Solar vapor generation(SVC)represents a promising technique for seawater desalination to alleviate the global water crisis and energy shortage.One of its main bottleneck problems is that the evaporation efficiency and...Solar vapor generation(SVC)represents a promising technique for seawater desalination to alleviate the global water crisis and energy shortage.One of its main bottleneck problems is that the evaporation efficiency and stability are limited by salt crystallization under high-salinity brines.Herein,we demonstrate that the 3D porous melamine-foam(MF)wrapped by a type of self-assembling composite materials based on reduced polyoxometalates(i.e.heteropoly blue,HPB),oleic acid(OA),and polypyrrole(PPy)(labeled with MF@HPB-PPy_(n)-OA)can serve as efficient and stable SVC material at high salinity.Structural characterizations of MF@HPB-PPy_(n)-OA indicate that both hydrophilic region of HPBs and hydrophobic region of OA co-exist on the surface of composite materials,optimizing the hydrophilic and hydrophobic interfaces of the SVC materials,and fully exerting its functionality for ultrahigh water-evaporation and anti-salt fouling.The optimal MF@HPB-PPy_(10)-OA operates continuously and stably for over 100 h in 10wt%brine.Furthermore,MF@HPB-PPy_(10)-OA accomplishes complete salt-water separation of 10wt%brine with 3.3kgm^(-2)h^(-1)under 1-sun irradiation,yielding salt harvesting efficiency of 96.5%,which belongs to the record high of high-salinity systems reported so far and is close to achieving zero liquid discharge.Moreover,the low cost of MF@HPB-PPy_(10)-OA(2.56$m^(-2))suggests its potential application in the practical SVC technique.展开更多
Due to the well condition and the un-expected imbalance movement of the pumping unit in use, the energy consumes a lot. The existing balancing equipment cannot adjust and monitor the pumping units in real time. Theref...Due to the well condition and the un-expected imbalance movement of the pumping unit in use, the energy consumes a lot. The existing balancing equipment cannot adjust and monitor the pumping units in real time. Therefore this paper introduces the new adaptive balancing equipment—fan-shaped adaptive balancing intelligent device, projects a design of such control system based on PLC, and determines the principle of the control system, the execution software and the design flow. Site commissioning effect on Daqing Oilfield shows this fan-shaped adaptive balancing intelligent device can effectively adjust and monitor the pumping unit in real time, the balance even adjusts from 0.787 to 0.901, and integrated energy saving rate is 14.2%. It is approved that this control device is professionally designed, with strong compatibility, and high reliability.展开更多
Shockwave detection is critical in analyzing shockwave structure and location. High speed video imaging systems are commonly used to obtain image frames during shockwave control experiments. Image edge detection algor...Shockwave detection is critical in analyzing shockwave structure and location. High speed video imaging systems are commonly used to obtain image frames during shockwave control experiments. Image edge detection algorithms become natural choices in detecting shockwaves. In this paper, a computer software system designed for shockwave detection is introduced. Different image edge detection algorithms, including Roberts, Prewitt, Sobel, Canny, and Laplacian of Gaussian, are implemented and can be chosen by the users to easily and accurately detect the shockwaves. Experimental results show that the system meets the design requirements and can accurately detect shockwave for further analysis and applications.展开更多
The population factors have an important influence on the housing market. Based on forecasting the change of population quantity, family size, age composition, and population migration, this paper estimates and analyz...The population factors have an important influence on the housing market. Based on forecasting the change of population quantity, family size, age composition, and population migration, this paper estimates and analyzes the future demand for residence in China and its purpose is to provide a guide for the residential construction by the supply-demand rule.展开更多
Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors,osteoinductive biofactors and biocompatible scaffold materials.Mesenchymal stem cells(MSCs)represent the most pro...Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors,osteoinductive biofactors and biocompatible scaffold materials.Mesenchymal stem cells(MSCs)represent the most promising seed cells for bone tissue engineering.As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat,MSCs can be isolated from numerous tissues and exhibit varied differentiation potential.To identify an optimal progenitor cell source for bone tissue engineering,we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources,including immortalized mouse embryonic fibroblasts(iMEF),immortalized mouse bone marrow stromal stem cells(imBMSC),immortalized mouse calvarial mesenchymal progenitors(iCAL),and immortalized mouse adipose-derived mesenchymal stem cells(iMAD).We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro,whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair.Transcriptomic analysis revealed that,while each MSC line regulated a distinct set of target genes upon BMP9 stimulation,all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt,TGF-β,PI3K/AKT,MAPK,Hippo and JAK-STAT pathways.Collectively,our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.展开更多
The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡcl...The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡclinical trial to treat rectal cancer.However,the precise mechanism underlying its dual-antagonistic properties remains elusive.Herein,we report crystal structures of the A_(2A)R complexed with AB928 and a selective A_(2A)R antagonist 2-118.The structures revealed a common binding mode on A_(2A)R,wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets.In contrast,the cAMP assay and A_(2A)R and A_(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A_(2B)R.Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A_(2B)R pocket,while 2-118 did not due to intrinsic differences.This disparity potentially accounted for the difference in inhibitory efficacy between A_(2B)R and A_(2A)R.This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A_(2A)R/A_(2B)R for cancer therapy.展开更多
The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across species.Wnt proteins are secreted,lipid-modified signaling molecules that activate the canoni...The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across species.Wnt proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling pathways.Cellular behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling paths.Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues.This includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem cells.Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties.Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders.Not surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including cancer.Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and metastasis.Altogether,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway.Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.展开更多
Recombinant adenovirus(rAdV)is a commonly used vector system for gene transfer.Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive,possibly attributable to rAdv inf...Recombinant adenovirus(rAdV)is a commonly used vector system for gene transfer.Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive,possibly attributable to rAdv infection-associated oxidative stress and reactive oxygen species(ROS)production.Here,we show that exogenous GAPDH expression mitigates adenovirus-induced ROS-associated apoptosis in HEK293 cells,and expedites adenovirus production.By stably overexpressing GAPDH in HEK293(293G)and 293pTP(293GP)cells,respectively,we demonstrated that rAdV-induced RoS production and cell apoptosis were significantly suppressed in 293G and 293GP cells.Transfection of 293G cells with adenoviral plasmid pAd-G2Luc yielded much higher titers of Ad-G2Luc at day 7 than that in HEK293 cells.Similarly,Ad-G2Luc was amplified more efficiently in 293G than in HEK293 cells.We further showed that transfection of 293GP cells with pAd-G2Luc produced much higher titers of Ad-G2Luc at day 5 than that of 293pTP cells.293GP cells amplified the Ad-G2Luc much more efficiently than 293pTP cells,indicating that exogenous GAPDH can further augment pTP-enhanced adenovirus production.These results demonstrate that exogenous GAPDH can effectively suppress adenovirus-induced ROS and thus accelerate adenovirus production.Therefore,the engineered 293GP cells represent a superfast rAdV production system for adenovirus-based gene transfer and gene therapy.展开更多
Wnt signaling plays a major role in regulating cell proliferation and differentiation.The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors an...Wnt signaling plays a major role in regulating cell proliferation and differentiation.The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical pathway.Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling pathways.This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes.Dys-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic lethality.The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments.However,both stimulatory and inhibitory treatments come with potential risks that need to be addressed.This review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt signaling.It thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+pathway.Further description involved each of its components and their involvement in other cellular processes.Finally,this review explained the various other pathways and processes that crosstalk with Wnt signaling.展开更多
Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of...Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding RNAs(ncRNAs).It has been shown that ncRNAs,especially long non-coding RNAs(lncRNAs),may play crucial regulatory roles in gene expression.As one of the first isolated and reported lncRNAs,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and metabolism.Mechanistically,H19 mediates diverse regulatory functions by serving as competing endogenous RNAs(CeRNAs),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mRNAs or lncRNAs.Here,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic diseases.We discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of H19.Ultimately,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.展开更多
Ovarian cancer(OC)is one of the most lethal malignancies of the female reproduc-tive system.OC patients are usually diagnosed at advanced stages due to the lack of early diag-nosis.The standard treatment for OC includ...Ovarian cancer(OC)is one of the most lethal malignancies of the female reproduc-tive system.OC patients are usually diagnosed at advanced stages due to the lack of early diag-nosis.The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy,while several targeted therapies have recently been approved for maintenance treatment.The vast majority of OC patients relapse with chemoresistant tu-mors after an initial response.Thus,there is an unmet clinical need to develop new therapeu-tic agents to overcome the chemoresistance of OC.The anti-parasite agent niclosamide(NA)has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC.Here,we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant(CR)in human OC cells.To this end,we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer.We showed that NA inhibited cell proliferation,sup-pressed cell migration,and induced cell apoptosis in both CR lines at a low micromole range.Mechanistically,NA inhibited multiple cancer-related pathways including AP1,ELK/SRF,HIF1,and TCF/LEF,in SKOV3CR and OVCAR8CR cells.NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells.Collectively,our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant hu-man OC,and further clinical trials are highly warranted.展开更多
因具有高安全性和高性价比的优势,水系锌离子电池(AZIBs)成为了当前研究的热点.然而,电极材料溶解、固有电导率低、反应动力学慢等问题严重阻碍了其实际应用.在本文中,我们合成了一种在黑色素瘤治疗中发挥重要作用的含硫有机小分子(seri...因具有高安全性和高性价比的优势,水系锌离子电池(AZIBs)成为了当前研究的热点.然而,电极材料溶解、固有电导率低、反应动力学慢等问题严重阻碍了其实际应用.在本文中,我们合成了一种在黑色素瘤治疗中发挥重要作用的含硫有机小分子(seriniquinone,SQ),将其作为电极材料应用于锌离子电池.通过导电碳修饰的方法制备了SQ/CMK-3复合电极,进一步解决了活性物质SQ的溶解问题并提高了其导电性.在Zn||SQ/CMK-3半电池中,SQ/CMK-3正极在100 mA g^(−1)电流密度下的初始放电比容量达到234.4 mA h g^(−1).在1 A g^(−1)的高电流密度下经过5000次超长循环后,比容量仍保持100.2 mA h g^(−1).此外,通过密度泛函理论计算,我们提出了在两个SQ分子之间嵌入四个Zn^(2+)的储存机理,并通过多种非原位表征测试进行了证实.在采用SQ/CMK-3复合材料作为正负两极的全有机对称电池中,SQ不仅在100 mA g^(−1)的电流密度下获得高达110.9 mA h g^(−1)的可逆比容量,而且在循环2500次后具有82.4%的稳定容量保持率和99.5%的平均库仑效率.展开更多
3D printing technology has great potential for the reconstruction of human skin.However,the reconstructed skin has some differences from natural skin,largely because the hydrogel used does not have the appropriate bio...3D printing technology has great potential for the reconstruction of human skin.However,the reconstructed skin has some differences from natural skin,largely because the hydrogel used does not have the appropriate biological and physical properties to allow healing and regeneration.This study examines the swelling,degradability,microstructure and biological properties of Collagen/Sodium Alginate(Col/SA)hydrogels of differing compositions for the purposes of skin printing.Increasing the content of sodium alginate causes the hydrogel to exhibit stronger mechanical and swelling properties,a faster degradation ratio,smaller pore size,and less favorable biological properties.An optimal 1%collagen hydrogel was used to print bi-layer skin in which fibroblasts and keratinocytes showed improved spreading and proliferation as compared to other developed formulations.The Col/SA hydrogels presented suitable tunability and properties to be used as a bioink for bioprinting of skin aiming at finding applications as 3D models for wound healing research.展开更多
Adult neurogenesis occurs in two specialized regions of the mammalian brain,the subventricular zone(SVZ)and the subgranular zone(SGZ)of the dentate gyrus(DG).^(1)Adult hippocampal neural stem cells(NSCs),referred to a...Adult neurogenesis occurs in two specialized regions of the mammalian brain,the subventricular zone(SVZ)and the subgranular zone(SGZ)of the dentate gyrus(DG).^(1)Adult hippocampal neural stem cells(NSCs),referred to as Type 1 cells represented by radial glia-like cells(RGLs),generate Type 2 cells that are divided into Type 2a and Type 2 b subpopulations,the latter of which give rise to Type 3 cells(neuroblasts).展开更多
Specialized therapeutic delivery, or use of pharmaceuticals and other biomaterials to target specific parts of the body or diseased tissue, has long been sought as an ideal way of treating human diseases. A recent art...Specialized therapeutic delivery, or use of pharmaceuticals and other biomaterials to target specific parts of the body or diseased tissue, has long been sought as an ideal way of treating human diseases. A recent article published in Nature Biomedical Engineering revealed an innovative strategy to engineer nucleus-free human mesenchymal stem cells (MSCs) for targeted delivery of therapeutics to disease site.1 MSCs have emerged as promising vehicles of therapeutic delivery.2,3 MSCs are undifferentiated pluripotent stem cells derived from areas such as bone marrow and adipose tissue.4,5 MSCs are sought after for their chemotaxis, or ability to home towards a chemical stimulus, and capacity for modification with elements such as chemoattractant receptors and adhesion molecules.1 These properties allow for site-specific and minimally-invasive therapeutic administration and treatment.展开更多
基金financially supported by the National Key Basic Research Program of China(grant no.2020YFA0406101)National Natural Science Foundation of China(grant nos.22171041,22071020,21901035,22271043)+1 种基金Natural Science Foundation of Jilin Province Science and Technology Department(grant nos.20230508094RC,20220101045JC)the Fundamental Research Funds for the Central Universities(grant no.2412021QD008)
文摘Solar vapor generation(SVC)represents a promising technique for seawater desalination to alleviate the global water crisis and energy shortage.One of its main bottleneck problems is that the evaporation efficiency and stability are limited by salt crystallization under high-salinity brines.Herein,we demonstrate that the 3D porous melamine-foam(MF)wrapped by a type of self-assembling composite materials based on reduced polyoxometalates(i.e.heteropoly blue,HPB),oleic acid(OA),and polypyrrole(PPy)(labeled with MF@HPB-PPy_(n)-OA)can serve as efficient and stable SVC material at high salinity.Structural characterizations of MF@HPB-PPy_(n)-OA indicate that both hydrophilic region of HPBs and hydrophobic region of OA co-exist on the surface of composite materials,optimizing the hydrophilic and hydrophobic interfaces of the SVC materials,and fully exerting its functionality for ultrahigh water-evaporation and anti-salt fouling.The optimal MF@HPB-PPy_(10)-OA operates continuously and stably for over 100 h in 10wt%brine.Furthermore,MF@HPB-PPy_(10)-OA accomplishes complete salt-water separation of 10wt%brine with 3.3kgm^(-2)h^(-1)under 1-sun irradiation,yielding salt harvesting efficiency of 96.5%,which belongs to the record high of high-salinity systems reported so far and is close to achieving zero liquid discharge.Moreover,the low cost of MF@HPB-PPy_(10)-OA(2.56$m^(-2))suggests its potential application in the practical SVC technique.
文摘Due to the well condition and the un-expected imbalance movement of the pumping unit in use, the energy consumes a lot. The existing balancing equipment cannot adjust and monitor the pumping units in real time. Therefore this paper introduces the new adaptive balancing equipment—fan-shaped adaptive balancing intelligent device, projects a design of such control system based on PLC, and determines the principle of the control system, the execution software and the design flow. Site commissioning effect on Daqing Oilfield shows this fan-shaped adaptive balancing intelligent device can effectively adjust and monitor the pumping unit in real time, the balance even adjusts from 0.787 to 0.901, and integrated energy saving rate is 14.2%. It is approved that this control device is professionally designed, with strong compatibility, and high reliability.
文摘Shockwave detection is critical in analyzing shockwave structure and location. High speed video imaging systems are commonly used to obtain image frames during shockwave control experiments. Image edge detection algorithms become natural choices in detecting shockwaves. In this paper, a computer software system designed for shockwave detection is introduced. Different image edge detection algorithms, including Roberts, Prewitt, Sobel, Canny, and Laplacian of Gaussian, are implemented and can be chosen by the users to easily and accurately detect the shockwaves. Experimental results show that the system meets the design requirements and can accurately detect shockwave for further analysis and applications.
文摘The population factors have an important influence on the housing market. Based on forecasting the change of population quantity, family size, age composition, and population migration, this paper estimates and analyzes the future demand for residence in China and its purpose is to provide a guide for the residential construction by the supply-demand rule.
基金by research grants from the Natural Science Foundation of China(82102696 to JF)the Chongqing Bayu Young Scholar Award(JF),the 2019 Chongqing Support Program for Entrepreneurship and Innovation(No.cx2019113 to JF)+4 种基金the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298 to JF),the National Institutes of Health(CA226303 to TCH,and DE030480 to RRR)supported by the Medical Scientist Training Program of the National Institutes of Health(T32 GM007281)supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1TR002389-07.
文摘Effective bone regeneration through tissue engineering requires a combination of osteogenic progenitors,osteoinductive biofactors and biocompatible scaffold materials.Mesenchymal stem cells(MSCs)represent the most promising seed cells for bone tissue engineering.As multipotent stem cells that can self-renew and differentiate into multiple lineages including bone and fat,MSCs can be isolated from numerous tissues and exhibit varied differentiation potential.To identify an optimal progenitor cell source for bone tissue engineering,we analyzed the proliferative activity and osteogenic potential of four commonly-used mouse MSC sources,including immortalized mouse embryonic fibroblasts(iMEF),immortalized mouse bone marrow stromal stem cells(imBMSC),immortalized mouse calvarial mesenchymal progenitors(iCAL),and immortalized mouse adipose-derived mesenchymal stem cells(iMAD).We found that iMAD exhibited highest osteogenic and adipogenic capabilities upon BMP9 stimulation in vitro,whereas iMAD and iCAL exhibited highest osteogenic capability in BMP9-induced ectopic osteogenesis and critical-sized calvarial defect repair.Transcriptomic analysis revealed that,while each MSC line regulated a distinct set of target genes upon BMP9 stimulation,all MSC lines underwent osteogenic differentiation by regulating osteogenesis-related signaling including Wnt,TGF-β,PI3K/AKT,MAPK,Hippo and JAK-STAT pathways.Collectively,our results demonstrate that adipose-derived MSCs represent optimal progenitor sources for cell-based bone tissue engineering.
基金supported by the National Key Research and Development Program of China(2018YFA0507001)the Basic Research Program of Science and Technology Commission of Shanghai Municipality(21JC1402400)+1 种基金the National Natural Science Foundation of China(32171215,81972828,82172644,82273857 and 81830083)the National Key Scientific Infrastructure for Translational Medicine(Shanghai)(TMSK-2021-120)。
文摘The adenosine subfamily G protein-coupled receptors A_(2A)R and A_(2B)R have been identified as promising cancer immunotherapy candidates.One of the A_(2A)R/A_(2B)R dual antagonists,AB928,has progressed to a phaseⅡclinical trial to treat rectal cancer.However,the precise mechanism underlying its dual-antagonistic properties remains elusive.Herein,we report crystal structures of the A_(2A)R complexed with AB928 and a selective A_(2A)R antagonist 2-118.The structures revealed a common binding mode on A_(2A)R,wherein the ligands established extensive interactions with residues from the orthosteric and secondary pockets.In contrast,the cAMP assay and A_(2A)R and A_(2B)R molecular dynamics simulations indicated that the ligands adopted distinct binding modes on A_(2B)R.Detailed analysis of their chemical structures suggested that AB928 readily adapted to the A_(2B)R pocket,while 2-118 did not due to intrinsic differences.This disparity potentially accounted for the difference in inhibitory efficacy between A_(2B)R and A_(2A)R.This study serves as a valuable structural template for the future development of selective or dual inhibitors targeting A_(2A)R/A_(2B)R for cancer therapy.
基金supported in part by research grants from the National Institutes of Health(No.CA226303 to TCH and No.DE030480 to RRR)JF was supported in part by research grants from the Natural Science Foundation of China(No.82102696)+4 种基金the 2019 Science and Technology Research Plan Project of Chongqing Education Commission(China)(No.KJQN201900410)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298,Chongqing,China)WW was supported by the Medical Scientist Training Program of the National Institutes of Health(No.T32 GM007281)This project was also supported in part by The University of Chicago Cancer Center Support Grant(No.P30CA014599)the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health(No.5UL1TR002389).
文摘The evolutionarily conserved Wnt signaling pathway plays a central role in develop-ment and adult tissue homeostasis across species.Wnt proteins are secreted,lipid-modified signaling molecules that activate the canonical(β-catenin dependent)and non-canonical(β-catenin independent)Wnt signaling pathways.Cellular behaviors such as proliferation,differ-entiation,maturation,and proper body-axis specification are carried out by the canonical pathway,which is the best characterized of the known Wnt signaling paths.Wnt signaling has emerged as an important factor in stem cell biology and is known to affect the self-renewal of stem cells in various tissues.This includes but is not limited to embryonic,hematopoietic,mesenchymal,gut,neural,and epidermal stem cells.Wnt signaling has also been implicated in tumor cells that exhibit stem cell-like properties.Wnt signaling is crucial for bone formation and presents a potential target for the development of therapeutics for bone disorders.Not surprisingly,aberrant Wnt signaling is also associated with a wide variety of diseases,including cancer.Mutations of Wnt pathway members in cancer can lead to unchecked cell proliferation,epithelial-mesenchymal transition,and metastasis.Altogether,advances in the understand-ing of dysregulated Wnt signaling in disease have paved the way for the development of novel therapeutics that target components of the Wnt pathway.Beginning with a brief overview of the mechanisms of canonical and non-canonical Wnt,this review aims to summarize the cur-rent knowledge of Wnt signaling in stem cells,aberrations to the Wnt pathway associated with diseases,and novel therapeutics targeting the Wnt pathway in preclinical and clinical studies.
基金supported in part by research grants from the Natural Science Foundation of China (No.82000744 to ZT,and 82102696 to J.F.)the Chongqing Bayu Young Scholar Award (China) (to J.F.)+5 种基金the 2019 Funding for Postdoctoral Research (Chongqing Human Resources and Social Security Bureau of China) (No.298 to J.F.)the National Institutes of Health (No.CA226303 to T.C.H.,DE030480 to R.R.R.)supported by the Medical Scientist Training Program of the National Institutes of Health (USA) (No.T32 GM007281)supported in part by The University of Chicago Cancer Center Support Grant (No.P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through grant number 2UL1TR002389-06 that funds the Institute for Translational Medicine (ITM)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Recombinant adenovirus(rAdV)is a commonly used vector system for gene transfer.Efficient initial packaging and subsequent production of rAdV remains time-consuming and labor-intensive,possibly attributable to rAdv infection-associated oxidative stress and reactive oxygen species(ROS)production.Here,we show that exogenous GAPDH expression mitigates adenovirus-induced ROS-associated apoptosis in HEK293 cells,and expedites adenovirus production.By stably overexpressing GAPDH in HEK293(293G)and 293pTP(293GP)cells,respectively,we demonstrated that rAdV-induced RoS production and cell apoptosis were significantly suppressed in 293G and 293GP cells.Transfection of 293G cells with adenoviral plasmid pAd-G2Luc yielded much higher titers of Ad-G2Luc at day 7 than that in HEK293 cells.Similarly,Ad-G2Luc was amplified more efficiently in 293G than in HEK293 cells.We further showed that transfection of 293GP cells with pAd-G2Luc produced much higher titers of Ad-G2Luc at day 5 than that of 293pTP cells.293GP cells amplified the Ad-G2Luc much more efficiently than 293pTP cells,indicating that exogenous GAPDH can further augment pTP-enhanced adenovirus production.These results demonstrate that exogenous GAPDH can effectively suppress adenovirus-induced ROS and thus accelerate adenovirus production.Therefore,the engineered 293GP cells represent a superfast rAdV production system for adenovirus-based gene transfer and gene therapy.
基金supported in part by research grants from the National Institutes of Health(No.CA226303 to TCH and No.DE030480 to RRR)the American Shoulder and Elbow Surgeons PJI Research Grant(LLS).JF was supported in part by research grants from the Natural Science Foundation of China(No.82102696)+4 种基金the 2019 Science and Technology Research Plan Project of Chongqing Education Commission(China)(No.KJQN201900410)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298)WW was supported by the Medical Scientist Training Program of the National Institutes of Health(No.T32 GM007281)This project was also supported in partby The University of Chicago Cancer Center Support Grant(No.P30CA014599)the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health through Grant Number 5UL1TR002389.
文摘Wnt signaling plays a major role in regulating cell proliferation and differentiation.The Wnt ligands are a family of 19 secreted glycoproteins that mediate their signaling effects via binding to Frizzled receptors and LRP5/6 coreceptors and transducing the signal either throughβ-catenin in the canonical pathway or through a series of other proteins in the nonca-nonical pathway.Many of the individual components of both canonical and noncanonical Wnt signaling have additional functions throughout the body,establishing the complex interplay between Wnt signaling and other signaling pathways.This crosstalk between Wnt signaling and other pathways gives Wnt signaling a vital role in many cellular and organ processes.Dys-regulation of this system has been implicated in many diseases affecting a wide array of organ systems,including cancer and embryological defects,and can even cause embryonic lethality.The complexity of this system and its interacting proteins have made Wnt signaling a target for many therapeutic treatments.However,both stimulatory and inhibitory treatments come with potential risks that need to be addressed.This review synthesized much of the current knowl-edge on the Wnt signaling pathway,beginning with the history of Wnt signaling.It thoroughly described the different variants of Wnt signaling,including canonical,noncanonical Wnt/PCP,and the noncanonical Wnt/Ca2+pathway.Further description involved each of its components and their involvement in other cellular processes.Finally,this review explained the various other pathways and processes that crosstalk with Wnt signaling.
基金supported by the National Natural Science Foundation of China(NSFC)(No.82002312,81972069)supported in part by research grants from the National Institutes of Health,USA(No.CA226303 to TCH,No.DE030480 to RRR)+10 种基金supported by the Science and Technology Research Program of Chongqing Education Commission,China(No.KJQN202100431,KJZD-M202100401)the Top Talent Award from The First Affiliated Hospital of Chongqing Medical University,China(No.BJRC2021-04)Cultivation Program of Postdoctoral Research of The First Affiliated Hospital of Chongqing Medical University,China(No.CYYY-BSHPYXM-202202)supported by a post-doctoral fellowship from Chongqing Medical University and rewarded by China Postdoctoral Science Foundation(No.2022M720605)supported in part by research grants from the 2019 Science and Technology Project of Chongqing Education Commission,China(No.KJQN201900410)the 2019 Funding for Postdoctoral Research(Chongqing Human Resources and Social Security Bureau No.298)the Natural Science Foundation of China(No.82102696)supported by the Medical Scientist Training Program of the National Institutes of Health,USA(No.T32 GM007281)supported in part by The University of Chicago Cancer Center Support Grant,USA(No.P30CA014599)the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health,USA(No.5UL1TR002389)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopedics Alumni Fund.
文摘Recent advances in deep sequencing technologies have revealed that,while less than 2%of the human genome is transcribed into mRNA for protein synthesis,over 80%of the genome is transcribed,leading to the production of large amounts of noncoding RNAs(ncRNAs).It has been shown that ncRNAs,especially long non-coding RNAs(lncRNAs),may play crucial regulatory roles in gene expression.As one of the first isolated and reported lncRNAs,H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis,development,tumorigenesis,osteogen-esis,and metabolism.Mechanistically,H19 mediates diverse regulatory functions by serving as competing endogenous RNAs(CeRNAs),Igf2/H19 imprinted tandem gene,modular scaffold,cooperating with H19 antisense,and acting directly with other mRNAs or lncRNAs.Here,we summarized the current understanding of H19 in embryogenesis and development,cancer development and progression,mesenchymal stem cell lineage-specific differentiation,and metabolic diseases.We discussed the potential regulatory mechanisms underlying H19’s func-tions in those processes although more in-depth studies are warranted to delineate the exact molecular,cellular,epigenetic,and genomic regulatory mechanisms underlying the physiolog-ical and pathological roles of H19.Ultimately,these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.
基金supported in part by research grants from the National Institutes of Health(No.CA226303 to TCH,No.DE030480 to RRR)supported by the Medical Scientist Training Program of the National Institutes of Health(USA)(No.T32 GM007281)+2 种基金supported in part by The University of Chicago Cancer Center Support Grant(No.P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health(USA)(No.UL1 TR000430)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Ovarian cancer(OC)is one of the most lethal malignancies of the female reproduc-tive system.OC patients are usually diagnosed at advanced stages due to the lack of early diag-nosis.The standard treatment for OC includes a combination of debulking surgery and platinum-taxane chemotherapy,while several targeted therapies have recently been approved for maintenance treatment.The vast majority of OC patients relapse with chemoresistant tu-mors after an initial response.Thus,there is an unmet clinical need to develop new therapeu-tic agents to overcome the chemoresistance of OC.The anti-parasite agent niclosamide(NA)has been repurposed as an anti-cancer agent and exerts potent anti-cancer activities in human cancers including OC.Here,we investigated whether NA could be repurposed as a therapeutic agent to overcome cisplatin-resistant(CR)in human OC cells.To this end,we first established two CR lines SKOV3CR and OVCAR8CR that exhibit the essential biological characteristics of cisplatin resistance in human cancer.We showed that NA inhibited cell proliferation,sup-pressed cell migration,and induced cell apoptosis in both CR lines at a low micromole range.Mechanistically,NA inhibited multiple cancer-related pathways including AP1,ELK/SRF,HIF1,and TCF/LEF,in SKOV3CR and OVCAR8CR cells.NA was further shown to effectively inhibit xenograft tumor growth of SKOV3CR cells.Collectively,our findings strongly suggest that NA may be repurposed as an efficacious agent to combat cisplatin resistance in chemoresistant hu-man OC,and further clinical trials are highly warranted.
基金financially supported by the National Natural Science Foundation of China (21875206 and 21403187)the Subsidy for Hebei Key Laboratory of Applied Chemistry after Operation Performance (22567616H)+1 种基金the Open Project in the Key Laboratory of Advanced Energy Materials Chemistry (Nankai University)the Postgraduate Innovation Funding Project of Hebei Province (CXZZBS2022144)
文摘因具有高安全性和高性价比的优势,水系锌离子电池(AZIBs)成为了当前研究的热点.然而,电极材料溶解、固有电导率低、反应动力学慢等问题严重阻碍了其实际应用.在本文中,我们合成了一种在黑色素瘤治疗中发挥重要作用的含硫有机小分子(seriniquinone,SQ),将其作为电极材料应用于锌离子电池.通过导电碳修饰的方法制备了SQ/CMK-3复合电极,进一步解决了活性物质SQ的溶解问题并提高了其导电性.在Zn||SQ/CMK-3半电池中,SQ/CMK-3正极在100 mA g^(−1)电流密度下的初始放电比容量达到234.4 mA h g^(−1).在1 A g^(−1)的高电流密度下经过5000次超长循环后,比容量仍保持100.2 mA h g^(−1).此外,通过密度泛函理论计算,我们提出了在两个SQ分子之间嵌入四个Zn^(2+)的储存机理,并通过多种非原位表征测试进行了证实.在采用SQ/CMK-3复合材料作为正负两极的全有机对称电池中,SQ不仅在100 mA g^(−1)的电流密度下获得高达110.9 mA h g^(−1)的可逆比容量,而且在循环2500次后具有82.4%的稳定容量保持率和99.5%的平均库仑效率.
基金funded by the National Key R&D Program of China(2018YFE0207900)People's Liberation Army(BWS17J036,18-163-13-ZT-003-011-01)+2 种基金the National Natural Science Foundation of China(51835010 and 51375371)Xi’an Science and Technology Plan Project(21ZCZZHXJS-QCY6-0012)Shaanxi Science and Technology Project(2022KXJ-147)。
文摘3D printing technology has great potential for the reconstruction of human skin.However,the reconstructed skin has some differences from natural skin,largely because the hydrogel used does not have the appropriate biological and physical properties to allow healing and regeneration.This study examines the swelling,degradability,microstructure and biological properties of Collagen/Sodium Alginate(Col/SA)hydrogels of differing compositions for the purposes of skin printing.Increasing the content of sodium alginate causes the hydrogel to exhibit stronger mechanical and swelling properties,a faster degradation ratio,smaller pore size,and less favorable biological properties.An optimal 1%collagen hydrogel was used to print bi-layer skin in which fibroblasts and keratinocytes showed improved spreading and proliferation as compared to other developed formulations.The Col/SA hydrogels presented suitable tunability and properties to be used as a bioink for bioprinting of skin aiming at finding applications as 3D models for wound healing research.
基金supported in part by research grants from the National Institutes of Health(USA)(CA226303 to TCH,DE030480 to RRR)supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)+1 种基金the National Center for Advancing Translational Sciences of the National Institutes of Health(USA)(No.5UL1TR002389)supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund(USA).
文摘Adult neurogenesis occurs in two specialized regions of the mammalian brain,the subventricular zone(SVZ)and the subgranular zone(SGZ)of the dentate gyrus(DG).^(1)Adult hippocampal neural stem cells(NSCs),referred to as Type 1 cells represented by radial glia-like cells(RGLs),generate Type 2 cells that are divided into Type 2a and Type 2 b subpopulations,the latter of which give rise to Type 3 cells(neuroblasts).
基金supported in part by research grants from the National Institutes of Health(No.CA226303 to TCH and No.DE030480 to RRR)supported in part by The University of Chicago Cancer Center Support Grant(No.P30CA014599)+1 种基金the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health(No.5UL1TR002389)TCH was also supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.Funding sources were not involved in the study design。
文摘Specialized therapeutic delivery, or use of pharmaceuticals and other biomaterials to target specific parts of the body or diseased tissue, has long been sought as an ideal way of treating human diseases. A recent article published in Nature Biomedical Engineering revealed an innovative strategy to engineer nucleus-free human mesenchymal stem cells (MSCs) for targeted delivery of therapeutics to disease site.1 MSCs have emerged as promising vehicles of therapeutic delivery.2,3 MSCs are undifferentiated pluripotent stem cells derived from areas such as bone marrow and adipose tissue.4,5 MSCs are sought after for their chemotaxis, or ability to home towards a chemical stimulus, and capacity for modification with elements such as chemoattractant receptors and adhesion molecules.1 These properties allow for site-specific and minimally-invasive therapeutic administration and treatment.
