Regulated MicroRNA Circuits

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Highlights? Diminished PTB expression is sufficient to trans-differentiate fibroblasts to neurons ? PTB plays a key role in a regulatory loop to suppress neuronal-specific genes ? PTB regulates gene expression at both the splicing and RNA stability levels ? PTB modulates microRNA targeting by competition or switching RNA structure     

Noncanonical Role of the 9-1-1 Clamp in the Error-Free DNA Damage Tolerance Pathway

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Highlights? 9-1-1 and Exo1 are components of the error-free RAD6 pathway ? 9-1-1 promotes postreplicative template switching ? Polyubiquitylated PCNA and 9-1-1 cooperate in the error-free RAD6 pathway ? 9-1-1’s role in the error-free RAD6 pathway is uncoupled from checkpoint functions     

Comprehensive Analysis of Silencing Mutants Reveals Complex Regulation of the Arabidopsis Methylome

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Highlights? Genome-wide single-nucleotide resolution methylation maps in 86 silencing mutants ? Complex interplays between different DNA methylation pathways ? Identification of novel regulators of DNA methylation     

Sculpting of DNA at Abasic Sites by DNA Glycosylase Homolog Mag2

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Highlights? Unflipped AP site stabilized by helix-hairpin-helix DNA glycosylase homolog Mag2 ? Nonenzymatic AP site recognition and DNA sculpting ? Sculpting of DNA conformation enhances substrate transfer between proteins     

System-wide Rewiring Underlies Behavioral Differences in Predatory and Bacterial-Feeding Nematodes

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Highlights? Massive neural circuit rewiring between nematodes with divergent feeding behavior ? Striking patterns correlate with known functional differences ? Motor synapse differences indicate a substantial change in information flow ? Correlates of predatory feeding behavior are identified     

Repeated,Long-Term Cycling of Putative Stem Cells between Niches in a Basal Chordate

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Highlights? Identification of a niche for germline and somatic stem cells in a basal chordate ? Stem cells repeatedly migrate between aged or damaged niches into developing niches     

Myosin-V Opposes Microtubule-Based Cargo Transport and Drives Directional Motility on Cortical Actin

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Highlights? Myosin-V alternates between active and passive actin-binding modes ? Myosin-V opposes kinesin-propelled cargo redistribution ? Myosin-V anchors kinesin-propelled cargo in actin-rich areas ? Myosin-V can drive medium-range directional transport at the cell periphery     

Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations

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Highlights? Complex chromosomal alterations (chromothripsis) observed in medulloblastomas ? Cancers with such alterations harbor TP53 mutations ? Context-specific link between the status of p53 and likelihood of chromothripsis ? p53 status and chromothripsis also correlate with aggressive acute myeloid leukemia     

Bax Exists in a Dynamic Equilibrium between the Cytosol and Mitochondria to Control Apoptotic Priming

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Highlights? Bax exists in equilibrium between the cytosol and mitochondria ? The retrotranslocation of Bax is independent of direct-activator BH3 proteins ? Changes in survival signaling modulate the dissociation rate of mitochondrial Bax ? Accumulation of Bax on mitochondria sensitizes cells to apoptosis     

Keeping cell identity in Arabidopsis requires PRC1 RING-finger homologs that catalyze H2A monoubiquitination

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Highlights? AtBMI1A/B proteins prevent misexpression of embryonic traits in somatic cells ? PRC2 and AtBMI1A/B proteins maintain cells in their differentiated state ? AtBMI1A/B proteins mediate H2A monoubiquitination     

Structure of NPP1, an Ectonucleotide Pyrophosphatase/Phosphodiesterase Involved in Tissue Calcification

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Highlights? We determine the crystal structure of mouse NPP1 ? We elucidate the mechanism of NPP1 dimer formation and secretion ? The structure explains the dramatic functional differences between NPP1 and NPP2 ? The structure allows defining the impact of pathogenic mutations in human NPP1     

The Perception and Misperception of Specular Surface Reflectance

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Highlights? Investigated why irrelevant scene attributes influence perception of surface gloss ? Found gloss judgments exhibit complex interactions between illumination and 3D shape ? Four proximal cues can account for interactions between light field, shape, and gloss ? Suggests that these cues mediate the perception and misperception of gloss     

SIP1 Mediates Cell-Fate Decisions between Neuroectoderm and Mesendoderm in Human Pluripotent Stem Cells

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Highlights? Smad-interacting protein 1 (SIP1) regulates hESC differentiation ? SIP1 upregulation promotes neuroectodermal differentiation ? SIP1 inhibits mesendodermal and endodermal differentiation ? SMAD2/3 and NANOG/OCT4/SOX2 cooperatively regulate SIP1 expression     

Dynamin 2 Potentiates Invasive Migration of Pancreatic Tumor Cells through Stabilization of the Rac1 GEF Vav1

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Highlights? Dyn2 promotes lamellipodia formation and pancreatic tumor cell migration ? Direct binding between Dyn2 and Vav1 promotes Rac1 activation and migration ? Dyn2 binding protects Vav1 from degradation by the lysosome ? Vav1 is targeted for degradation through an interaction with Hsc70     

Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-Induced Glioma Cells

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Highlights? Perivascular niche nitric oxide activates Notch in PDGF-induced gliomas ? Notch signaling drives tumor stem-like characteristics and reduces survival ? Loss of eNOS activity decreases tumor stem-like characteristics ? Suppressing eNOS activity prolongs survival in glioma-bearing mice     

Asymmetric mode of Ca²⁺-S100A4 interaction with nonmuscle myosin IIA generates nanomolar affinity required for filament remodeling

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Highlights? S100A4 dimer binds single-myosin IIA molecule in an asymmetrical mode ? Synergy between Ca-dependent sites in S100A4 leads to high-affinity interaction ? Electron microscopy shows that two S100A4 dimers bind to the myosin coiled coil ? S100A4 has direct effect on formation of stress fibers and cell migration