Throughout most of the mammalian genome, genetically regulated developmental programming establishes diverse yet predictable epigenetic states across differentiated cells and tissues. At metastable epialleles (MEs), conversely, epigenotype is established stochastically in the early embryo then maintained in differentiated lineages, resulting in dramatic and systemic interindividual variation in epigenetic regulation. In the mouse, maternal nutrition affects this process, with permanent phenotypic consequences for the offspring. MEs have not previously been identified in humans. Here, using an innovative 2-tissue parallel epigenomic screen, we identified putative MEs in the human genome. In autopsy samples, we showed that DNA methylation at these loci is highly correlated across tissues representing all 3 embryonic germ layer lineages. Monozygotic twin pairs exhibited substantial discordance in DNA methylation at these loci, suggesting that their epigenetic state is established stochastically. We then tested for persistent epigenetic effects of periconceptional nutrition in rural Gambians, who experience dramatic seasonal fluctuations in nutritional status. DNA methylation at MEs was elevated in individuals conceived during the nutritionally challenged rainy season, providing the first evidence of a permanent, systemic effect of periconceptional environment on human epigenotype. At MEs, epigenetic regulation in internal organs and tissues varies among individuals and can be deduced from peripheral blood DNA. MEs should therefore facilitate an improved understanding of the role of interindividual epigenetic variation in human disease.

. CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/302216 doi: bioRxiv preprint first posted online Apr. 16, 2018; 2 and biochemical differences suggesting that they may be able to adopt 26 disease-specific molecular conformations 6,7 . Such conformers may give rise 27 to different neuropathological phenotypes 8,9 , reminiscent of prion strains 10 . 28 However, the underlying structures are not known. Using electron cryo-29 microscopy (cryo-EM), we recently reported the structures of tau filaments 30 from Alzheimer's disease, which contain both 3R and 4R tau 11 . Here we 31 have determined the structures of tau filaments from Pick's disease, a 32 neurodegenerative disorder characterised by frontotemporal dementia. Extended Data Table 1) [12][13][14][15][16][17] . As in Alzheimer's disease 18 , a fuzzy coat composed 48 of the disordered N-and C-terminal regions of tau surrounded the filament cores 49 and was removed by mild pronase treatment ( Fig. 1e and Extended Data Fig. 1). 50 . CC-BY 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/302216 doi: bioRxiv preprint first posted online Apr. 16, 2018; 3 Narrow (93%) and wide (7%) filaments could be distinguished (Fig. 1e). The 51 narrow filaments have previously been described as straight [19][20][21] , but they do 52 have a helical twist with a cross-over distance of ~1000 Å and a projected width 53varying from approximately 50 to 150 Å. The wide filaments have a similar 54 cross-over distance, but their width varies from approximately 50 to 300 Å. We 55 named them narrow and wide Pick filaments (NPFs and WPFs). Their 56 morphologies and relative abundance match those reported in cortical biopsies 57 from Pick's disease brain 21 . 58 59 Using helical reconstruction in RELION 22 , we determined a 3.2 Å resolution map 60 of the ordered core of NPFs, in which side-chain densities were well resolved and 61 β-strands were clearly separated along the helical axis ( Fig. 1f and Extended Data 62 Fig. 2). We also determined an 8 Å resolution map of WPFs, which showed well-63 separated β-sheets perpendicular to the helical axis, but no separation of β-64 strands along the helical axis ( Fig. 1g and Extended Data Fig. 3). NPFs are 65 composed of a single protofilament with an elongated structure that is markedly 66 different from the C-shaped protofilament of Alzheimer's disease paired helical 67 and straight filaments (PHFs and SFs) 11,23 . WPFs are formed by the association of 68 two NPF protofilaments at their distal tips. In support, we observed WPFs where 69 one protofilament had been lost in some parts (Extended Data Fig. 3). Our results 70 reveal that the tau filam...

Neddylation, a post-translational modification that conjugates an ubiquitin-like protein NEDD8 to substrate proteins, is an important biochemical process that regulates protein function. The best-characterized substrates of neddylation are the cullin subunits of Cullin-RING ligases (CRLs), which, as the largest family of E3 ubiquitin ligases, control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. Recently, increasing pieces of experimental evidence strongly indicate that the process of protein neddylation modification is elevated in multiple human cancers, providing sound rationale for its targeting as an attractive anticancer therapeutic strategy. Indeed, neddylation inactivation by MLN4924 (also known as pevonedistat), a small molecule inhibitor of E1 NEDD8-activating enzyme currently in phase I/II clinical trials, exerts significant anticancer effects by inducing cell cycle arrest, apoptosis, senescence and autophagy in a cell-type and context dependent manner. Here, we summarize the latest progresses in the field with a major focus on preclinical studies in validation of neddylation modification as a promising anticancer target.

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Bell's palsy is the most common condition involving a rapid and unilateral onset of peripheral paresis/paralysis of the seventh cranial nerve. It affects 11.5-53.3 per 100,000 individuals a year across different populations. Bell's palsy is a health issue causing concern and has an extremely negative effect on both patients and their families. Therefore, diagnosis and prompt cause determination are key for early treatment. However, the etiology of Bell's palsy is unclear, and this affects its treatment. Thus, it is critical to determine the causes of Bell's palsy so that targeted treatment approaches can be developed and employed. This article reviews the literature on the diagnosis of Bell's palsy and examines possible etiologies of the disorder. It also suggests that the diagnosis of idiopathic facial palsy is based on exclusion and is most often made based on five factors including anatomical structure, viral infection, ischemia, inflammation, and cold stimulation responsivity.

Circular RNAs (circRNAs) are significantly dysregulated in various cancer types. However, the roles and mechanisms of circRNAs in cancer remain largely unknown. In this study, we demonstrated that a novel circRNA (circITGA7) and its linear host gene ITGA7 are both significantly downregulated in colorectal cancer (CRC) tissues and cell lines. These decreased expression levels correlated with CRC progression. Functional assays demonstrated that ectopic circITGA7 expression suppressed the growth and metastasis of CRC cells in vitro and in vivo. Knockdown of circITGA7 or ITGA7 promoted the proliferation and migration of CRC cells in vitro, and enhanced CRC growth in vivo. Mechanistically, by using RNA-sequencing and KEGG enrichment analysis, we found that circITGA7 is a negative regulator of the Ras signalling pathway, and that ITGA7 is associated with cytokine-related signalling pathways. In addition, circITGA7 binds to miR-370-3p to antagonise its suppression of neurofibromin 1, which is a well-known negative regulator of the Ras pathway. Finally, circITGA7 upregulates the transcription of ITGA7 by suppressing RREB1 via the Ras pathway. In conclusion, our findings indicate a suppressor role of circITGA7 and ITGA7 in CRC, and reveal that circITGA7 inhibits the proliferation and metastasis of CRC cells by suppressing the Ras signalling pathway and promoting the transcription of ITGA7, suggesting that circITGA7 is a potential target for CRC treatment. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Turn you inside out: A novel method for performing in situ separation and recycling of submicrometer-sized solid catalysts is developed based on the pH-triggered inversion of Pickering emulsions (see scheme; o = oil, w = water). Solid catalysts can be recycled 36 times without significant loss of activity. The method differs from conventional methods in terms of speed, energy consumption, catalyst separation, and recycling effectiveness.

GH is an important regulator of body growth and composition as well as numerous other metabolic processes. In particular, liver plays a key role in the GH/IGF-I axis, because the majority of circulating "endocrine" IGF-I results from GH-stimulated liver IGF-I production. To develop a better understanding of the role of liver in the overall function of GH, we generated a strain of mice with liver-specific GH receptor (GHR) gene knockout (LiGHRKO mice). LiGHRKO mice had a 90% decrease in circulating IGF-I levels, a 300% increase in circulating GH, and significant changes in IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, IGFBP-5, and IGFBP-7. LiGHRKO mice were smaller than controls, with body length and body weight being significantly decreased in both sexes. Analysis of body composition over time revealed a pattern similar to those found in GH transgenic mice; that is, LiGHRKO mice had a higher percentage of body fat at early ages followed by lower percentage of body fat in adulthood. Local IGF-I mRNA levels were significantly increased in skeletal muscle and select adipose tissue depots. Grip strength was increased in LiGHRKO mice. Finally, circulating levels of leptin, resistin, and adiponectin were increased in LiGHRKO mice. In conclusion, LiGHRKO mice are smaller despite increased local mRNA expression of IGF-I in several tissues, suggesting that liver-derived IGF-I is indeed important for normal body growth. Furthermore, our data suggest that novel GH-dependent cross talk between liver and adipose is important for regulation of adipokines in vivo.