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BACKGROUND: Previous studies identified several separate risk factors

PIEZO1 is a mechanosensitive channel that converts applied force into electrical signals. Partial molecular structures show that PIEZO1 is a bowl-shaped trimer with extended arms. Here we use cryo-electron microscopy to show that PIEZO1 adopts different degrees of curvature in lipid vesicles of different sizes. We also use high-speed atomic force microscopy to analyse the deformability of PIEZO1 under force in membranes on a mica surface, and show that PIEZO1 can be flattened reversibly into the membrane plane. By approximating the absolute force applied, we estimate a range of values for the mechanical spring constant of PIEZO1. Both methods of microscopy demonstrate that PIEZO1 can deform its shape towards a planar structure. This deformation could explain how lateral membrane tension can be converted into a conformation-dependent change in free energy to gate the PIEZO1 channel in response to mechanical perturbations

Background: Hyperactivity of the IL-23/IL-17 axis is central to plaque

Drug-like inhibitors are often designed by mimicking cofactor or

During mammalian embryogenesis, extensive cellular remodeling is needed

To the Editor: We are delighted that our discovery of autoantibodies directed against LINE‐1 retroelement–encoded p40/ORF1p in SLE patients has been so rapidly replicated, and we thank Dr. Crow for her excellent summary of our findings. Her laboratory's detection of LINE‐1 messenger RNA (mRNA) and immunoreactive p40 protein in salivary gland specimens from patients with primary Sjögren's syndrome and kidney specimens from SLE patients 1 was an important impetus for our study. We also agree with Dr. Crow that anti–LINE‐1 immunity is indicative of a potential role of LINE‐1 in SLE pathogenesis. Besides the presence of autoantibodies against p40, the literature suggests at least 2 additional reasons to suspect this hypothesis: 1) LINE‐1–encoded proteins are physically associated with Ro 60 and other well‐recognized autoantigens in SLE, together with LINE‐1 mRNA or short RNA species such as Alu and YRNA transcripts and 2) the other LINE‐1–encoded protein, p145/ORF2p, is a reverse transcriptase that uses p40‐bound RNA as a template for DNA synthesis. The presence of autoantibodies against p40 therefore suggests that the autoimmune reaction in the SLE patient is targeting a protein–RNA complex that may also include DNA newly synthesized by reverse transcription, which has been shown to trigger the GMP‐AMP synthase (cGAS)/stimulator of IFN genes (STING) pathway to induce type I IFN production in senescent cells 2. Indeed, Dr. Crow's group has shown that introduction of full‐length LINE‐1 can induce type I IFN production in transfected cells 1. Furthermore, it has also been reported that activation of cGAS does occur in a subset of SLE patients 3.

Stress has both a good and bad side which are discussed in terms of the

Female Aedes aegypti mosquitoes require protein from blood to develop

Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis1-4. They are also implicated in human developmental disorders and cancers5-8, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies9-11. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)8,12,13), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.