•ACE2 are highly expressed in human small intestinal enterocytes.•2019-nCoV may have same tissue tropism such as small intestine with SARS-CoV.•The gastrointestinal tract may be an alternative route ...for 2019-nCoV.•Distribution pattern of ACE2 gene insinuates the possibility of a fecal–oral transmission for COVID-19.
The coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China and rapidly spread in other countries in December 2019. The infected patients presented with fever, respiratory symptoms, sometimes with digestive and other systemic manifestations, and some progressed with a severe acute respiratory syndrome or even death. Associated digestive symptoms were frequently observed in the patients, with an unknown significance and mechanism. ACE2, as the major known functional receptor of the 2019 novel coronavirus (2019-nCoV) attracted our attention. We collected the clinical data of the 2019-nCoV-infected patients from published studies and extracted the data about the incidence of gastrointestinal symptoms. Furthermore, we used online datasets to analyze ACE2 expression in different human organs, especially in the small intestine, to explore the relationship between ACE2 expression patterns and clinical symptoms. We found that diarrhea accounted for a notable proportion of COVID-19 patients, ranging from 8.0% to 12.9%. The results reveal that ACE2 mRNA and protein are highly expressed in the small intestinal enterocytes but not in the goblet cells or intestinal immune cells. High expression of ACE2 on the surface cells in the digestive tract may lead to gastrointestinal symptoms and inflammation susceptibility. Overall, digestive symptoms were common in the COVID-19 patients. ACE2 expression on surface cells of the small intestine may mediate the invasion and amplification of the virus and activation of gastrointestinal inflammation. It is a possible mechanism of digestive symptoms in the COVID-19 patients and explains the presence of the virus in patients’ stool samples. The study also highlights the necessity of taking stool samples for suspected patients to help in early diagnosis and assessment of disease status.
The reticulons and receptor expression-enhancing proteins (REEPs) in the endoplasmic reticulum (ER) are necessary and sufficient for generating ER tubules. However, the mechanism of curvature ...generation remains elusive. Here, we systematically analyze components of the REEP family based on AI-predicted structures. In yeast REEP Yop1p, TM1/2 and TM3/4 form hairpins and TM2-4 exist as a bundle. Site-directed cross-linking reveals that TM2 and TM4 individually mediate homotypic dimerization, allowing further assembly into a curved shape. Truncated Yop1p lacking TM1 (equivalent to REEP1) retains the curvature-generating capability, undermining the role of the intrinsic wedge. Unexpectedly, both REEP1 and REEP5 fail to replace Yop1p in the maintenance of ER morphology, mostly due to a subtle difference in oligomerization tendency, which involves not only the TM domains, but also the TM-connecting cytosolic loop and previously neglected C-terminal helix. Several hereditary spastic paraplegia-causing mutations in REEP1 appear at the oligomeric interfaces identified here, suggesting compromised self-association of REEP as a pathogenic mechanism. These results indicate that membrane curvature stabilization by integral membrane proteins is dominantly achieved by curved, oligomeric scaffolding.
Examination of a series of naturally-occurring trypsin inhibitor proteins, led to identification of a set of three residues (which we call the "interface triplet") to be determinant of trypsin ...binding affinity, hence excellent templates for small molecule mimicry. Consequently, we attempted to use the Exploring Key Orientation (EKO) strategy developed in our lab to evaluate small molecules that mimic the interface triplet regions of natural trypsin inhibitors, and hence potentially might bind and inhibit the catalytic activity of trypsin. A bis-triazole scaffold ("TT-mer") was the most promising of the molecules evaluated
in silico
. Twelve such compounds were synthesized and assayed against trypsin, among which the best showed a
K
d
of 2.1 μM. X-ray crystallography revealed a high degree of matching between an illustrative TT-mer's actual binding mode and that of the mimics that overlaid the interface triplet in the crystal structure. Deviation of the third side chain from the PPI structure seems to be due to alleviation of an unfavorable dipole-dipole interaction in the small molecule's actual bound conformation.
A commonality noticed between structures of trypsin and natural trypsin inhibitors leads to a new small molecule inhibitor design strategy.
We study proximity-induced spin–orbit coupling (SOC) in bilayer graphene/few-layer WSe2 heterostructure devices. Contact mode atomic force microscopy (AFM) cleaning yields ultraclean interfaces and ...high-mobility devices. In a perpendicular magnetic field, we measure the quantum Hall effect to determine the Landau level structure in the presence of out-of-plane Ising and in-plane Rashba SOC. A distinct Landau level crossing pattern emerges when tuning the charge density and displacement field independently with dual gates, originating from a layer-selective SOC proximity effect. Analyzing the Landau level crossings and measured inter-Landau level energy gaps yields the proximity-induced SOC energy scale. The Ising SOC is ∼2.2 meV, 100 times higher than the intrinsic SOC in graphene, whereas its sign is consistent with theories predicting a dependence of SOC on interlayer twist angle. The Rashba SOC is ∼15 meV. Finally, we infer the magnetic field dependence of the inter-Landau level Coulomb interactions. These ultraclean bilayer graphene/WSe2 heterostructures provide a high mobility system with the potential to realize novel topological electronic states and manipulate spins in nanostructures.
This paper constructs an abstract symbol integration system based on big data applied in advertising design. Firstly, the abstract symbols are regarded as high-dimensional data, and the abstract ...symbols are collected using the local differential privacy algorithm in the big data algorithm. Secondly, the collected data are clustered, which is the process of big data processing. Finally, data classification is achieved by calculating the information gain rate and information entropy using the C4.5 decision tree. To verify the effectiveness of the built platform, this paper uses the platform to filter the most appropriate abstract symbols, and audiences of different age groups rate the ads and derive the online and offline sales of the products involved in the ads before and after the application of the abstract symbols. The results show that the ads’ quality improved significantly after applying abstract symbols. The post-90s raised 43 points for the prominent theme of the ads. Meanwhile, the online sales of products increased by 1.08 million units, and offline store sales increased by 840,000 units after applying abstract symbols. This shows that applying abstract symbols in advertising design can attract consumers to buy products and promote consumption.
An active segment of the research community designing small molecules ("minimalist mimics" of peptide fragments) to interfere with protein-protein interactions have based their studies on an implicit ...hypothesis. Here we refer to this as the Secondary Structure Hypothesis, that might be defined as, "If a small molecule can orient amino acid side-chains in directions that resemble side-chains of the parent secondary structure at the interface, then that small molecule is a candidate to perturb the protein-protein interaction". Rigorous tests of this hypothesis require co-crystallization of minimalist mimics with protein receptors, and comparison of the bound conformations with the interface secondary structures they were designed to resemble. Unfortunately, to the best of our knowledge, there is no such analysis in the literature, and it is unlikely that enough examples will emerge in the near future to test the hypothesis. Research described here was designed to challenge this hypothesis from a different perspective. In a previous study, preferred conformations of a series of novel minimalist mimics were simulated then systematically overlaid on >240 000 crystallographically characterized protein-protein interfaces. Select data from that overlay procedure revealed chemotypes that overlay side chains on various PPI interfaces with a relatively high frequency of occurrence. The first aim of this work was to determine if good secondary structure mimics overlay frequently on PPI interfaces. The second aim of this work was to determine if overlays of preferred conformers at interface regions involve secondary structures. Thus situations where these conformations overlaid extremely well on PPI interfaces were analyzed to determine if secondary structures featured the PPI regions where these molecules overlaid in the previous study. Combining conclusions from these two studies enabled us to formulate a hypothesis that is complementary to the Secondary Structure Hypothesis, but, unlike this, is supported by abundant data. We call this the Interface Mimicry Hypothesis.
Human embryonic stem cells (hESCs) are self-renewing and pluripotent cells that originate from the inner cell mass of the blastocyst. Mitosis is fundamental to organism survival and reproduction and ...is responsible for the equal distribution of duplicated chromosomes into daughter cells. Mitotic dysfunction is associated with a wide variety of human diseases, not least cancer. hESCs have a unique cell cycle distribution, but it is unclear exactly how the mitotic activity of hESCs is related to their proliferation and differentiation. Here, we established a cell line of hESCs stably expressing GFP-α-tubulin and mCherry-H2B by lentiviral infection to analyze and visualize mitosis in detail. During metaphase, the mitotic spindle was smaller and wider and contained a greater proportion of astral microtubules than normal cells. In addition, spindle microtubules were more stable, and chromosome alignment was faster in hESCs than in somatic cells. We also found that the spindle assembly checkpoint was functional in hESCs. These findings thus reveal a specialized mitotic behavior of hESCs.
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