The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regul...The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.展开更多
Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ~ 1200 che...Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ~ 1200 chemically induced mutations on the X chromosome in Drosophila fat body clones and discovered that shibire （shi） plays an essential role in starvation-induced autophagy, shi encodes a dynamin protein required for fission of clathrin-coated vesicles from the plasma membrane during endocytosis. We showed that Shi is dispensable for autophagy initiation and autophagosome--lysosome fusion, but required for lysosomal/autolysosomal acidification. We also showed that other endocytic core machinery components like clathrin and AP2 play similar but not identical roles in regulating autophagy and lysosomal function as dynamin. Previous studies suggested that dynamin directly regulates autophagosome formation and autophagic lysosome reformation （ALR） through its excision activity, Here, we provide evidence that dynamin also regulates autophagy indirectly by regulating lysosomal function.展开更多
Research has shown that dissatisfied couples in the relationship commonly exhibit facial expressions of contempt in interactions. At this point, based on the study of cognition and physiology, researchers were able to...Research has shown that dissatisfied couples in the relationship commonly exhibit facial expressions of contempt in interactions. At this point, based on the study of cognition and physiology, researchers were able to predict by longitudinal studies the probability of divorce in a marriage, with accuracy of up to 94%. Our objective was to investigate whether the occurrence of facial expressions of disgust and contempt in married women is associated with marital dissatisfaction. This is an experimental study that correlated, through filmed interviews, the frequency of facial expressions of disgust and disgust (Facial Action Coding System) to the Marital State’s Golombok Rust Inventory, in a sample composed of 20 women. Data analysis based on the Spearman Correlation Test showed a positive correlation between facial expressions of disgust and disdain and conjugal dissatisfaction (rs = 0.2198, p = 0.0280), corroborating the data in the literature.展开更多
The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells （NSCs）, are important for learning and memory as well as m...The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells （NSCs）, are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associatedcognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has garnered significant interest because targeting it could be a novel potential therapeutic strategy for these disorders. However, if we are to use nenrogenesis to halt or reverse hippocampal-related pathology, we need to understand better the core molecular machinery that governs NSC and their progeny. In this review, we summarize a wide variety of mouse models used in adult neurogenesis field, present their advantages and disadvantages based on specificity and efficiency of labeling of different cell types, and review their contribution to our understanding of the biology and the heterogeneity of different cell types found in adult neurogenic niches.展开更多
The mechanical properties of tissues are pivotal for morphogenesis and disease progression.Recent approaches have enabled measurements of the spatial distributions of viscoelastic properties among embryonic and pathol...The mechanical properties of tissues are pivotal for morphogenesis and disease progression.Recent approaches have enabled measurements of the spatial distributions of viscoelastic properties among embryonic and pathological model systems and facilitated the generation of important hypotheses such as durotaxis and tissue-scale phase transition.There likely are many unexpected aspects of embryo biomechanics we have yet to discover which will change our views of mechanisms that govern development and disease.One area in the blind spot of even the most recent approaches to measuring tissue stiffness is the potentially anisotropic nature of that parameter.Here,we report a magnetic micromanipulation device that generates a uniform magnetic field gradient within a large workspace and permits measurement of the variation of tissue stiffness along three orthogonal axes.By applying the device to the organ-stage mouse embryo,we identify spatially heterogenous and directionally anisotropic stiffness within the mandibular arch.Those properties correspond to the domain of expression and the angular distribution of fibronectin and have potential implications for mechanisms that orient collective cell movements and shape tissues during development.Assessment of anisotropic properties extends the repertoire of current methods and will enable the generation and testing of hypotheses.展开更多
Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treatin...Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treating cancer, diabetes, cardiovascular and neurodegenerative diseases. Central to developing these strategies is improving our understanding of biological mechanisms responsible for governing stem cell fate and self-renewal. Increasing attention is being given to the significance of metabolism, through the production of energy and generation of small molecules, as a critical regulator of stem cell functioning. Rapid advances in the field of metabolomics now allow for in-depth profiling of stem cells both in vitro and in vivo, providing a systems perspective on key metabolic and molecular pathways which influence stem cell biology. Understanding the analytical platforms and techniques that are currently used to study stem cell metabolomics, as well as how new insights can be derived from this knowledge, will accelerate new research in the field and improve future efforts to expand our understanding of the interplay between metabolism and stem cell biology.展开更多
Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats...Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats,e.g.,as from olive oil.In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds,the isothiocyanates(ITCs)as found in the cabbage family.The ITCs have raised great interest for their health benefits over the past few decades.Some of the key ITC compounds,sulforaphane,phenethylisothiocyanate and benzyl isothiocyanate,have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention,as anti-tumor agents,and for chemoprotection of normal tissues and organs.Along with other polyphenolic compounds in the diet,in general,they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression.In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.展开更多
The ectoderm has the capability to generate epidermis and neuroectoderm and plays imperative roles during the early embryonic development.Our recent study uncovered a region with ectodermal progenitor potential in mou...The ectoderm has the capability to generate epidermis and neuroectoderm and plays imperative roles during the early embryonic development.Our recent study uncovered a region with ectodermal progenitor potential in mouse embryo at embryonic day 7.0 and revealed that Nodal inhibition is essential for its formation.Here,we demonstrate that through brief inhibition of Nodal signaling in vitro,mouse embryonic stem cell(ESC)-derived epiblast stem cells(ESD-EpiSCs)could be committed to transient ectodermal progenitor populations,which possess the ability to give rise to neural or epidermal ectoderm in the absence or presence of BMP4,respectively.Mechanistic studies reveal that BMP4 recruits distinct transcriptional targets in ESD-EpiSCs and ectoderm-like cells.Furthermore,FGF–Erk signaling may also be alleviated during the generation of ectoderm-like cells.Thus,our data suggest that instructive interactions among several extracellular signals participate in the commitment of ectoderm from ESD-EpiSCs,which shed new light on the understanding of the formation of ectoderm during the gastrulation in early mouse embryo development.展开更多
Background： Sequence-specific binding by transcription factors （TFs） plays a significant role in the selection and regulation of target genes. At the protein：DNA interface, amino acid side-chains construct a diver...Background： Sequence-specific binding by transcription factors （TFs） plays a significant role in the selection and regulation of target genes. At the protein：DNA interface, amino acid side-chains construct a diverse physicochemical network of specific and non-specific interactions, and seemingly subtle changes in amino acid identity at certain positions may dramatically impact TF：DNA binding. Variation of these specificity-determining residues （SDRs） is a major mechanism of functional divergence between TFs with strong structural or sequence homology. Methods： In this study, we employed a combination of high-throughput specificity profiling by SELEX and Spec-seq, structural modeling, and evolutionary analysis to probe the binding preferences of winged helix-turn-helix TFs belonging to the OmpR sub-family in Escherichia coil Results： We found that E. coli OmpR paralogs recognize tandem, variably spaced repeats composed of＂GT-A＂ or ＂GCT＂-containing half-sites. Some divergent sequence preferences observed within the ＂GT-A＂ mode correlate with amino acid similarity; conversely, ＂GCT＂-based motifs were observed for a subset of paralogs with low sequence homology. Direct specificity profiling of a subset of OmpR homologues （CpxR, RstA, and OmpR） as well as predicted ＂SDR-swap＂ variants revealed that individual SDRs may impact sequence preferences locally through direct contact with DNA bases or distally via the DNA backbone. Conclusions： Overall, our work provides evidence for a common structural code for sequence-specific wHTH：DNA interactions, and demonstrates that surprisingly modest residue changes can enable recognition of highly divergent sequence motifs. Further examination of SDR predictions will likely reveal additional mechanisms controlling the evolutionary divergence of this important class of transcriptional regulators.展开更多
The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense agai...The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense against gastrointestinal viral infections.While norovirus is known to be the most common cause of gastroenteritis,leading to an estimated 200,000 deaths every year,identification of bacterial strains with protective effects against norovirus infection remains elusive.Here,we discovered Lactobacillus salivarius HHuMin-U(HHuMin-U)as a potent antiviral strain against norovirus infection.HHuMin-U significantly suppressed murine norovirus replication and lowered viral RNA titers in macrophages.The transcriptome sequencing(RNA sequencing)analysis revealed that HHuMin-U markedly enhanced the expression level of antiviral interferon-stimulated genes compared to mock treatment.HHuMin-U treatment dose-dependently induced type I interferons(IFN-αand IFN-β)and tumor necrosis factor-αproduction in mouse and human macrophages,promoting antiviral innate responses against norovirus infection.Investigation on the molecular mechanism demonstrated that HHuMin-U can activate nuclear factorκB and TANK-binding kinase 1(TBK1)–interferon regulatory factor 3 signaling pathways,leading to the phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 2,the key mediators of interferon-stimulated genes.Finally,oral administration of HHuMin-U increased IFN-βlevels in the ileum of mice and altered the gut microbiome profile.These results suggest the species/strain-specific importance of gut microbial composition for antiviral immune responses and the potential use of HHuMin-U as a probiotic agent.展开更多
基金supported by grants from Simons Foundation (SFARI 479754),CIHR (PJT-180565)the Scottish Rite Charitable Foundation of Canada (to YL)funding from the Canada Research Chairs program。
文摘The mechanistic target of rapamycin(m TOR) is a serine/threonine kinase that plays a pivotal role in cellular growth, proliferation, survival, and metabolism. In the central nervous system(CNS), the mTOR pathway regulates diverse aspects of neural development and function. Genetic mutations within the m TOR pathway lead to severe neurodevelopmental disorders, collectively known as “mTORopathies”(Crino, 2020). Dysfunctions of m TOR, including both its hyperactivation and hypoactivation, have also been implicated in a wide spectrum of other neurodevelopmental and neurodegenerative conditions, highlighting its importance in CNS health.
基金supported by the National Natural Science Foundation of China(No.31271432)the National Basic Research Program of China(Nos.2012CB966600 and 2014CB943100)the Specialized Research Fund for the Doctoral Program of Higher Education(No.20130101110116)
文摘Autophagy is a central lysosomal degradation pathway required for maintaining cellular homeostasis and its dysfunction is associated with numerous human diseases. To identify players in autophagy, we tested ~ 1200 chemically induced mutations on the X chromosome in Drosophila fat body clones and discovered that shibire （shi） plays an essential role in starvation-induced autophagy, shi encodes a dynamin protein required for fission of clathrin-coated vesicles from the plasma membrane during endocytosis. We showed that Shi is dispensable for autophagy initiation and autophagosome--lysosome fusion, but required for lysosomal/autolysosomal acidification. We also showed that other endocytic core machinery components like clathrin and AP2 play similar but not identical roles in regulating autophagy and lysosomal function as dynamin. Previous studies suggested that dynamin directly regulates autophagosome formation and autophagic lysosome reformation （ALR） through its excision activity, Here, we provide evidence that dynamin also regulates autophagy indirectly by regulating lysosomal function.
文摘Research has shown that dissatisfied couples in the relationship commonly exhibit facial expressions of contempt in interactions. At this point, based on the study of cognition and physiology, researchers were able to predict by longitudinal studies the probability of divorce in a marriage, with accuracy of up to 94%. Our objective was to investigate whether the occurrence of facial expressions of disgust and contempt in married women is associated with marital dissatisfaction. This is an experimental study that correlated, through filmed interviews, the frequency of facial expressions of disgust and disgust (Facial Action Coding System) to the Marital State’s Golombok Rust Inventory, in a sample composed of 20 women. Data analysis based on the Spearman Correlation Test showed a positive correlation between facial expressions of disgust and disdain and conjugal dissatisfaction (rs = 0.2198, p = 0.0280), corroborating the data in the literature.
文摘The mammalian hippocampus shows a remarkable capacity for continued neurogenesis throughout life. Newborn neurons, generated by the radial neural stem cells （NSCs）, are important for learning and memory as well as mood control. During aging, the number and responses of NSCs to neurogenic stimuli diminish, leading to decreased neurogenesis and age-associatedcognitive decline and psychiatric disorders. Thus, adult hippocampal neurogenesis has garnered significant interest because targeting it could be a novel potential therapeutic strategy for these disorders. However, if we are to use nenrogenesis to halt or reverse hippocampal-related pathology, we need to understand better the core molecular machinery that governs NSC and their progeny. In this review, we summarize a wide variety of mouse models used in adult neurogenesis field, present their advantages and disadvantages based on specificity and efficiency of labeling of different cell types, and review their contribution to our understanding of the biology and the heterogeneity of different cell types found in adult neurogenic niches.
基金This work was funded by the Canadian Institutes of Health Research(CIHR)Natural Sciences and Engineering Research Council of Canada(NSERC),Ontario Research Funds,and Medicine by Design–New Ideas Program.
文摘The mechanical properties of tissues are pivotal for morphogenesis and disease progression.Recent approaches have enabled measurements of the spatial distributions of viscoelastic properties among embryonic and pathological model systems and facilitated the generation of important hypotheses such as durotaxis and tissue-scale phase transition.There likely are many unexpected aspects of embryo biomechanics we have yet to discover which will change our views of mechanisms that govern development and disease.One area in the blind spot of even the most recent approaches to measuring tissue stiffness is the potentially anisotropic nature of that parameter.Here,we report a magnetic micromanipulation device that generates a uniform magnetic field gradient within a large workspace and permits measurement of the variation of tissue stiffness along three orthogonal axes.By applying the device to the organ-stage mouse embryo,we identify spatially heterogenous and directionally anisotropic stiffness within the mandibular arch.Those properties correspond to the domain of expression and the angular distribution of fibronectin and have potential implications for mechanisms that orient collective cell movements and shape tissues during development.Assessment of anisotropic properties extends the repertoire of current methods and will enable the generation and testing of hypotheses.
文摘Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treating cancer, diabetes, cardiovascular and neurodegenerative diseases. Central to developing these strategies is improving our understanding of biological mechanisms responsible for governing stem cell fate and self-renewal. Increasing attention is being given to the significance of metabolism, through the production of energy and generation of small molecules, as a critical regulator of stem cell functioning. Rapid advances in the field of metabolomics now allow for in-depth profiling of stem cells both in vitro and in vivo, providing a systems perspective on key metabolic and molecular pathways which influence stem cell biology. Understanding the analytical platforms and techniques that are currently used to study stem cell metabolomics, as well as how new insights can be derived from this knowledge, will accelerate new research in the field and improve future efforts to expand our understanding of the interplay between metabolism and stem cell biology.
文摘Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats,e.g.,as from olive oil.In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds,the isothiocyanates(ITCs)as found in the cabbage family.The ITCs have raised great interest for their health benefits over the past few decades.Some of the key ITC compounds,sulforaphane,phenethylisothiocyanate and benzyl isothiocyanate,have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention,as anti-tumor agents,and for chemoprotection of normal tissues and organs.Along with other polyphenolic compounds in the diet,in general,they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression.In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.
基金Thisworkwas supported in part by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA01010201)the National Key Basic Research and Development Program of China(2014CB964804,2015CB964500)the National Natural Science Foundation of China(91219303,31430058).
文摘The ectoderm has the capability to generate epidermis and neuroectoderm and plays imperative roles during the early embryonic development.Our recent study uncovered a region with ectodermal progenitor potential in mouse embryo at embryonic day 7.0 and revealed that Nodal inhibition is essential for its formation.Here,we demonstrate that through brief inhibition of Nodal signaling in vitro,mouse embryonic stem cell(ESC)-derived epiblast stem cells(ESD-EpiSCs)could be committed to transient ectodermal progenitor populations,which possess the ability to give rise to neural or epidermal ectoderm in the absence or presence of BMP4,respectively.Mechanistic studies reveal that BMP4 recruits distinct transcriptional targets in ESD-EpiSCs and ectoderm-like cells.Furthermore,FGF–Erk signaling may also be alleviated during the generation of ectoderm-like cells.Thus,our data suggest that instructive interactions among several extracellular signals participate in the commitment of ectoderm from ESD-EpiSCs,which shed new light on the understanding of the formation of ectoderm during the gastrulation in early mouse embryo development.
文摘Background： Sequence-specific binding by transcription factors （TFs） plays a significant role in the selection and regulation of target genes. At the protein：DNA interface, amino acid side-chains construct a diverse physicochemical network of specific and non-specific interactions, and seemingly subtle changes in amino acid identity at certain positions may dramatically impact TF：DNA binding. Variation of these specificity-determining residues （SDRs） is a major mechanism of functional divergence between TFs with strong structural or sequence homology. Methods： In this study, we employed a combination of high-throughput specificity profiling by SELEX and Spec-seq, structural modeling, and evolutionary analysis to probe the binding preferences of winged helix-turn-helix TFs belonging to the OmpR sub-family in Escherichia coil Results： We found that E. coli OmpR paralogs recognize tandem, variably spaced repeats composed of＂GT-A＂ or ＂GCT＂-containing half-sites. Some divergent sequence preferences observed within the ＂GT-A＂ mode correlate with amino acid similarity; conversely, ＂GCT＂-based motifs were observed for a subset of paralogs with low sequence homology. Direct specificity profiling of a subset of OmpR homologues （CpxR, RstA, and OmpR） as well as predicted ＂SDR-swap＂ variants revealed that individual SDRs may impact sequence preferences locally through direct contact with DNA bases or distally via the DNA backbone. Conclusions： Overall, our work provides evidence for a common structural code for sequence-specific wHTH：DNA interactions, and demonstrates that surprisingly modest residue changes can enable recognition of highly divergent sequence motifs. Further examination of SDR predictions will likely reveal additional mechanisms controlling the evolutionary divergence of this important class of transcriptional regulators.
基金a National Research Foundation of Korea(NRF)grant funded by the Korean Government(Ministry of Science,ICT and Future Planning)(2020R1A2C1010703).
文摘The composition of commensal bacteria plays a critical role in controlling immune responses in the intestine.Studies have shown that specific bacterial strains may have the capacity to enhance host immune defense against gastrointestinal viral infections.While norovirus is known to be the most common cause of gastroenteritis,leading to an estimated 200,000 deaths every year,identification of bacterial strains with protective effects against norovirus infection remains elusive.Here,we discovered Lactobacillus salivarius HHuMin-U(HHuMin-U)as a potent antiviral strain against norovirus infection.HHuMin-U significantly suppressed murine norovirus replication and lowered viral RNA titers in macrophages.The transcriptome sequencing(RNA sequencing)analysis revealed that HHuMin-U markedly enhanced the expression level of antiviral interferon-stimulated genes compared to mock treatment.HHuMin-U treatment dose-dependently induced type I interferons(IFN-αand IFN-β)and tumor necrosis factor-αproduction in mouse and human macrophages,promoting antiviral innate responses against norovirus infection.Investigation on the molecular mechanism demonstrated that HHuMin-U can activate nuclear factorκB and TANK-binding kinase 1(TBK1)–interferon regulatory factor 3 signaling pathways,leading to the phosphorylation of signal transducer and activator of transcription 1 and signal transducer and activator of transcription 2,the key mediators of interferon-stimulated genes.Finally,oral administration of HHuMin-U increased IFN-βlevels in the ileum of mice and altered the gut microbiome profile.These results suggest the species/strain-specific importance of gut microbial composition for antiviral immune responses and the potential use of HHuMin-U as a probiotic agent.
