We consider nonparametric estimation of the mean and covariance functions for functional/longitudinal data. Strong uniform convergence rates are developed for estimators that are local-linear ...smoothers. Our results are obtained in a unified framework in which the number of observations within each curve/cluster can be of any rate relative to the sample size. We show that the convergence rates for the procedures depend on both the number of sample curves and the number of observations on each curve. For sparse functional data, these rates are equivalent to the optimal rates in nonparametric regression. For dense functional data, root-n rates of convergence can be achieved with proper choices of bandwidths. We further derive almost sure rates of convergence for principal component analysis using the estimated covariance function. The results are illustrated with simulation studies.
Abstract
Resistance change under mechanical stimuli arouses mass operational heat, damaging the performance, lifetime, and reliability of stretchable electronic devices, therefore rapid thermal heat ...dissipating is necessary. Here we report a stretchable strain sensor with outstanding thermal management. Besides a high stretchability and sensitivity testified by human motion monitoring, as well as long-term durability, an enhanced thermal conductivity from the casted thermoplastic polyurethane-boron nitride nanosheets layer helps rapid heat transmission to the environments, while the porous electrospun fibrous thermoplastic polyurethane membrane leads to thermal insulation. A 32% drop of the real time saturated temperature is achieved. For the first time we in-situ investigated the dynamic operational temperature fluctuation of stretchable electronics under repeating stretching-releasing processes. Finally, cytotoxicity test confirms that the nanofillers are tightly restricted in the nanocomposites, making it harmless to human health. All the results prove it an excellent candidate for the next-generation of wearable devices.
The intestinal epithelium possesses a remarkable self-renewal ability, which is mediated by actively proliferating Lgr5
stem cells. Bone morphogenetic protein (BMP) signalling represents one major ...counterforce that limits the hyperproliferation of intestinal epithelium, but the exact mechanism remains elusive. Here we demonstrate that epithelial BMP signalling plays an indispensable role in restricting Lgr5
stem cell expansion to maintain intestinal homeostasis and prevent premalignant hyperproliferation on damage. Mechanistically, BMP inhibits stemness of Lgr5
stem cells through Smad-mediated transcriptional repression of a large number of stem cell signature genes, including Lgr5, and this effect is independent of Wnt/β-catenin signalling. Smad1/Smad4 recruits histone deacetylase HDAC1 to the promoters to repress transcription, and knockout of Smad4 abolishes the negative effects of BMP on stem cells. Our findings therefore demonstrate that epithelial BMP constrains the Lgr5
stem cell self-renewal via Smad-mediated repression of stem cell signature genes to ensure proper homeostatic renewal of intestinal epithelium.
The mammalian STE20-like protein kinase 1 (MST1)–MOB kinase activator 1 (MOB1) complex has been shown to suppress the oncogenic activity of Yes-associated protein (YAP) in the mammalian Hippo ...pathway, which is involved in the development of multiple tumors, including pancreatic cancer (PC). However, it remains unclear whether other MST–MOB complexes are also involved in regulating Hippo–YAP signaling and have potential roles in PC. Here, we report that mammalian STE20-like kinase 4 (MST4), a distantly related ortholog of the MST1 kinase, forms a complex with MOB4 in a phosphorylation-dependent manner. We found that the overall structure of the MST4–MOB4 complex resembles that of the MST1–MOB1 complex, even though the two complexes exhibited opposite biological functions in PC. In contrast to the tumor-suppressor effect of the MST1–MOB1 complex, the MST4–MOB4 complex promoted growth and migration of PANC-1 cells. Moreover, expression levels of MST4 and MOB4 were elevated in PC and were positively correlated with each other, whereas MST1 expression was down-regulated. Because of divergent evolution of key interface residues, MST4 and MOB4 could disrupt assembly of the MST1–MOB1 complex through alternative pairing and thereby increased YAP activity. Collectively, these findings identify the MST4–MOB4 complex as a noncanonical regulator of the Hippo–YAP pathway with an oncogenic role in PC. Our findings highlight that although MST–MOB complexes display some structural conservation, they functionally diverged during their evolution.
Isorhamnetin (ISO), a naturally occurring plant flavonoid, is widely used as a phytomedicine. The major treatment modality for non-small-cell lung carcinoma (NSCLC) is radiotherapy. However, ...radiotherapy can induce radioresistance in cancer cells, thereby resulting in a poor response rate. Our results demonstrated that pretreatment with ISO induced radiosensitizing effect in A549 cells using colony formation, micronucleus, and γH2AX foci assays. In addition, ISO pretreatment significantly enhanced the radiation-induced incidence of apoptosis, the collapse of mitochondrial membrane potential, and the expressions of proteins associated with cellular apoptosis and suppressed the upregulation of NF-κBp65 induced by irradiation in A549 cells. Interestingly, the expression of interleukin-13 (IL-13), an anti-inflammatory cytokine, was positively correlated with the ISO-mediated radiosensitization of A549 cells. The knockdown of IL-13 expression by RNA interference decreased the IL-13 level and thus reduced ISO-mediated radiosensitivity in cells. We also found that the IR-induced NF-κB signaling activation was inhibited by ISO pretreatment, and it was abrogated in IL-13 silenced cells. We speculated that ISO may confer radiosensitivity on A549 cells via increasing the expression of IL-13 and inhibiting the activation of NF-κB. To our knowledge, this is the first report demonstrating the effects of ISO treatment on the responsiveness of lung cancer cells to irradiation through IL-13 and the NF-κB signaling pathway. In summary, ISO is a naturally occurring radiosensitizer with a potential application in adjuvant radiotherapy.
In this paper, we consider regression models with a Hilbert-space-valued predictor and a scalar response, where the response depends on the predictor only through a finite number of projections. The ...linear subspace spanned by these projections is called the effective dimension reduction (EDR) space. To determine the dimensionality of the EDR space, we focus on the leading principal component scores of the predictor, and propose two sequential X² testing procedures under the assumption that the predictor has an elliptically contoured distribution. We further extend these procedures and introduce a test that simultaneously takes into account a large number of principal component scores. The proposed procedures are supported by theory, validated by simulation studies, and illustrated by a real-data example. Our methods and theory are applicable to functional data and high-dimensional multivariate data.
In this work, Al2O3-AlN composite ceramics with high bending strength and thermal conductivity were fabricated by Digital Light Processing (DLP). The influence of AlN content on the rheological and ...cure behavior of Al2O3-AlN suspensions, as well as the microstructure, thermal conductivity, and bending strength of Al2O3-AlN ceramics, were systematically investigated. The result shows that the viscosity and cure ability of the suspensions were decreased with the increase of AlN content, which are beneficial to the spreading and printing accuracy of the suspensions. Besides, the bending strength of ceramics can be improved due to the residual stress by the introduction of AlN. Approaches were employed to minimize the formation of AlON in Al2O3-AlN ceramics by optimizing the amount of AlN and the sintering temperature. The thermal conductivity and bending strength of Al2O3-AlN ceramics were 31.72 ± 0.45 W/(m·K) and 572.73 ± 59.40 MPa, respectively, which are much higher than those of Al2O3 ceramics fabricated under the same condition. Finally, complex-shaped Al2O3-AlN ceramics components have been successfully fabricated by DLP, which may provide an opportunity to broaden the application of Al2O3-AlN composite ceramics in heat dissipation components.
Activation of both the DNA damage response (DDR) and transforming growth factor β (TGF-β) signaling induces growth arrest of most cell types. However, it is unclear whether the DDR activates TGF-β ...signaling that in turn contributes to cell growth arrest. Here, we show that in response to DNA damage, ataxia telangiectasia mutated (ATM) stabilizes the TGF-β type II receptor (TβRII) and thus enhancement of TGF-β signaling. Mechanistically, ATM phosphorylates and stabilizes c-Cbl, which promotes TβRII neddylation and prevents its ubiquitination-dependent degradation. Consistently, DNA damage enhances the interaction among ATM, c-Cbl, and TβRII. The ATM-c-Cbl-TβRII axis plays a pivotal role in intestinal regeneration after X-ray-induced DNA damage in mouse models. Therefore, ATM not only mediates the canonical DDR pathway but also activates TGF-β signaling by stabilizing TβRII. The double brake system ensures full cell-cycle arrest, allowing efficient DNA damage repair and avoiding passage of the damaged genome to the daughter cells.
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•Upon DNA damage, ATM activates TGF-β signaling by stabilizing the receptor TβRII•ATM phosphorylates and stabilizes c-Cbl, which enhances TβRII neddylation•DNA damage enhances the interaction among ATM, c-Cbl, and TβRII•The ATM-c-Cbl-TβRII axis plays a pivotal role in intestinal regeneration
Li et al. report that DNA damage stabilizes the TGF-β receptor TβRII via ATM and c-Cbl and thus promotes TGF-β signaling. This pathway works together with the known canonical DNA damage response pathway to ensure complete cell-cycle arrest and allow efficient DNA damage repair.
Lgr5+ stem cells are crucial to gut epithelium homeostasis, and therapies targeting these cells hold promise for treatment of gastrointestinal diseases. Here we report that the non-muscle-myosin-II ...(NMII) heavy chain Myh9 accumulates at epithelial injury sites in mice distal colon treated with dextran sulphate sodium (DSS). Gut-epithelium-specific Myh9 monoallelic deletion alleviates DSS-induced colonic crypt damage and acute colitis. Consistently, the NMII inhibitor blebbistatin can improve the survival of Lgr5+ stem cells and the growth of Lgr5 organoids. Mechanistically, inhibition of NMII by blebbistatin or Myh9 monoallelic deletion activates Akt through Rac1 and PAK1, which is essential for the survival and pluripotency of Lgr5+ cells. These results establish a critical role of the Myh9-Rac1-PAK1-Akt pathway in the maintenance of Lgr5+ stem cells. As blebbistatin can mitigate DSS-induced colitis and preserve Lgr5+ colonic stem cells in vivo, our findings provide a potential therapeutic intervention of gastrointestinal epithelium injury and degenerative diseases.
This paper investigates the rate of convergence of estimating the regression weight function in a functional linear regression model. It is assumed that the predictor as well as the weight function ...are smooth and periodic in the sense that the derivatives are equal at the boundary points. Assuming that the functional data are observed at discrete points with measurement error, the complex Fourier basis is adopted in estimating the true data and the regression weight function based on the penalized least-squares criterion. The rate of convergence is then derived for both estimators. A simulation study is also provided to illustrate the numerical performance of our approach, and to make a comparison with the principal component regression approach.
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