资源环境科技发展态势分析平台

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Long noncoding RNAs and certain unstable transcripts tend to localize to chromatin, in a process that is shown here to depend on an RNA motif that recognizes the small nuclear ribonuclear protein U1, and to rely on transcription.

Spin-based logic architectures provide nonvolatile data retention, near-zero leakage, and scalability, extending the technology roadmap beyond complementary metal-oxide-semiconductor logic(1-13). Architectures based on magnetic domain walls take advantage of the fast motion, high density, non-volatility and flexible design of domain walls to process and store information(1,3,14-16). Such schemes, however, rely on domain-wall manipulation and clocking using an external magnetic field, which limits their implementation in dense, large-scale chips. Here we demonstrate a method for performing all-electric logic operations and cascading using domain-wall racetracks. We exploit the chiral coupling between neighbouring magnetic domains induced by the interfacial Dzyaloshinskii-Moriya interaction(17-20), which promotes non-collinear spin alignment, to realize a domain-wall inverter, the essential basic building block in all implementations of Boolean logic. We then fabricate reconfigurable NAND and NOR logic gates, and perform operations with current-induced domain-wall motion. Finally, we cascade several NAND gates to build XOR and full adder gates, demonstrating electrical control of magnetic data and device interconnection in logic circuits. Our work provides a viable platform for scalable all-electric magnetic logic, paving the way for memory-in-logic applications.

The mechanics of the cellular microenvironment continuously modulates cell functions such as growth, survival, apoptosis, differentiation and morphogenesis via cytoskeletal remodelling and actomyosin contractility(1-3). Although all of these processes consume energy(4,5), it is unknown whether and how cells adapt their metabolic activity to variable mechanical cues. Here we report that the transfer of human bronchial epithelial cells from stiff to soft substrates causes a downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK). PFK degradation is triggered by the disassembly of stress fibres, which releases the PFK-targeting E3 ubiquitin ligase tripartite motif (TRIM)-containing protein 21 (TRIM21). Transformed non-small-cell lung cancer cells, which maintain high glycolytic rates regardless of changing environmental mechanics, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress-fibre subset that is insensitive to substrate stiffness. Our data reveal a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to tune energy production in variable microenvironments, whereas the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolytic rates in cancer cells despite constant alterations of the tumour tissue.

Glycolysis in normal epithelial cells responds to microenvironmental mechanics via the modulation of actin bundles that sequester the phosphofructokinase-targeting ubiquitin ligase TRIM21, a process superseded by persistent actin bundles in cancer cells.

Epithelial-to-mesenchymal transitions (EMTs) are phenotypic plasticity processes that confer migratory and invasive properties to epithelial cells during development, wound-healing, fibrosis and cancer(1-4). EMTs are driven by SNAIL, ZEB and TWIST transcription factors(5,6) together with microRNAs that balance this regulatory network(7,8). Transforming growth factor beta (TGF-beta) is a potent inducer of developmental and fibrogenic EMTs4,9,10. Aberrant TGF-beta signalling and EMT are implicated in the pathogenesis of renal fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, pulmonary fibrosis and cancer(4,11). TGF-beta depends on RAS and mitogen-activated protein kinase (MAPK) pathway inputs for the induction of EMTs12-19. Here we show how these signals coordinately trigger EMTs and integrate them with broader pathophysiological processes. We identify RAS-responsive element binding protein 1 (RREB1), a RAS transcriptional effector(20,21), as a key partner of TGF-beta-activated SMAD transcription factors in EMT. MAPK-activated RREB1 recruits TGF-beta-activated SMAD factors to SNAIL. Context-dependent chromatin accessibility dictates the ability of RREB1 and SMAD to activate additional genes that determine the nature of the resulting EMT. In carcinoma cells, TGF-beta-SMAD and RREB1 directly drive expression of SNAIL and fibrogenic factors stimulating myofibroblasts, promoting intratumoral fibrosis and supporting tumour growth. In mouse epiblast progenitors, Nodal-SMAD and RREB1 combine to induce expression of SNAIL and mesendoderm-differentiation genes that drive gastrulation. Thus, RREB1 provides a molecular link between RAS and TGF-beta pathways for coordinated induction of developmental and fibrogenic EMTs. These insights increase our understanding of the regulation of epithelial plasticity and its pathophysiological consequences in development, fibrosis and cancer.

RAS and TGF-beta pathways regulate distinct modes of epithelial-to-mesenchymal transition via RAS-responsive element binding protein 1.