Objective Pituitary adenomas(PAs)can adapt an aggressive phenotype by invading adjacent brain structures with rapid cellular proliferation.Previous studies demonstrated that excessive expression of metalloproteases AD...Objective Pituitary adenomas(PAs)can adapt an aggressive phenotype by invading adjacent brain structures with rapid cellular proliferation.Previous studies demonstrated that excessive expression of metalloproteases ADAM12 and MMP-14 is instrumental for the active proliferation and invasiveness of PA cells in vitro and of tumors in vivo.However,the mechanisms regulating ADAM12 and MMP-14 expression in PAs remain unclear.Methods Target gene prediction and transcriptomic profiling of invasive vs.noninvasive human PA samples were performed to identify miRNA species potentially involved in the regulation of ADAM12 and MMP14.For cellular analyses of miRNA functions,two mouse PA cell lines(AtT20 and TtT/GF)were transfected with miR-149-3p and miR-149-5p,respectively.The effects of miR-149(3p and 5p)on expression levels of ADAM12 and MMP14 were determined by Western blotting followed by an analysis of proliferation and colony formation assays,scratch migration assays,and invasion assays.Results A significant downregulation of miRNA-149 was observed in invasive vs.noninvasive PA(0.32 vs.0.09,P<0.0001).In AtT-20 and TtT/GF mouse PAs cells,transfection of mimic miRNA-149(3p and 5p)caused a significantly reduced cell proliferation and matrigel invasion,whilst the effect on cell migration was less pronounced.Both strands of miRNA-149(3p and 5p)markedly reduced protein levels of ADAM12 and MMP-14 by at least 40%in both cell lines.Conclusion This study proved that the invasiveness of PA cells is,at least partly,regulated by miRNA-149-dependent expression of ADAM12 and MMP-14.展开更多
The evolutionary dynamics of behavioral traits reflect phenotypic and genetic changes. Methodological difficulties in analyzing the genetic dynamics of complex traits have left open questions on the mechanisms that ha...The evolutionary dynamics of behavioral traits reflect phenotypic and genetic changes. Methodological difficulties in analyzing the genetic dynamics of complex traits have left open questions on the mechanisms that have shaped complex beha- viors and cognitive abilities. A strategy to investigate the change of behavior across generations is to assume that genetic con- straints have a negligible role in evolution （the phenotypic gambit） and focus on the phenotype as a proxy for genetic evolution. Empirical evidence and technologic advances in genomics question the choice of neglecting the genetic underlying the dynamics of behavioral evolution. I first discuss the relevance of genetic factors - e.g. genetic variability, genetic linkage, gene interactions - in shaping evolution, showing the importance of taking genetic factors into account when dealing with evolutionary dynamics. I subsequently describe the recent advancements in genetics and genomics that make the investigation of the ongoing evolutionary process of behavioral traits finally attainable. In particular, by applying genomic resequencing to experimental evolution - a me- thod called Evolve ＆ Resequence - it is possible to monitor at the same time phenotypic and genomie changes in populations exposed to controlled selective pressures. Experimental evolution of associative learning, a well-known trait that promptly re- sponds to selection, is a convenient model to illustrate this approach applied to behavior and cognition. Taking into account the recent achievements of the field, I discuss how to design and conduct an effective Evolve ＆ Resequence study on associative learning in Drosophila. By integrating phenotypic and genomic data in the investigation of evolutionary dynamics, new insights can be gained on longstanding questions such as the modularity of mind and its evolution .展开更多
Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stoo...Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stood,targeting microglia is central to promoting neuroprotection.Microglia are the resident immune cells of the central nervous system.These cells are crucial in the pathogenesis of ischemic stroke.They respond rapidly to the site of injury by releasing pro-inflammatory cytokines,phagocytizing dead cells and debris,and recruiting peripheral immune cells to the ischemic area.Although these responses are essential for clearing damage and initiating tissue repair,excessive or prolonged microglial activation can exacerbate brain injury,leading to secondary neuroinflammation and neurodegeneration.Moreover,microglia exhibit a dynamic range of activation states with the so-called M1 pro-inflammatory and M2 anti-inflammatory phenotypes,representing the two ends of the spectrum.The delivery of both EVs and stem cells modulates microglial activation,suppressing pro-inflammatory genes,influencing the expression of transcription factors,and altering receptor expression,ultimately contributing to neuroprotection.These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke.In this review,we examine the current state of knowledge regarding the role of microglia in ischemic stroke,including their molecular and cellular mechanisms,activation states,and interactions with other cells.We also discuss the multifaceted contributions of microglia to stem cell-and EV-based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.展开更多
In a recent study published in Cell,Marin Vargas and Bisi et al.1 present an innovative approach to unravel the computational principles underlying proprioceptive processing in non-human primates.Their findings showca...In a recent study published in Cell,Marin Vargas and Bisi et al.1 present an innovative approach to unravel the computational principles underlying proprioceptive processing in non-human primates.Their findings showcase the utility of task-driven modeling in advancing neuroscience and offer translational potential by providing seminal insights into the goals and mechanisms by which the brain encodes body position and movements.展开更多
基金This research was funded in part by the ERANET PerMed consortium“PerProGlio”(to J.W.B.and A.S.).
文摘Objective Pituitary adenomas(PAs)can adapt an aggressive phenotype by invading adjacent brain structures with rapid cellular proliferation.Previous studies demonstrated that excessive expression of metalloproteases ADAM12 and MMP-14 is instrumental for the active proliferation and invasiveness of PA cells in vitro and of tumors in vivo.However,the mechanisms regulating ADAM12 and MMP-14 expression in PAs remain unclear.Methods Target gene prediction and transcriptomic profiling of invasive vs.noninvasive human PA samples were performed to identify miRNA species potentially involved in the regulation of ADAM12 and MMP14.For cellular analyses of miRNA functions,two mouse PA cell lines(AtT20 and TtT/GF)were transfected with miR-149-3p and miR-149-5p,respectively.The effects of miR-149(3p and 5p)on expression levels of ADAM12 and MMP14 were determined by Western blotting followed by an analysis of proliferation and colony formation assays,scratch migration assays,and invasion assays.Results A significant downregulation of miRNA-149 was observed in invasive vs.noninvasive PA(0.32 vs.0.09,P<0.0001).In AtT-20 and TtT/GF mouse PAs cells,transfection of mimic miRNA-149(3p and 5p)caused a significantly reduced cell proliferation and matrigel invasion,whilst the effect on cell migration was less pronounced.Both strands of miRNA-149(3p and 5p)markedly reduced protein levels of ADAM12 and MMP-14 by at least 40%in both cell lines.Conclusion This study proved that the invasiveness of PA cells is,at least partly,regulated by miRNA-149-dependent expression of ADAM12 and MMP-14.
文摘The evolutionary dynamics of behavioral traits reflect phenotypic and genetic changes. Methodological difficulties in analyzing the genetic dynamics of complex traits have left open questions on the mechanisms that have shaped complex beha- viors and cognitive abilities. A strategy to investigate the change of behavior across generations is to assume that genetic con- straints have a negligible role in evolution （the phenotypic gambit） and focus on the phenotype as a proxy for genetic evolution. Empirical evidence and technologic advances in genomics question the choice of neglecting the genetic underlying the dynamics of behavioral evolution. I first discuss the relevance of genetic factors - e.g. genetic variability, genetic linkage, gene interactions - in shaping evolution, showing the importance of taking genetic factors into account when dealing with evolutionary dynamics. I subsequently describe the recent advancements in genetics and genomics that make the investigation of the ongoing evolutionary process of behavioral traits finally attainable. In particular, by applying genomic resequencing to experimental evolution - a me- thod called Evolve ＆ Resequence - it is possible to monitor at the same time phenotypic and genomie changes in populations exposed to controlled selective pressures. Experimental evolution of associative learning, a well-known trait that promptly re- sponds to selection, is a convenient model to illustrate this approach applied to behavior and cognition. Taking into account the recent achievements of the field, I discuss how to design and conduct an effective Evolve ＆ Resequence study on associative learning in Drosophila. By integrating phenotypic and genomic data in the investigation of evolutionary dynamics, new insights can be gained on longstanding questions such as the modularity of mind and its evolution .
文摘Stem cell-based therapies and extracellular vesicle(EV)treatment have demonstrated significant potential for neuroprotection against ischemic stroke.Although the neuroprotective mechanisms are not yet fully under-stood,targeting microglia is central to promoting neuroprotection.Microglia are the resident immune cells of the central nervous system.These cells are crucial in the pathogenesis of ischemic stroke.They respond rapidly to the site of injury by releasing pro-inflammatory cytokines,phagocytizing dead cells and debris,and recruiting peripheral immune cells to the ischemic area.Although these responses are essential for clearing damage and initiating tissue repair,excessive or prolonged microglial activation can exacerbate brain injury,leading to secondary neuroinflammation and neurodegeneration.Moreover,microglia exhibit a dynamic range of activation states with the so-called M1 pro-inflammatory and M2 anti-inflammatory phenotypes,representing the two ends of the spectrum.The delivery of both EVs and stem cells modulates microglial activation,suppressing pro-inflammatory genes,influencing the expression of transcription factors,and altering receptor expression,ultimately contributing to neuroprotection.These findings underscore the importance of understanding the complex and dynamic role of microglia in the development of effective neuroprotective strategies to reduce the effects of ischemic stroke.In this review,we examine the current state of knowledge regarding the role of microglia in ischemic stroke,including their molecular and cellular mechanisms,activation states,and interactions with other cells.We also discuss the multifaceted contributions of microglia to stem cell-and EV-based neuroprotection during an ischemic stroke to provide a comprehensive understanding of microglial functions and their potential implications in stroke therapies.
基金This work was supported by the German Academic Scholarship Foundation(doctoral scholarship)to L.v.D.The Adaptive Mind'funded by the Excellence Program of the Hessian Ministry of Higher Education,Research,Science and the Arts to F.B.and K.D.+1 种基金the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-project number 222641018-SFB/TRR 135 to F.B.and K.D.the European Union(ERC,DEEPFUNC,ERC-2023-STG-101117441)to K.D.
文摘In a recent study published in Cell,Marin Vargas and Bisi et al.1 present an innovative approach to unravel the computational principles underlying proprioceptive processing in non-human primates.Their findings showcase the utility of task-driven modeling in advancing neuroscience and offer translational potential by providing seminal insights into the goals and mechanisms by which the brain encodes body position and movements.
