Bone Morphogenetic Proteins(BMPs)are a group of signaling molecules that belongs to the Transforming Growth Factor-b(TGF-b)superfamily of proteins.Initially discovered for their ability to induce bone formation,BMPs a...Bone Morphogenetic Proteins(BMPs)are a group of signaling molecules that belongs to the Transforming Growth Factor-b(TGF-b)superfamily of proteins.Initially discovered for their ability to induce bone formation,BMPs are now known to play crucial roles in all organ systems.BMPs are important in embryogenesis and development,and also in maintenance of adult tissue homeostasis.Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects,highlighting the essential functions of BMPs.In this review,we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development.A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling.展开更多
We report an improved measurement of the neutrino mixing angle θ13 from the Daya Bay Reactor Neutrino Experiment. We exclude a zero value for sin22θ13 with a significance of 7.7 standard deviations. Electron antineu...We report an improved measurement of the neutrino mixing angle θ13 from the Daya Bay Reactor Neutrino Experiment. We exclude a zero value for sin22θ13 with a significance of 7.7 standard deviations. Electron antineutrinos from six reactors of 2.9 GWm th were detected in six antineutrino detectors deployed in two near （flux-weighted baselines of 470 m and 576 m） and one far （1648 m） underground experimental halls. Using 139 days of data, 28909 （205308） electron antineutrino candidates were detected at the far hall （near halls）. The ratio of the observed to the expected number of antineutrinos assuming no oscillations at the far hall is 0.944± 0.007（stat.） ± 0.003（syst.）. An analysis of the relative rates in six detectors finds sin22θ13=0.089± 0.010（stat.）±0.005（syst.） in a three-neutrino framework.展开更多
With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become ava...With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies.Despite numerous setbacks,efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases.It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies.There has been a long-lasting interest in using viral vectors,especially adenoviral vectors,to deliver therapeutic genes for the past two decades.Among all currently available viral vectors,adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types.The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development.In fact,among over 2000 gene therapy clinical trials approved worldwide since 1989,a significant portion of the trials have utilized adenoviral vectors.This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors,including adenoviral biology,approaches to engineering adenoviral vectors,and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment,vaccination and regenerative medicine.Current challenges and future directions regarding the use of adenoviral vectors are also discussed.It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.展开更多
Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and c...Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and critical array of biological roles.These roles include regulating skeletal and bone formation,angiogenesis,and development and homeostasis of multiple organ systems.Disruptions of the members of the TGF-b/BMP superfamily result in severe skeletal and extra-skeletal irregularities,suggesting high therapeutic potential from understanding this family of BMP proteins.Although it was once one of the least characterized BMPs,BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo,with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs.The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants,revealing the great translational promise of BMP9.Furthermore,emerging evidence indicates that,besides its osteogenic activity,BMP9 exerts a broad range of biological functions,including stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism.This review aims to summarize our current understanding of BMP9 across biology and the body.展开更多
Tooth is a complex hard tissue organ and consists of multiple cell types that are regulated by important signaling pathways such as Wnt and BMP signaling.Serious injuries and/or loss of tooth or periodontal tissues ma...Tooth is a complex hard tissue organ and consists of multiple cell types that are regulated by important signaling pathways such as Wnt and BMP signaling.Serious injuries and/or loss of tooth or periodontal tissues may significantly impact aesthetic appearance,essential oral functions and the quality of life.Regenerative dentistry holds great promise in treating oral/dental disorders.The past decade has witnessed a rapid expansion of our understanding of the biological features of dental stem cells,along with the signaling mechanisms governing stem cell self-renewal and differentiation.In this review,we first summarize the biological characteristics of seven types of dental stem cells,including dental pulp stem cells,stem cells from apical papilla,stem cells from human exfoliated deciduous teeth,dental follicle precursor cells,periodontal ligament stem cells,alveolar bone-derived mesenchymal stem cells(MSCs),and MSCs from gingiva.We then focus on how these stem cells are regulated by bone morphogenetic protein(BMP)and/or Wnt signaling by examining the interplays between these pathways.Lastly,we analyze the current status of dental tissue engineering strategies that utilize oral/dental stem cells by harnessing the interplays between BMP and Wnt pathways.We also highlight the challenges that must be addressed before the dental stem cells may reach any clinical applications.Thus,we can expect to witness significant progresses to be made in regenerative dentistry in the coming decade.展开更多
The transcription factor Sox9 was first discovered in patients with campomelic dysplasia,a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis.Since t...The transcription factor Sox9 was first discovered in patients with campomelic dysplasia,a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis.Since then,its role as a cell fate determiner during embryonic development has been well characterized;Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs.However,recent data has shown that ectoderm-and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools,suggesting its role in cell maintenance and specification during adult life.The versatility of Sox9 may be explained by a combination of posttranscriptional modifications,binding partners,and the tissue type in which it is expressed.Considering its importance during both development and adult life,it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases,including fibrosis and cancer.This review provides a summary of the various roles of Sox9 in cell fate specification,stem cell biology,and related human diseases.Ultimately,understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage.展开更多
Mesenchymal stem cells(MSCs)are ubiquitously-existing multipotent progenitors that can self-renew and differentiate into multiple lineages including osteocytes,chondrocytes,adipocytes,tenocytes and myocytes.MSCs repre...Mesenchymal stem cells(MSCs)are ubiquitously-existing multipotent progenitors that can self-renew and differentiate into multiple lineages including osteocytes,chondrocytes,adipocytes,tenocytes and myocytes.MSCs represent one of the most commonly-used adult progenitors and serve as excellent progenitor cell models for investigating lineagespecific differentiation regulated by various cellular signaling pathways,such as bone morphogenetic proteins(BMPs).As members of TGFb superfamily,BMPs play diverse and important roles in development and adult tissues.At least 14 BMPs have been identified in mammals.Different BMPs exert distinct but overlapping biological functions.Through a comprehensive analysis of 14 BMPs in MSCs,we demonstrated that BMP9 is one of the most potent BMPs in inducing osteogenic differentiation of MSCs.Nonetheless,a global mechanistic view of BMP signaling in regulating the proliferation and differentiation of MSCs remains to be fully elucidated.Here,we conducted a comprehensive transcriptomic profiling in the MSCs stimulated by 14 types of BMPs.Hierarchical clustering analysis classifies 14 BMPs into three subclusters:an osteo/chondrogenic/adipogenic cluster,a tenogenic cluster,and BMP3 cluster.We also demonstrate that six BMPs(e.g.,BMP2,BMP3,BMP4,BMP7,BMP8,and BMP9)can induce ISmads effectively,while BMP2,BMP3,BMP4,BMP7,and BMP11 up-regulate Smad-independent MAP kinase pathway.Furthermore,we show that many BMPs can upregulate the expression of the signal mediators of Wnt,Notch and PI3K/AKT/mTOR pathways.While the reported transcriptomic changes need to be further validated,our expression profiling represents the first-of-its-kind to interrogate a comprehensive transcriptomic landscape regulated by the 14 types of BMPs in MSCs.展开更多
Over recent decades, many studies have reported that hypocrellin A(HA) can eliminate cancer cells with proper irradiation in several cancer cell lines. However, the precise molecular mechanism underlying its anticance...Over recent decades, many studies have reported that hypocrellin A(HA) can eliminate cancer cells with proper irradiation in several cancer cell lines. However, the precise molecular mechanism underlying its anticancer effect has not been fully defined. HA-mediated cytotoxicity and apoptosis in human lung adenocarcinoma A549 cells were evaluated after photodynamic therapy(PDT). A temporal quantitative proteomics approach by isobaric tag for relative and absolute quantitation(iTRAQ) 2 D liquid chromatography with tandem mass spectrometric(LC–MS/MS) was introduced to help clarify molecular cytotoxic mechanisms and identify candidate targets of HA-induced apoptotic cell death. Specific caspaseinhibitors were used to further elucidate the molecular pathway underlying apoptosis in PDT-treated A549 cells. Finally, down-stream apoptosis-related protein was evaluated. Apoptosis induced by HA was associated with cell shrinkage, externalization of cell membrane phosphatidylserine, DNA fragmentation,and mitochondrial disruption, which were preceded by increased intracellular reactive oxygen species(ROS) generations. Further studies showed that PDT treatment with 0.08 mmol/L HA resulted in mitochondrial disruption, pronounced release of cytochrome c, and activation of caspase-3,-9, and-7.Together, HA may be a possible therapeutic agent directed toward mitochondria and a promising photodynamic anticancer candidate for further evaluation.展开更多
Advances in three-dimensional(3D)printing have increased feasibility towards the synthesis of living tissues.Known as 3D bioprinting,this technology involves the precise layering of cells,biologic scaffolds,and growth...Advances in three-dimensional(3D)printing have increased feasibility towards the synthesis of living tissues.Known as 3D bioprinting,this technology involves the precise layering of cells,biologic scaffolds,and growth factors with the goal of creating bioidentical tissue for a variety of uses.Early successes have demonstrated distinct advantages over conventional tissue engineering strategies.Not surprisingly,there are current challenges to address before 3D bioprinting becomes clinically relevant.Here we provide an overview of 3D bioprinting technology and discuss key advances,clinical applications,and current limitations.While 3D bioprinting is a relatively novel tissue engineering strategy,it holds great potential to play a key role in personalized medicine.展开更多
Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant morbidity.The differentiation of mesenchymal stem cells into the osteogenic l...Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant morbidity.The differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth factors.Neural EGF Like-Like molecule 1(NELL-1)is a secreted glycoprotein that has proven,both in vitro and in vivo,to be a potent osteo-inductive factor.Furthermore,it has been shown to repress adipogenic differentiation and inflammation.NELL-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein(BMP)2 and9,and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of osteoporosis.Here we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.展开更多
Bone morphogenetic protein 9(BMP9)(or GDF2)was originally identified from fetal mouse liver cDNA libraries.Emerging evidence indicates BMP9 exerts diverse and pleiotropic functions during postnatal development and in ...Bone morphogenetic protein 9(BMP9)(or GDF2)was originally identified from fetal mouse liver cDNA libraries.Emerging evidence indicates BMP9 exerts diverse and pleiotropic functions during postnatal development and in maintaining tissue homeostasis.However,the expression landscape of BMP9 signaling during development and/or in adult tissues remains to be analyzed.Here,we conducted a comprehensive analysis of the expression landscape of BMP9 and its signaling mediators in postnatal mice.By analyzing mouse ENCODE transcriptome datasets we found Bmp9 was highly expressed in the liver and detectable in embryonic brain,adult lungs and adult placenta.We next conducted a comprehensive qPCR analysis of RNAs isolated from major mouse tissues/organs at various ages.We found that Bmp9 was highly expressed in the liver and lung tissues of young adult mice,but decreased in older mice.Interestingly,Bmp9 was only expressed at low to modest levels in developing bones.BMP9-associated TGFβ/BMPR type I receptor Alk1 was highly expressed in the adult lungs.Furthermore,the feedback inhibitor Smads Smad6 and Smad7 were widely expressed in mouse postnatal tissues.However,the BMP signaling antagonist noggin was highly expressed in fat and heart in the older age groups,as well as in kidney,liver and lungs in a biphasic fashion.Thus,our findings indicate that the circulating BMP9 produced in liver and lungs may account for its pleiotropic effects on postnatal tissues/organs although possible roles of BMP9 signaling in liver and lungs remain to be fully understood.展开更多
Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular nature.Current surgical treatment options do not ensure consistent regeneration of hyaline cartila...Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular nature.Current surgical treatment options do not ensure consistent regeneration of hyaline cartilage in favor of fibrous tissue.Here,we review the current understanding of the most important biological regulators of chondrogenesis and their interactions,to provide insight into potential applications for cartilage tissue engineering.These include various signaling pathways,including fibroblast growth factors(FGFs),transforming growth factor b(TGF-b)/bone morphogenic proteins(BMPs),Wnt/b-catenin,Hedgehog,Notch,hypoxia,and angiogenic signaling pathways.Transcriptional and epigenetic regulation of chondrogenesis will also be discussed.Advances in our understanding of these signaling pathways have led to promising advances in cartilage regeneration and tissue engineering.展开更多
Mesenchymal stem cells(MSCs)are multipotent stem cells and capable of differentiating into multiple cell types including osteoblastic,chondrogenic and adipogenic lineages.We previously identified BMP9 as one of the mo...Mesenchymal stem cells(MSCs)are multipotent stem cells and capable of differentiating into multiple cell types including osteoblastic,chondrogenic and adipogenic lineages.We previously identified BMP9 as one of the most potent BMPs that induce osteoblastic differentiation of MSCs although exact molecular mechanism through which BMP9 regulates osteogenic differentiation remains to be fully understood.Here,we seek to develop a recombinant adenovirus system to optimally silence mouse BMP9 and then characterize the important role of BMP9 in osteogenic differentiation of MSCs.Using two different siRNA bioinformatic prediction programs,we design five siRNAs targeting mouse BMP9(or simB9),which are expressed under the control of the converging H1 and U6 promoters in recombinant adenovirus vectors.We demonstrate that two of the five siRNAs,simB9-4 and simB9-7,exhibit the highest efficiency on silencing exogenous mouse BMP9 in MSCs.Furthermore,simB9-4 and simB9-7 act synergistically in inhibiting BMP9-induced expression of osteogenic markers,matrix mineralization and ectopic bone formation from MSCs.Thus,our findings demonstrate the important role of BMP9 in osteogenic differentiation of MSCs.The characterized simB9 siRNAs may be used as an important tool to investigate the molecular mechanism behind BMP9 osteogenic signaling.Our results also indicate that recombinant adenovirus-mediated expression of siRNAs is efficient and sustained,and thus may be used as an effective delivery vehicle of siRNA therapeutics.展开更多
A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9 GWth nuclear reactors and detected by eight a...A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9 GWth nuclear reactors and detected by eight antineutrino detectors deployed in two near（560 m and 600 m flux-weighted baselines） and one far（1640 m flux-weighted baseline） underground experimental halls. With 621 days of data, more than 1.2 million inverse beta decay（IBD） candidates were detected. The IBD yield in the eight detectors was measured, and the ratio of measured to predicted flux was found to be 0.946±0.020（0.992±0.021） for the Huber＋Mueller（ILL＋Vogel） model. A 2.9σ deviation was found in the measured IBD positron energy spectrum compared to the predictions. In particular, an excess of events in the region of 4–6 MeV was found in the measured spectrum, with a local significance of 4.4σ. A reactor antineutrino spectrum weighted by the IBD cross section is extracted for model-independent predictions.展开更多
With the significant financial burden of chronic cutaneous wounds on the healthcare system,not to the personal burden mention on those individuals afflicted,it has become increasingly essential to improve our clinical...With the significant financial burden of chronic cutaneous wounds on the healthcare system,not to the personal burden mention on those individuals afflicted,it has become increasingly essential to improve our clinical treatments.This requires the translation of the most recent benchtop approaches to clinical wound repair as our current treatment modalities have proven insufficient.The most promising potential treatment options rely on stem cellbased therapies.Stem cell proliferation and signaling play crucial roles in every phase of the wound healing process and chronic wounds are often associated with impaired stem cell function.Clinical approaches involving stem cells could thus be utilized in some cases to improve a body’s inhibited healing capacity.We aim to present the laboratory research behind the mechanisms and effects of this technology as well as current clinical trials which showcase their therapeutic potential.Given the current problems and complications presented by chronic wounds,we hope to show that developing the clinical applications of stem cell therapies is the rational next step in improving wound care.展开更多
A pilot wire drawing machine as well as wire end-pointing roller was developed. Using these machines, a wire drawing test for four different coating materials and two different lubricants was performed as the reductio...A pilot wire drawing machine as well as wire end-pointing roller was developed. Using these machines, a wire drawing test for four different coating materials and two different lubricants was performed as the reduction ratio increased from 10% to 30%. Materials used for a substrate in this study are plain carbon steel （AIS11045） and ultra low carbon bainite steel. To compute the friction coefficient between the coating layer of wire and the surface of die lbr a specific lubricant, a series of finite element analyses were carried out. SEM observations were also conducted to investigate the surface defects of wire deformed. Results show that the behavior of drawing force varies with the lubricant-type at the initial stage of drawing. The powder-typed lubricant with a large particle causes the retardation of lull lubrication on the entire contact surface and the local delamination of coating layer on the wire surface. As the flow stress of a substrate increases, the delamination becomes severe.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
The establishment of a possible connection between neutrino emission and gravitational-wave(GW)bursts is important to our understanding of the physical processes that occur when black holes or neutron stars merge.In t...The establishment of a possible connection between neutrino emission and gravitational-wave(GW)bursts is important to our understanding of the physical processes that occur when black holes or neutron stars merge.In the Daya Bay experiment,using the data collected from December 2011 to August 2017,a search was per-formed for electron-antineutrino signals that coincided with detected GW events,including GW150914,GW151012,GW151226,GW170104,GW170608,GW 170814,and GW 170817.We used three time windows of±10,±500,and±1000 s relative to the occurrence of the GW events and a neutrino energy range of 1.8 to 100 MeV to search for correlated neutrino candidates.The detected electron-antineutrino candidates were consistent with the expected background rates for all the three time windows.Assuming monochromatic spectra,we found upper limits(90%confidence level)of the electron-antineutrino fluence of(1.13-2.44)×10^(11)cm^(-2)at 5 MeV to 8.0×10^(7)cm^(-2)at 100 MeV for the three time w indows.Under the assumption of a Fermi-Dirac spectrum,the upper limits were found to be(5.4-7.0)×10^(9)cm^(2)for the three time windows.展开更多
Aim:To determine whether in utero and neonatal exposure to a 60 Hz extremely low frequency electromagnetic field (EMF) results in spermatotoxicity and reproductive dysfunction in the F1 offspring of rats.Methods:Age-m...Aim:To determine whether in utero and neonatal exposure to a 60 Hz extremely low frequency electromagnetic field (EMF) results in spermatotoxicity and reproductive dysfunction in the F1 offspring of rats.Methods:Age-matched, pregnant Sprague-Dawley rats were exposed continuously (21 h/day) to a 60 Hz EMF at field strengths of 0 (sham control),5,83.3 or 500 μT from day 6 of gestation through to day 21 of lactation.The experimentally generated magnetic field was monitored continuously (uninterrupted monitoring over the period of the study) throughout the study.Results:No exposure-related changes were found in exposed or sham-exposed animals with respect to the anogenital distance,preputial separation,testis weight,testicular histology,sperm count,daily sperm production, sperm motility,sperm morphology and reproductive capacity of F1 offspring.Conclusion:Exposure of Sprague- Dawley rats to a 60 Hz EMF at field strengths of up to 500 μT from day 6 of gestation to day 21 of lactation did not produce any detectable alterations in offspring spermatogenesis and fertility.展开更多
基金The reported work was in part supported by research grants from the National Institutes of Health(AR50142 and AR054381 to RCH and HHL)RW,JG,and OI were recipients of the Pritzker Summer Research Fellowship funded through a NIH T-35 training grant(NIDDK).AH was a recipient of the Urban Leadership Fellowship from Miami University.
文摘Bone Morphogenetic Proteins(BMPs)are a group of signaling molecules that belongs to the Transforming Growth Factor-b(TGF-b)superfamily of proteins.Initially discovered for their ability to induce bone formation,BMPs are now known to play crucial roles in all organ systems.BMPs are important in embryogenesis and development,and also in maintenance of adult tissue homeostasis.Mouse knockout models of various components of the BMP signaling pathway result in embryonic lethality or marked defects,highlighting the essential functions of BMPs.In this review,we first outline the basic aspects of BMP signaling and then focus on genetically manipulated mouse knockout models that have helped elucidate the role of BMPs in development.A significant portion of this review is devoted to the prominent human pathologies associated with dysregulated BMP signaling.
基金Supported by the Ministry of Science and Technology of Chinathe United States Department of Energy+15 种基金the Chinese Academy of Sciencesthe National Natural Science Foundation of Chinathe Guangdong provincial governmentthe Shenzhen municipal governmentthe China Guangdong Nuclear Power GroupShanghai Laboratory for Particle Physics and Cosmologythe Research Grants Council of the Hong Kong Special Administrative Region of ChinaUniversity Development Fund of The University of Hong Kongthe MOE program for Research of Excellence at NTU, NCTUNSC fund support from Taipeithe U.S. National Science Foundationthe Alfred P. Sloan Foundationthe Ministry of EducationYouth and Sports of the Czech Republicthe Czech Science Foundationthe Joint Institute of Nuclear Research in Dubna,Russia
文摘We report an improved measurement of the neutrino mixing angle θ13 from the Daya Bay Reactor Neutrino Experiment. We exclude a zero value for sin22θ13 with a significance of 7.7 standard deviations. Electron antineutrinos from six reactors of 2.9 GWm th were detected in six antineutrino detectors deployed in two near （flux-weighted baselines of 470 m and 576 m） and one far （1648 m） underground experimental halls. Using 139 days of data, 28909 （205308） electron antineutrino candidates were detected at the far hall （near halls）. The ratio of the observed to the expected number of antineutrinos assuming no oscillations at the far hall is 0.944± 0.007（stat.） ± 0.003（syst.）. An analysis of the relative rates in six detectors finds sin22θ13=0.089± 0.010（stat.）±0.005（syst.） in a three-neutrino framework.
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(AT004418,DE020140 to TCH and RRR)the US Department of Defense(OR130096 to JMW)+3 种基金the Scoliosis Research Society(TCH and MJL)the 973 Program of the Ministry of Science and Technology(MOST)of China(#2011CB707906 to TCH)The reported work was also 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 UL1 TR000430.
文摘With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies.Despite numerous setbacks,efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases.It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies.There has been a long-lasting interest in using viral vectors,especially adenoviral vectors,to deliver therapeutic genes for the past two decades.Among all currently available viral vectors,adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types.The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development.In fact,among over 2000 gene therapy clinical trials approved worldwide since 1989,a significant portion of the trials have utilized adenoviral vectors.This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors,including adenoviral biology,approaches to engineering adenoviral vectors,and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment,vaccination and regenerative medicine.Current challenges and future directions regarding the use of adenoviral vectors are also discussed.It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303,DE020140 to TCH and RRR)the U.S.Department of Defense(OR130096 to JMW)+5 种基金the Scoliosis Research Society(TCH and MJL)the Scoliosis Research Society(TCH and MJL)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906).This project was also supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)and the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430.SM and MP were supported by the Summer Research Program of The University of Chicago Pritzker School of Medicine.TCH was also supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedic Alumni Fund.Funding sources were not involved in the study designin the collection,analysis and interpretation of datain the writing of the reportand in the decision to submit the paper for publication.
文摘Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and critical array of biological roles.These roles include regulating skeletal and bone formation,angiogenesis,and development and homeostasis of multiple organ systems.Disruptions of the members of the TGF-b/BMP superfamily result in severe skeletal and extra-skeletal irregularities,suggesting high therapeutic potential from understanding this family of BMP proteins.Although it was once one of the least characterized BMPs,BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo,with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs.The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants,revealing the great translational promise of BMP9.Furthermore,emerging evidence indicates that,besides its osteogenic activity,BMP9 exerts a broad range of biological functions,including stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism.This review aims to summarize our current understanding of BMP9 across biology and the body.
基金The authors apologize to those investigators whose original work was not cited due to space constraints.The authors’research was supported in part by research grants from the National Institutes of Health(AT004418&AR054381 to TCH&HHL)Scoliosis Research Society(MJL&TCH),the 973 Program of Ministry of Science and Technology(MOST)of China(#2011CB707900 to TCH),the National Natural Science Foundation of China(#81400493 to FZ)+2 种基金Chongqing Municipal Commissions on Education(#KJ130303 to JW)Chongqing Municipal Commissions on Science&Technology(#cstc2013jcyjA0093 to JW)Chongqing Municipal Commissions Yubei District Science&Technology(#2014 Society of Human Resource Unit 14 to JW).MKM was a recipient of Howard Hughes Medical Institute Medical Research Fellowship.
文摘Tooth is a complex hard tissue organ and consists of multiple cell types that are regulated by important signaling pathways such as Wnt and BMP signaling.Serious injuries and/or loss of tooth or periodontal tissues may significantly impact aesthetic appearance,essential oral functions and the quality of life.Regenerative dentistry holds great promise in treating oral/dental disorders.The past decade has witnessed a rapid expansion of our understanding of the biological features of dental stem cells,along with the signaling mechanisms governing stem cell self-renewal and differentiation.In this review,we first summarize the biological characteristics of seven types of dental stem cells,including dental pulp stem cells,stem cells from apical papilla,stem cells from human exfoliated deciduous teeth,dental follicle precursor cells,periodontal ligament stem cells,alveolar bone-derived mesenchymal stem cells(MSCs),and MSCs from gingiva.We then focus on how these stem cells are regulated by bone morphogenetic protein(BMP)and/or Wnt signaling by examining the interplays between these pathways.Lastly,we analyze the current status of dental tissue engineering strategies that utilize oral/dental stem cells by harnessing the interplays between BMP and Wnt pathways.We also highlight the challenges that must be addressed before the dental stem cells may reach any clinical applications.Thus,we can expect to witness significant progresses to be made in regenerative dentistry in the coming decade.
基金supported in part by the research grant from the National Institutes of Health(AR50142 to RCH)supported in part by The University of Chicago Core Facility Subsidy grant from the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health through Grant UL1 TR000430.SD was a recipient of The University of Chicago Pritzker Fellowship and AOA Carolyn L.Kuckein Fellowship.
文摘The transcription factor Sox9 was first discovered in patients with campomelic dysplasia,a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis.Since then,its role as a cell fate determiner during embryonic development has been well characterized;Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs.However,recent data has shown that ectoderm-and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools,suggesting its role in cell maintenance and specification during adult life.The versatility of Sox9 may be explained by a combination of posttranscriptional modifications,binding partners,and the tissue type in which it is expressed.Considering its importance during both development and adult life,it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases,including fibrosis and cancer.This review provides a summary of the various roles of Sox9 in cell fate specification,stem cell biology,and related human diseases.Ultimately,understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage.
文摘Mesenchymal stem cells(MSCs)are ubiquitously-existing multipotent progenitors that can self-renew and differentiate into multiple lineages including osteocytes,chondrocytes,adipocytes,tenocytes and myocytes.MSCs represent one of the most commonly-used adult progenitors and serve as excellent progenitor cell models for investigating lineagespecific differentiation regulated by various cellular signaling pathways,such as bone morphogenetic proteins(BMPs).As members of TGFb superfamily,BMPs play diverse and important roles in development and adult tissues.At least 14 BMPs have been identified in mammals.Different BMPs exert distinct but overlapping biological functions.Through a comprehensive analysis of 14 BMPs in MSCs,we demonstrated that BMP9 is one of the most potent BMPs in inducing osteogenic differentiation of MSCs.Nonetheless,a global mechanistic view of BMP signaling in regulating the proliferation and differentiation of MSCs remains to be fully elucidated.Here,we conducted a comprehensive transcriptomic profiling in the MSCs stimulated by 14 types of BMPs.Hierarchical clustering analysis classifies 14 BMPs into three subclusters:an osteo/chondrogenic/adipogenic cluster,a tenogenic cluster,and BMP3 cluster.We also demonstrate that six BMPs(e.g.,BMP2,BMP3,BMP4,BMP7,BMP8,and BMP9)can induce ISmads effectively,while BMP2,BMP3,BMP4,BMP7,and BMP11 up-regulate Smad-independent MAP kinase pathway.Furthermore,we show that many BMPs can upregulate the expression of the signal mediators of Wnt,Notch and PI3K/AKT/mTOR pathways.While the reported transcriptomic changes need to be further validated,our expression profiling represents the first-of-its-kind to interrogate a comprehensive transcriptomic landscape regulated by the 14 types of BMPs in MSCs.
基金supported by the National Natural Science Foundation of China(Project No.81673214)The National Key Technology Research and National Key Technology Research and Development Program of the Ministry of Science and Technology of the People's Republic of China(Project No.2012BAD36B0502)the Priority Academic Program Development of Jiangsu Higher Educational Institutions(China)
文摘Over recent decades, many studies have reported that hypocrellin A(HA) can eliminate cancer cells with proper irradiation in several cancer cell lines. However, the precise molecular mechanism underlying its anticancer effect has not been fully defined. HA-mediated cytotoxicity and apoptosis in human lung adenocarcinoma A549 cells were evaluated after photodynamic therapy(PDT). A temporal quantitative proteomics approach by isobaric tag for relative and absolute quantitation(iTRAQ) 2 D liquid chromatography with tandem mass spectrometric(LC–MS/MS) was introduced to help clarify molecular cytotoxic mechanisms and identify candidate targets of HA-induced apoptotic cell death. Specific caspaseinhibitors were used to further elucidate the molecular pathway underlying apoptosis in PDT-treated A549 cells. Finally, down-stream apoptosis-related protein was evaluated. Apoptosis induced by HA was associated with cell shrinkage, externalization of cell membrane phosphatidylserine, DNA fragmentation,and mitochondrial disruption, which were preceded by increased intracellular reactive oxygen species(ROS) generations. Further studies showed that PDT treatment with 0.08 mmol/L HA resulted in mitochondrial disruption, pronounced release of cytochrome c, and activation of caspase-3,-9, and-7.Together, HA may be a possible therapeutic agent directed toward mitochondria and a promising photodynamic anticancer candidate for further evaluation.
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(AT004418,DE020140 to TCH and RRR)the US Department of Defense(OR130096 to JMW)+3 种基金the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust(RRR,GAA and TCH)the Scoliosis Research Society(TCH and MJL)a Cleft Palate Foundation Research Support Grant(RRR)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906 to TCH).
文摘Advances in three-dimensional(3D)printing have increased feasibility towards the synthesis of living tissues.Known as 3D bioprinting,this technology involves the precise layering of cells,biologic scaffolds,and growth factors with the goal of creating bioidentical tissue for a variety of uses.Early successes have demonstrated distinct advantages over conventional tissue engineering strategies.Not surprisingly,there are current challenges to address before 3D bioprinting becomes clinically relevant.Here we provide an overview of 3D bioprinting technology and discuss key advances,clinical applications,and current limitations.While 3D bioprinting is a relatively novel tissue engineering strategy,it holds great potential to play a key role in personalized medicine.
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(AT004418,DE020140 to TCH and RRR)the US Department of Defense(OR130096 to JMW)+4 种基金the Scoliosis Research Society(TCH and MJL)the 973 Program of the Ministry of Science and Technology(MOST)of China(#2011CB707906 to TCH)MP and SM were recipients of the Pritzker Summer Research Fellowship funded through the National Institute of Health(NIH)T-35 training grant(NIDDK)#T35DK062719-30The reported work was also 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 UL1 TR000430。
文摘Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant morbidity.The differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth factors.Neural EGF Like-Like molecule 1(NELL-1)is a secreted glycoprotein that has proven,both in vitro and in vivo,to be a potent osteo-inductive factor.Furthermore,it has been shown to repress adipogenic differentiation and inflammation.NELL-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein(BMP)2 and9,and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of osteoporosis.Here we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303 to TCH)the U.S.Department of Defense(OR130096 to JMW)+3 种基金the Scoliosis Research Society(TCH and MJL)This project was also 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 UL1 TR000430.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,in the collection,analysis and interpretation of datain the writing of the report,and in the decision to submit the paper for publication。
文摘Bone morphogenetic protein 9(BMP9)(or GDF2)was originally identified from fetal mouse liver cDNA libraries.Emerging evidence indicates BMP9 exerts diverse and pleiotropic functions during postnatal development and in maintaining tissue homeostasis.However,the expression landscape of BMP9 signaling during development and/or in adult tissues remains to be analyzed.Here,we conducted a comprehensive analysis of the expression landscape of BMP9 and its signaling mediators in postnatal mice.By analyzing mouse ENCODE transcriptome datasets we found Bmp9 was highly expressed in the liver and detectable in embryonic brain,adult lungs and adult placenta.We next conducted a comprehensive qPCR analysis of RNAs isolated from major mouse tissues/organs at various ages.We found that Bmp9 was highly expressed in the liver and lung tissues of young adult mice,but decreased in older mice.Interestingly,Bmp9 was only expressed at low to modest levels in developing bones.BMP9-associated TGFβ/BMPR type I receptor Alk1 was highly expressed in the adult lungs.Furthermore,the feedback inhibitor Smads Smad6 and Smad7 were widely expressed in mouse postnatal tissues.However,the BMP signaling antagonist noggin was highly expressed in fat and heart in the older age groups,as well as in kidney,liver and lungs in a biphasic fashion.Thus,our findings indicate that the circulating BMP9 produced in liver and lungs may account for its pleiotropic effects on postnatal tissues/organs although possible roles of BMP9 signaling in liver and lungs remain to be fully understood.
基金The authors’ laboratories were supported in part byresearch grants from the National Institutes of Health(AR50142, AR054381, and AT004418 to RCH, HHL, and TCH)and Scoliosis Research Society (MJL)JDG and VT were recipientsof the Pritzker Summer Research Fellowship fundedthrough a NIH T-35 training grant (NIDDK)MKM was arecipient of Howard Hughes Medical Institute MedicalResearch Fellowship.
文摘Defects of articular cartilage present a unique clinical challenge due to its poor self-healing capacity and avascular nature.Current surgical treatment options do not ensure consistent regeneration of hyaline cartilage in favor of fibrous tissue.Here,we review the current understanding of the most important biological regulators of chondrogenesis and their interactions,to provide insight into potential applications for cartilage tissue engineering.These include various signaling pathways,including fibroblast growth factors(FGFs),transforming growth factor b(TGF-b)/bone morphogenic proteins(BMPs),Wnt/b-catenin,Hedgehog,Notch,hypoxia,and angiogenic signaling pathways.Transcriptional and epigenetic regulation of chondrogenesis will also be discussed.Advances in our understanding of these signaling pathways have led to promising advances in cartilage regeneration and tissue engineering.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303,DE020140 to TCH and RRR)the U.S.Department of Defense(OR130096 to JMW)+1 种基金the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust(RRR,TCH),the Scoliosis Research Society(TCH and MJL)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906 to TCH).
文摘Mesenchymal stem cells(MSCs)are multipotent stem cells and capable of differentiating into multiple cell types including osteoblastic,chondrogenic and adipogenic lineages.We previously identified BMP9 as one of the most potent BMPs that induce osteoblastic differentiation of MSCs although exact molecular mechanism through which BMP9 regulates osteogenic differentiation remains to be fully understood.Here,we seek to develop a recombinant adenovirus system to optimally silence mouse BMP9 and then characterize the important role of BMP9 in osteogenic differentiation of MSCs.Using two different siRNA bioinformatic prediction programs,we design five siRNAs targeting mouse BMP9(or simB9),which are expressed under the control of the converging H1 and U6 promoters in recombinant adenovirus vectors.We demonstrate that two of the five siRNAs,simB9-4 and simB9-7,exhibit the highest efficiency on silencing exogenous mouse BMP9 in MSCs.Furthermore,simB9-4 and simB9-7 act synergistically in inhibiting BMP9-induced expression of osteogenic markers,matrix mineralization and ectopic bone formation from MSCs.Thus,our findings demonstrate the important role of BMP9 in osteogenic differentiation of MSCs.The characterized simB9 siRNAs may be used as an important tool to investigate the molecular mechanism behind BMP9 osteogenic signaling.Our results also indicate that recombinant adenovirus-mediated expression of siRNAs is efficient and sustained,and thus may be used as an effective delivery vehicle of siRNA therapeutics.
基金Supported in part by the Ministry of Science and Technology of Chinathe United States Department of Energy,the Chinese Academy of Sciences+11 种基金the CAS Center for Excellence in Particle Physicsthe National Natural Science Foundation of Chinathe Guangdong provincial governmentthe Shenzhen municipal governmentthe China General Nuclear Power Groupthe Research Grants Council of the Hong Kong Special Administrative Region of Chinathe MOST and MOE in Taiwanthe U.S.National Science Foundationthe Ministry of Education,Youth and Sports of the Czech Republicthe Joint Institute of Nuclear Research in Dubna,Russiathe NSFC-RFBR joint research programthe National Commission for Scientific and Technological Research of Chile
文摘A new measurement of the reactor antineutrino flux and energy spectrum by the Daya Bay reactor neutrino experiment is reported. The antineutrinos were generated by six 2.9 GWth nuclear reactors and detected by eight antineutrino detectors deployed in two near（560 m and 600 m flux-weighted baselines） and one far（1640 m flux-weighted baseline） underground experimental halls. With 621 days of data, more than 1.2 million inverse beta decay（IBD） candidates were detected. The IBD yield in the eight detectors was measured, and the ratio of measured to predicted flux was found to be 0.946±0.020（0.992±0.021） for the Huber＋Mueller（ILL＋Vogel） model. A 2.9σ deviation was found in the measured IBD positron energy spectrum compared to the predictions. In particular, an excess of events in the region of 4–6 MeV was found in the measured spectrum, with a local significance of 4.4σ. A reactor antineutrino spectrum weighted by the IBD cross section is extracted for model-independent predictions.
基金The contributing authors’laboratories were supported in part by research grants from the National Institutes of Health(CA226303,DE020140 to TCH and RRR)the U.S.Department of Defense(OR130096 to JMW)+4 种基金the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust(R.R.R.,T.C.H.,and G.A.A.)the Scoliosis Research Society(TCH and MJL),and the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906).This project was also supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430.EC was supported by the Summer Research Program of The University of Chicago Pritzker School of Medicine.TCH was also supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedic Alumni Fund.Funding sources were not involved in the study designin the collection,analysis and interpretation of datain the writing of the reportand in the decision to submit the paper for publication.
文摘With the significant financial burden of chronic cutaneous wounds on the healthcare system,not to the personal burden mention on those individuals afflicted,it has become increasingly essential to improve our clinical treatments.This requires the translation of the most recent benchtop approaches to clinical wound repair as our current treatment modalities have proven insufficient.The most promising potential treatment options rely on stem cellbased therapies.Stem cell proliferation and signaling play crucial roles in every phase of the wound healing process and chronic wounds are often associated with impaired stem cell function.Clinical approaches involving stem cells could thus be utilized in some cases to improve a body’s inhibited healing capacity.We aim to present the laboratory research behind the mechanisms and effects of this technology as well as current clinical trials which showcase their therapeutic potential.Given the current problems and complications presented by chronic wounds,we hope to show that developing the clinical applications of stem cell therapies is the rational next step in improving wound care.
基金supported by research funds from Dong-A University, Korea
文摘A pilot wire drawing machine as well as wire end-pointing roller was developed. Using these machines, a wire drawing test for four different coating materials and two different lubricants was performed as the reduction ratio increased from 10% to 30%. Materials used for a substrate in this study are plain carbon steel （AIS11045） and ultra low carbon bainite steel. To compute the friction coefficient between the coating layer of wire and the surface of die lbr a specific lubricant, a series of finite element analyses were carried out. SEM observations were also conducted to investigate the surface defects of wire deformed. Results show that the behavior of drawing force varies with the lubricant-type at the initial stage of drawing. The powder-typed lubricant with a large particle causes the retardation of lull lubrication on the entire contact surface and the local delamination of coating layer on the wire surface. As the flow stress of a substrate increases, the delamination becomes severe.
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Daya Bay is supported in part by the Ministry of Science and Technology o f China, the U.S. Department o f Energy, the Chinese Academy of Sciences, the CASCenter for Excellence in Particle Physics, the National Natural Science Foundation of China, the Guangdong provincial government, the Shenzhen municipal government,the China General Nuclear Power Group, Key Laboratory of Particle and Radiation Imaging (Tsinghua University), the Ministry of Education, Key Laboratory ofParticle Physics and Particle Irradiation (Shandong University), the Ministry o f Education, Shanghai Laboratory for Particle Physics and Cosmology, the ResearchGrants Council o f the Hong Kong Special Administrative Region of China, the University Development Fund of the University of Hong Kong, the MOE program forResearch of Excellence at National Taiwan University, National Chiao-Tung University, NSC fund support from Taiwan, the U.S. National Science Foundation, the AlfredP. Sloan Foundation, the Ministry o f Education, Youth, and Sports of the Czech Republic, the Charles University GAUK (284317), the Joint Institute o f NuclearResearch in Dubna, Russia, the National Commission of Scientific and Technological Research of Chile, and the Tsinghua University Initiative Scientific Research Program.
文摘The establishment of a possible connection between neutrino emission and gravitational-wave(GW)bursts is important to our understanding of the physical processes that occur when black holes or neutron stars merge.In the Daya Bay experiment,using the data collected from December 2011 to August 2017,a search was per-formed for electron-antineutrino signals that coincided with detected GW events,including GW150914,GW151012,GW151226,GW170104,GW170608,GW 170814,and GW 170817.We used three time windows of±10,±500,and±1000 s relative to the occurrence of the GW events and a neutrino energy range of 1.8 to 100 MeV to search for correlated neutrino candidates.The detected electron-antineutrino candidates were consistent with the expected background rates for all the three time windows.Assuming monochromatic spectra,we found upper limits(90%confidence level)of the electron-antineutrino fluence of(1.13-2.44)×10^(11)cm^(-2)at 5 MeV to 8.0×10^(7)cm^(-2)at 100 MeV for the three time w indows.Under the assumption of a Fermi-Dirac spectrum,the upper limits were found to be(5.4-7.0)×10^(9)cm^(2)for the three time windows.
文摘Aim:To determine whether in utero and neonatal exposure to a 60 Hz extremely low frequency electromagnetic field (EMF) results in spermatotoxicity and reproductive dysfunction in the F1 offspring of rats.Methods:Age-matched, pregnant Sprague-Dawley rats were exposed continuously (21 h/day) to a 60 Hz EMF at field strengths of 0 (sham control),5,83.3 or 500 μT from day 6 of gestation through to day 21 of lactation.The experimentally generated magnetic field was monitored continuously (uninterrupted monitoring over the period of the study) throughout the study.Results:No exposure-related changes were found in exposed or sham-exposed animals with respect to the anogenital distance,preputial separation,testis weight,testicular histology,sperm count,daily sperm production, sperm motility,sperm morphology and reproductive capacity of F1 offspring.Conclusion:Exposure of Sprague- Dawley rats to a 60 Hz EMF at field strengths of up to 500 μT from day 6 of gestation to day 21 of lactation did not produce any detectable alterations in offspring spermatogenesis and fertility.
