Odontogenic keratocysts(OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome(NBCCS). OKCs are locally aggressive, ca...Odontogenic keratocysts(OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome(NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations(at ～80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog(SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1^(R135 X/+) cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403 C>T(p.R135 X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated 9(Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 R135 X/+heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.展开更多
Li–S batteries(LSBs)are promising next-generation energy-storage devices due to their high theoretical capacity and cost effectiveness.However,the widespread use of LSBs is still impeded by the low conductivity of su...Li–S batteries(LSBs)are promising next-generation energy-storage devices due to their high theoretical capacity and cost effectiveness.However,the widespread use of LSBs is still impeded by the low conductivity of sulfur,the volume expansion of active materials,and the shuttle effect of lithium polysulfides(LiPSs)in practical conditions.In this work,a novel sulfur matrix integrating self-branched Nb_(2)O_(5)nanoarrays and flexible carbon cloth(NBCC)is designed and prepared.The conformal S@NBCC composite provides surface-to-surface contact between sulfur and the catalytic mediator,thus exposing more active sites for trapping LiPSs.Meanwhile,the selected Nb_(2)O_(5)nanoarrays with ultrafast Li+motion capability can work as“electron-ion reservoirs”to further accelerate the conversion reaction of LiPSs.Moreover,the extra-free space among the branched nanoarrays can not only facilitate the infiltration of the liquid electrolyte,but also enhance its tolerance to volume expansion of sulfur during the lithiation process.Benefitting from these synergistic effects,the self-supported S@NBCC shows a high specific capacity of 1262.5 mA h g^(−1)at 0.1 C and maintains an impressive specific capacity of 759.6 mA h g^(−1)even after 300 cycles at 1 C,showing great potential in promoting the practical application of flexible LSBs.展开更多
基金supported by the National Natural Science Foundation of China (81671006, 81300894)Beijing Natural Science Foundation (7172238)
文摘Odontogenic keratocysts(OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome(NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations(at ～80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog(SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1^(R135 X/+) cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403 C>T(p.R135 X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated 9(Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 R135 X/+heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.
基金financial support of the National Natural Science Foundation of China(Grant No.51902089,21773059,and 21873026)the China Postdoctoral Science Foundation(2018M640676)+1 种基金the Postdoctoral research grant in Henan Province(001703066)the 111 Project(D17007).
文摘Li–S batteries(LSBs)are promising next-generation energy-storage devices due to their high theoretical capacity and cost effectiveness.However,the widespread use of LSBs is still impeded by the low conductivity of sulfur,the volume expansion of active materials,and the shuttle effect of lithium polysulfides(LiPSs)in practical conditions.In this work,a novel sulfur matrix integrating self-branched Nb_(2)O_(5)nanoarrays and flexible carbon cloth(NBCC)is designed and prepared.The conformal S@NBCC composite provides surface-to-surface contact between sulfur and the catalytic mediator,thus exposing more active sites for trapping LiPSs.Meanwhile,the selected Nb_(2)O_(5)nanoarrays with ultrafast Li+motion capability can work as“electron-ion reservoirs”to further accelerate the conversion reaction of LiPSs.Moreover,the extra-free space among the branched nanoarrays can not only facilitate the infiltration of the liquid electrolyte,but also enhance its tolerance to volume expansion of sulfur during the lithiation process.Benefitting from these synergistic effects,the self-supported S@NBCC shows a high specific capacity of 1262.5 mA h g^(−1)at 0.1 C and maintains an impressive specific capacity of 759.6 mA h g^(−1)even after 300 cycles at 1 C,showing great potential in promoting the practical application of flexible LSBs.
