FAK Promotes Early Osteoprogenitor Cell Proliferation by Enhancing mTORC1 Signaling

Focal adhesion kinase (FAK) has important functions in bone homeostasis but its role in early osteoprogenitor cells is unknown. We show herein that mice lacking FAK in Dermo1- expressing cells exhibited low bone mass and decreased osteoblast number. Mechanistically, FAK- deficient early osteoprogenitor cells had decreased proliferation and significantly reduced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, a central regulator of cell growth and proliferation. Furthermore, our data showed that the pharmacological inhibition of FAK kinase- dependent function alone was sufficient to decrease the proliferation and compromise the mineralization of early osteoprogenitor cells. In contrast to the Fak deletion in early osteoprogenitor cells, FAK loss in Col3.6 Cre- targeted osteoblasts did not cause bone loss, and Fak deletion in osteoblasts did not affect proliferation, differentiation, and mTORC1 signaling but increased the level of active proline- rich tyrosine kinase 2 (PYK2), which belongs to the same non- receptor tyrosine kinase family as FAK. Importantly, mTORC1 signaling in bone marrow stromal cells (BMSCs) was reduced if FAK kinase was inhibited at the early osteogenic differentiation stage. In contrast, mTORC1 signaling in BMSCs was not affected if FAK kinase was inhibited at a later osteogenic differentiation stage, in which, however, the concomitant inhibition of both FAK kinase and PYK2 kinase reduced mTORC1 signaling. In summary, our data suggest that FAK promotes early osteoprogenitor cell proliferation by enhancing mTORC1 signaling via its kinase- dependent function and the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2. © 2020 American Society for Bone and Mineral Research.Schematic model of the differential roles of FAK in the cells of osteoblast lineage. The model depicts the mechanisms of FAK action at three distinct stages of osteoblast lineage in which the roles of FAK have been addressed by genetic and pharmacological approaches as well as the respective Cre transgenes used to target Fak, including Dermo1- Cre (this study), Osterix- Cre,(10) Col3.6- Cre (this study), and Col2.3- Cre.(9) Red - indicates that the loss of FAK in osteoblasts can be compensated by the upregulated active PYK2.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/3/jbmr4029-sup-0001-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/2/jbmr4029_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162813/1/jbmr4029.pd

Topological edge and corner states in Bi fractals on InSb

Topological materials hosting metallic edges characterized by integer quantized conductivity in an insulating bulk have revolutionized our understanding of transport in matter. The topological protection of these edge states is based on symmetries and dimensionality. However, only integer-dimensional models have been classified, and the interplay of topology and fractals, which may have a non-integer dimension, remained largely unexplored. Quantum fractals have recently been engineered in metamaterials, but up to present no topological states were unveiled in fractals realized in real materials. Here, we show theoretically and experimentally that topological edge and corner modes arise in fractals formed upon depositing thin layers of bismuth on an indium antimonide substrate. Scanning tunneling microscopy reveals the appearance of (nearly) zero-energy modes at the corners of Sierpi\'nski triangles, as well as the formation of outer and inner edge modes at higher energies. Unexpectedly, a robust and sharp depleted mode appears at the outer and inner edges of the samples at negative bias voltages. The experimental findings are corroborated by theoretical calculations in the framework of a continuum muffin-tin and a lattice tight-binding model. The stability of the topological features to the introduction of a Rashba spin-orbit coupling and disorder is discussed. This work opens the perspective to novel electronics in real materials at non-integer dimensions with robust and protected topological states.Comment: Main manuscript 14 pages, supplementary material 34 page

Quantum phase transition in magnetic nanographenes on a lead superconductor

Quantum spins, referred to the spin operator preserved by full SU(2) symmetry in the absence of the magnetic anistropy, have been proposed to host exotic interactions with superconductivity4. However, spin orbit coupling and crystal field splitting normally cause a significant magnetic anisotropy for d/f-shell spins on surfaces6,9, breaking SU(2) symmetry and fabricating the spins with Ising properties10. Recently, magnetic nanographenes have been proven to host intrinsic quantum magnetism due to their negligible spin orbital coupling and crystal field splitting. Here, we fabricate three atomically precise nanographenes with the same magnetic ground state of spin S=1/2 on Pb(111) through engineering sublattice imbalance in graphene honeycomb lattice. Scanning tunneling spectroscopy reveals the coexistence of magnetic bound states and Kondo screening in such hybridized system. Through engineering the magnetic exchange strength between the unpaired spin in nanographenes and cooper pairs, quantum phase transition from the singlet to the doublet state has been observed, in consistent with quantum models of spins on superconductors. Our work demonstrates delocalized graphene magnetism host highly tunable magnetic bound states with cooper pairs, which can be further developed to study the Majorana bound states and other rich quantum physics of low-dimensional quantum spins on superconductors.Comment: 13 pages, 4figure

WSP from “Nostoc commune” Vauch. suppresses gastric cancer migration via EGFRVIII signaling

IntroductionA number of evidences have proved that “Nostoc commune” Vauch can improve human immunity and prevent diseases, however, the specific mechanism remains unclear. The biological activity of the main protein component of “Nostoc commune” Vauch extracellular matrix– a water-stress protein (WSP) still needs to be elucidated.MethodsIn our study, we validated the role of WSP in gastric cancer metastasis at the cellular level, the organoid level and in mouse models, and also studied the role of EGFRVIII and downstream signaling molecules after WSP treatment.ResultsWe found that WSP can significantly inhibit the metastasis of gastric cancer cells. Interestingly, we found that the anti-metastasis ability of WSP on gastric cancer was related to membrane protein receptor EGFRVIII, which was realized by inhibiting the downstream EGFRVIII signaling pathway. In terms of mechanism, WSP can inhibit the downstream EGFRVIII signaling pathway Akt-PI3K and further inhibit the secretion of cancer-related metastasis proteins such as MMP2 and MMP9, thus, significantly affecting the metastasis of gastric cancer cells.DiscussionGiven the anticancer properties of WSP, drug developers and manufacturers can further develop protein drugs for cancer patients using protein engineering techniques based on the properties of WSP

Genome of Pythium myriotylum Uncovers an Extensive Arsenal of Virulence-Related Genes among the Broad-Host-Range Necrotrophic Pythium Plant Pathogens

The Pythium (Peronosporales, Oomycota) genus includes devastating plant pathogens that cause widespread diseases and severe crop losses. Here, we have uncovered a far greater arsenal of virulence factor-related genes in the necrotrophic Pythium myriotylum than in other Pythium plant pathogens. The genome of a plant-virulent P. myriotylum strain (~70 Mb and 19,878 genes) isolated from a diseased rhizome of ginger (Zingiber officinale) encodes the largest repertoire of putative effectors, proteases, and plant cell wall-degrading enzymes (PCWDEs) among the studied species. P. myriotylum has twice as many predicted secreted proteins than any other Pythium plant pathogen. Arrays of tandem duplications appear to be a key factor of the enrichment of the virulence factor-related genes in P. myriotylum. The transcriptomic analysis performed on two P. myriotylum isolates infecting ginger leaves showed that proteases were a major part of the upregulated genes along with PCWDEs, Nep1-like proteins (NLPs), and elicitin-like proteins. A subset of P. myriotylum NLPs were analyzed and found to have necrosis-inducing ability from agroinfiltration of tobacco (Nicotiana benthamiana) leaves. One of the heterologously produced infection-upregulated putative cutinases found in a tandem array showed esterase activity with preferences for longer-chain-length substrates and neutral to alkaline pH levels. Our results allow the development of science-based targets for the management of P. myriotylum-caused disease, as insights from the genome and transcriptome show that gene expansion of virulence factor-related genes play a bigger role in the plant parasitism of Pythium spp. than previously thought. IMPORTANCE Pythium species are oomycetes, an evolutionarily distinct group of filamentous fungus-like stramenopiles. The Pythium genus includes several pathogens of important crop species, e.g., the spice ginger. Analysis of our genome from the plant pathogen Pythium myriotylum uncovered a far larger arsenal of virulence factor-related genes than found in other Pythium plant pathogens, and these genes contribute to the infection of the plant host. The increase in the number of virulence factor-related genes appears to have occurred through the mechanism of tandem gene duplication events. Genes from particular virulence factor-related categories that were increased in number and switched on during infection of ginger leaves had their activities tested. These genes have toxic activities toward plant cells or activities to hydrolyze polymeric components of the plant. The research suggests targets to better manage diseases caused by P. myriotylum and prompts renewed attention to the genomics of Pythium plant pathogens

Prediction of overall survival for patients with metastatic castration-resistant prostate cancer : development of a prognostic model through a crowdsourced challenge with open clinical trial data

Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0.791; Bayes factor >5) and surpassed the reference model (iAUC 0.743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3.32, 95% CI 2.39-4.62, p Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer.Peer reviewe

Representing Words as Lymphocytes

Similarity between words is becoming a generic problem for many applications of computational linguistics, and computing word similarities is determined by word representations. Inspired by the analogies between words and lymphocytes, a lymphocyte-style word representation is proposed. The word representation is built on the basis of dependency syntax of sentences and represent word context as head properties and dependent properties of the word. Lymphocyte-style word representations are evaluated by computing the similarities between words, and experiments are conducted on the Penn Chinese Treebank 5.1. Experimental results indicate that the proposed word representations are effective