Notes

LncRNA NEAT1_1 inhibits tumor-like biologics behaviours of fibroblast-like synoviocytes through individuals miR-221-3p/uPAR axis throughout rheumatoid arthritis.
Nonsense-mediated mRNA decay (NMD) is a translation-dependent RNA degradation pathway that is important for the elimination of faulty, and the regulation of normal, mRNAs. The molecular details of the early steps in NMD are not fully understood but previous work suggests that NMD activation occurs as a consequence of ribosome stalling at the termination codon (TC). To test this hypothesis, we established an in vitro translation-coupled toeprinting assay based on lysates from human cells that allows monitoring of ribosome occupancy at the TC of reporter mRNAs. In contrast to the prevailing NMD model, our in vitro system reveals similar ribosomal occupancy at the stop codons of NMD-sensitive and NMD-insensitive reporter mRNAs. Moreover, ribosome profiling reveals a similar density of ribosomes at the TC of endogenous NMD-sensitive and NMD-insensitive mRNAs in vivo. Together, these data show that NMD activation is not accompanied by stable stalling of ribosomes at TCs.Crustal properties of young oceanic lithosphere have been examined extensively, but the nature of the mantle lithosphere underneath remains elusive. Using a novel wide-angle seismic imaging technique, here we show the presence of two sub-horizontal reflections at ∼11 and ∼14.5 km below the seafloor over the 0.51-2.67 Ma old Juan de Fuca Plate. We find that the observed reflectors originate from 300-600-m-thick layers, with an ∼7-8% drop in P-wave velocity. They could be explained either by the presence of partially molten sills or frozen gabbroic sills. If partially molten, the shallower sill would define the base of a thin lithosphere with the constant thickness (11 km), requiring the presence of a mantle thermal anomaly extending up to 2.67 Ma. In contrast, if these reflections were frozen melt sills, they would imply the presence of thick young oceanic lithosphere (20-25 km), and extremely heterogeneous upper mantle.Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. In this report, we demonstrate that the CCCTC-binding factor (CTCF), a crucial chromatin organizer, is essential for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of CTCF or its deletion blocks Schwann cell differentiation at the pro-myelinating stage, whereas overexpression of CTCF promotes the myelination program. We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2 (PRC2), to repress the transcriptional program associated with negative regulation of Schwann cell maturation. Together, our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block Schwann cell differentiation inhibitors to control peripheral myelination and repair.Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. selleck chemical Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8+ T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.Modern advanced photonic integrated circuits require dense integration of high-speed electro-optic functional elements on a compact chip that consumes only moderate power. Energy efficiency, operation speed, and device dimension are thus crucial metrics underlying almost all current developments of photonic signal processing units. Recently, thin-film lithium niobate (LN) emerges as a promising platform for photonic integrated circuits. Here, we make an important step towards miniaturizing functional components on this platform, reporting high-speed LN electro-optic modulators, based upon photonic crystal nanobeam resonators. The devices exhibit a significant tuning efficiency up to 1.98 GHz V-1, a broad modulation bandwidth of 17.5 GHz, while with a tiny electro-optic modal volume of only 0.58 μm3. The modulators enable efficient electro-optic driving of high-Q photonic cavity modes in both adiabatic and non-adiabatic regimes, and allow us to achieve electro-optic switching at 11 Gb s-1 with a bit-switching energy as low as 22 fJ. The demonstration of energy efficient and high-speed electro-optic modulation at the wavelength scale paves a crucial foundation for realizing large-scale LN photonic integrated circuits that are of immense importance for broad applications in data communication, microwave photonics, and quantum photonics.Autism spectrum disorder (ASD) has phenotypically and genetically heterogeneous characteristics. A simulation study demonstrated that attempts to categorize patients with a complex disease into more homogeneous subgroups could have more power to elucidate hidden heritability. We conducted cluster analyses using the k-means algorithm with a cluster number of 15 based on phenotypic variables from the Simons Simplex Collection (SSC). As a preliminary study, we conducted a conventional genome-wide association study (GWAS) with a data set of 597 ASD cases and 370 controls. In the second step, we divided cases based on the clustering results and conducted GWAS in each of the subgroups vs controls (cluster-based GWAS). We also conducted cluster-based GWAS on another SSC data set of 712 probands and 354 controls in the replication stage. In the preliminary study, which was conducted in conventional GWAS design, we observed no significant associations. In the second step of cluster-based GWASs, we identified 65 chromosomal loci, which included 30 intragenic loci located in 21 genes and 35 intergenic loci that satisfied the threshold of P  less then  5.
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