Estrogen is imperative to mammalian reproductivity,metabolism,and aging.However,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain...Estrogen is imperative to mammalian reproductivity,metabolism,and aging.However,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain malignancies.In contrast,ERβis more broadly expressed in metabolic tissues and the skin.Thus,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERαactivation.Here,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or genistein.Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in vitro.We further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound healing.Therefore,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.展开更多
The pluripotent state of embryonic stem cells(ESCs)is regulated by a sophisticated network of transcription factors.High expression of KLF17 has recently been identified as a hallmark of naive state of human ESCs(h ES...The pluripotent state of embryonic stem cells(ESCs)is regulated by a sophisticated network of transcription factors.High expression of KLF17 has recently been identified as a hallmark of naive state of human ESCs(h ESCs).However,the functional role of KLF17 in naive state is not clear.Here,by employing various gain and loss-of-function approaches,we demonstrate that KLF17 is essential for the maintenance of naive state and promotes the primed to naive state transition in h ESCs.Mechanistically,we identify MAPK3 and ZIC2 as two direct targets repressed by KLF17.Overexpression of MAPK3 or ZIC2 partially blocks KLF17 from promoting the naive pluripotency.Furthermore,we find that human and mouse homologs of KLF17 retain conserved functions in promoting naive pluripotency of both species.Finally,we show that Klf17 may be essential for early embryo development in mouse.These findings demonstrate the important and conserved function of KLF17 in promoting naive pluripotency and reveal two essential transcriptional targets of KLF17 that underlie its function.展开更多
Pluripotency is recognized as a spectrum of cellular states spanning the na?ve pluripotency established in the preimplantation blastocyst and its transition into primed pluripotency in the postimplantation epiblast ce...Pluripotency is recognized as a spectrum of cellular states spanning the na?ve pluripotency established in the preimplantation blastocyst and its transition into primed pluripotency in the postimplantation epiblast cells. The exit from pluripotency is followed by the initiation of gastrulation(Brennan et al., 2001;Nichols and Smith, 2009).展开更多
This study aims to examine the effect of transformational leadership on employee voice behavior. Specifically, this study investigates the mediating role of positive affect in linking sformational leadership with voic...This study aims to examine the effect of transformational leadership on employee voice behavior. Specifically, this study investigates the mediating role of positive affect in linking sformational leadership with voice and the moderating role of over-qualification in influencing the mediation of positive affect. In particular, a twowave survey was con ducted. A sample of 271 participa nts complete a questionnaire measuring tran sformati on al leadership, positive affect and various demographic variables in the first wave. Then, they complete a second questionnaire measuring perceived over-qualification and voice behavior 2 weeks later. We conduct a series of multiple regression analyses to test the model. The results show that positive affect partially mediated the relationship between transformational leadership and employee voice behavior. Over-qualification moderated the relationship between positive affect and voice. In addition, moderated mediation analyses reveal that positive affect mediates the relationship between transformational leadership and voice only for highly over-qualified employees. This study investigates a new method linking transformational leadership and voice from an affective perspective by finding the mediating effect of positive affect. We also verify the role of "energized to" process in shaping proactive behaviors. Finally, this study examines the boundary conditions of the effect of positive affect on voice.展开更多
Dear Editor,Cell-fate decisions are governed by comprehensive generegulatory programs.During the preimplantation development,at least two waves of cell fate decisions are made while the cells gradually lose their toti...Dear Editor,Cell-fate decisions are governed by comprehensive generegulatory programs.During the preimplantation development,at least two waves of cell fate decisions are made while the cells gradually lose their totipotency(Schrode et al.,2013).The first decision involves the spatial separation of outer-residing trophectoderm(TE)cells from inner cell mass(ICM)in E3.5 mouse blastocyst.The second decision involves gene expression refinements and active cell sorting within the ICM that ultimately results in epiblast(EPI)cells,residing deep within the ICM,and the primitive endoderm(PrE)cells comprising a monolayer of blastocoel-facing cells at the surface of the ICM(Schrode et al.,2013).OCT4,SOX2,and NANOG are master transcription factors(TFs)essential for the formation and maintenance of the pluripotent ICM cells and their in vitro counterparts mouse embryonic stem cells(ESCs).On the other hand,GATA4,GATA6,and SOX17 are master TFs of the PrE cells and their in vitro counterparts extraembryonic endoderm stem cells(XENs).展开更多
CORRECTION TO:PROTEIN CELL HTTPS://DOI.ORG/10.1007/S13238-020-00775-X In the original publication the labelling in middle and bottom panels of Fig.2K is published incorrectly as“Soc17”.The correct labeling is availa...CORRECTION TO:PROTEIN CELL HTTPS://DOI.ORG/10.1007/S13238-020-00775-X In the original publication the labelling in middle and bottom panels of Fig.2K is published incorrectly as“Soc17”.The correct labeling is available in this correction as“Sox17”.展开更多
基金This work was supported by the Columbia University startup packages(Li Qiang and Jianwen Que)and the University of Tennessee College of Pharmacy Drug Discovery Center(Wei Li).
文摘Estrogen is imperative to mammalian reproductivity,metabolism,and aging.However,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain malignancies.In contrast,ERβis more broadly expressed in metabolic tissues and the skin.Thus,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERαactivation.Here,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or genistein.Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in vitro.We further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound healing.Therefore,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.
基金supported by the National Key Research and Development Program of China(2018YFA0107601 and2021YFA0100200)the National Natural Science Foundation of China(91940302,32130017,82070294 and 32025007)。
文摘The pluripotent state of embryonic stem cells(ESCs)is regulated by a sophisticated network of transcription factors.High expression of KLF17 has recently been identified as a hallmark of naive state of human ESCs(h ESCs).However,the functional role of KLF17 in naive state is not clear.Here,by employing various gain and loss-of-function approaches,we demonstrate that KLF17 is essential for the maintenance of naive state and promotes the primed to naive state transition in h ESCs.Mechanistically,we identify MAPK3 and ZIC2 as two direct targets repressed by KLF17.Overexpression of MAPK3 or ZIC2 partially blocks KLF17 from promoting the naive pluripotency.Furthermore,we find that human and mouse homologs of KLF17 retain conserved functions in promoting naive pluripotency of both species.Finally,we show that Klf17 may be essential for early embryo development in mouse.These findings demonstrate the important and conserved function of KLF17 in promoting naive pluripotency and reveal two essential transcriptional targets of KLF17 that underlie its function.
基金funded by grants from the National Institutes of Health (R01GM129157, R01HD095938, R01HD097268, and R01HL146664)by contracts from New York State Stem Cell Science (NYSTEM#C35583GG and C35584GG)。
文摘Pluripotency is recognized as a spectrum of cellular states spanning the na?ve pluripotency established in the preimplantation blastocyst and its transition into primed pluripotency in the postimplantation epiblast cells. The exit from pluripotency is followed by the initiation of gastrulation(Brennan et al., 2001;Nichols and Smith, 2009).
文摘This study aims to examine the effect of transformational leadership on employee voice behavior. Specifically, this study investigates the mediating role of positive affect in linking sformational leadership with voice and the moderating role of over-qualification in influencing the mediation of positive affect. In particular, a twowave survey was con ducted. A sample of 271 participa nts complete a questionnaire measuring tran sformati on al leadership, positive affect and various demographic variables in the first wave. Then, they complete a second questionnaire measuring perceived over-qualification and voice behavior 2 weeks later. We conduct a series of multiple regression analyses to test the model. The results show that positive affect partially mediated the relationship between transformational leadership and employee voice behavior. Over-qualification moderated the relationship between positive affect and voice. In addition, moderated mediation analyses reveal that positive affect mediates the relationship between transformational leadership and voice only for highly over-qualified employees. This study investigates a new method linking transformational leadership and voice from an affective perspective by finding the mediating effect of positive affect. We also verify the role of "energized to" process in shaping proactive behaviors. Finally, this study examines the boundary conditions of the effect of positive affect on voice.
基金We thank Dr.Philippe Soriano for providing the XENB1 cell line.Research in Wang laboratory was funded by grants from the NIH(R01GM129157,R01HD095938,and R01HD097268)and NYSTEM(C32583GG and C32569GG).
文摘Dear Editor,Cell-fate decisions are governed by comprehensive generegulatory programs.During the preimplantation development,at least two waves of cell fate decisions are made while the cells gradually lose their totipotency(Schrode et al.,2013).The first decision involves the spatial separation of outer-residing trophectoderm(TE)cells from inner cell mass(ICM)in E3.5 mouse blastocyst.The second decision involves gene expression refinements and active cell sorting within the ICM that ultimately results in epiblast(EPI)cells,residing deep within the ICM,and the primitive endoderm(PrE)cells comprising a monolayer of blastocoel-facing cells at the surface of the ICM(Schrode et al.,2013).OCT4,SOX2,and NANOG are master transcription factors(TFs)essential for the formation and maintenance of the pluripotent ICM cells and their in vitro counterparts mouse embryonic stem cells(ESCs).On the other hand,GATA4,GATA6,and SOX17 are master TFs of the PrE cells and their in vitro counterparts extraembryonic endoderm stem cells(XENs).
文摘CORRECTION TO:PROTEIN CELL HTTPS://DOI.ORG/10.1007/S13238-020-00775-X In the original publication the labelling in middle and bottom panels of Fig.2K is published incorrectly as“Soc17”.The correct labeling is available in this correction as“Sox17”.