Moodycrews5985

The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered "undruggable," and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail's interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.Disordered hyperuniformity (DHU) is a recently proposed new state of matter, which has been observed in a variety of classical and quantum many-body systems. DHU systems are characterized by vanishing infinite-wavelength normalized density fluctuations and are endowed with unique novel physical properties. Alantolactone TGF-beta modulator Here, we report the discovery of disordered hyperuniformity in atomic-scale two-dimensional materials, i.e., amorphous silica composed of a single layer of atoms, based on spectral-density analysis of high-resolution transmission electron microscopy images. Moreover, we show via large-scale density functional theory calculations that DHU leads to almost complete closure of the electronic bandgap compared to the crystalline counterpart, making the material effectively a metal. This is in contrast to the conventional wisdom that disorder generally diminishes electronic transport and is due to the unique electron wave localization induced by the topological defects in the DHU state.Cyclin-dependent kinase 2 (CDK2) controls cell division and is central to oncogenic signaling. We used an "in situ" approach to identify CDK2 substrates within nuclei isolated from cells expressing CDK2 engineered to use adenosine 5'-triphosphate analogs. We identified 117 candidate substrates, ~40% of which are known CDK substrates. Previously unknown candidates were validated to be CDK2 substrates, including LSD1, DOT1L, and Rad54. The identification of many chromatin-associated proteins may have been facilitated by labeling conditions that preserved nuclear architecture and physiologic CDK2 regulation by endogenous cyclins. Candidate substrates include proteins that regulate histone modifications, chromatin, transcription, and RNA/DNA metabolism. Many of these proteins also coexist in multi-protein complexes, including epigenetic regulators, that may provide new links between cell division and other cellular processes mediated by CDK2. In situ phosphorylation thus revealed candidate substrates with a high validation rate and should be readily applicable to other nuclear kinases.Many load-bearing tissues, such as muscles and cartilages, show high elasticity, toughness, and fast recovery. However, combining these mechanical properties in the same synthetic biomaterials is fundamentally challenging. Here, we show that strong, tough, and fast-recovery hydrogels can be engineered using cross-linkers involving cooperative dynamic interactions. We designed a histidine-rich decapeptide containing two tandem zinc binding motifs. Because of allosteric structural change-induced cooperative binding, this decapeptide had a higher thermodynamic stability, stronger binding strength, and faster binding rate than single binding motifs or isolated ligands. The engineered hybrid network hydrogels containing the peptide-zinc complex exhibit a break stress of ~3.0 MPa, toughness of ~4.0 MJ m-3, and fast recovery in seconds. We expect that they can function effectively as scaffolds for load-bearing tissue engineering and as building blocks for soft robotics. Our results provide a general route to tune the mechanical and dynamic properties of hydrogels at the molecular level.How neural form and function are connected is a central question of neuroscience. One prominent functional hypothesis, from the beginnings of neuroanatomical study, states that laterally extending dendrites of insect lamina monopolar cells (LMCs) spatially integrate visual information. We provide the first direct functional evidence for this hypothesis using intracellular recordings from type II LMCs in the hawkmoth Macroglossum stellatarum. We show that their spatial receptive fields broaden with decreasing light intensities, thus trading spatial resolution for higher sensitivity. These dynamic changes in LMC spatial properties can be explained by the density and lateral extent of their dendritic arborizations. Our results thus provide the first physiological evidence for a century-old hypothesis, directly correlating physiological response properties with distinctive dendritic morphology.Genomic instability is common in human embryos, but the underlying causes are largely unknown. Here, we examined the consequences of sperm DNA damage on the embryonic genome by single-cell whole-genome sequencing of individual blastomeres from bovine embryos produced with sperm damaged by γ-radiation. Sperm DNA damage primarily leads to fragmentation of the paternal chromosomes followed by random distribution of the chromosomal fragments over the two sister cells in the first cell division. An unexpected secondary effect of sperm DNA damage is the induction of direct unequal cleavages, which include the poorly understood heterogoneic cell divisions. As a result, chaotic mosaicism is common in embryos derived from fertilizations with damaged sperm. The mosaic aneuploidies, uniparental disomies, and de novo structural variation induced by sperm DNA damage may compromise fertility and lead to rare congenital disorders when embryos escape developmental arrest.