Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal burden.At the neuropathological level,the brains of A...Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal burden.At the neuropathological level,the brains of AD patients exhibit amyloid-β(Aβ)plaques,neurofibrillary tangles,and neuroinflammation(Sala Frigerio and De Strooper,2016).展开更多
Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment o...Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.展开更多
The present study aimed at determining whether short-term exposure to art in shared common areas in congregate housing units could affect health and health determinants among the residents. Ten residents (mean age 80....The present study aimed at determining whether short-term exposure to art in shared common areas in congregate housing units could affect health and health determinants among the residents. Ten residents (mean age 80.4 years) at one block were exposed to visual art environmental enrichment in common areas over a period of three months. Thirteen persons (mean age 86.6 years) living in another block played in-house boule. Cornell’s test, Mini-Mental tests (MMT), and face recognition test were performed to assess depression, cognition, and episodic memory, respectively before and after the intervention. The results show that visual art environmental enrichment in common areas and lack of stimulating and guiding dialogues show a change in depression scores in the intervention group (p = 0.018) and the control group (p = 0.009). MMT scores improved only in the control group (p = 0.003). No changes in episodic memory in any of the groups were observed. It could be concluded that in order to obtain a positive result of short term visual art environmental enrichment, guiding art dialogues conducted by nurses, as described in previous research, should be added to visual art environmental enrichment in healthcare settings.展开更多
Astrocytes protect neurons by modulating neuronal function and survival.Astrocytes support neurons in several ways.They provide energy through the astrocyte-neuron lactate shuttle,protect neurons from excitotoxicity,a...Astrocytes protect neurons by modulating neuronal function and survival.Astrocytes support neurons in several ways.They provide energy through the astrocyte-neuron lactate shuttle,protect neurons from excitotoxicity,and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support,as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine.A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine,such as aminochrome and other o-quinones,were generated under neuromelanin synthesis by oxidizing dopamine catechol structure.Astrocytes secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome neurotoxicity.The role of this new astrocyte protective mechanism in Parkinson´s disease is discussed.展开更多
Nonalcoholic fatty liver disease is a common medical condition worldwide and its prevalence has increased notably in the past few years due to the increases in prevalence of obesity and metabolic syndrome. However, di...Nonalcoholic fatty liver disease is a common medical condition worldwide and its prevalence has increased notably in the past few years due to the increases in prevalence of obesity and metabolic syndrome. However, diagnosis of this disease is still a matter of debate because of disease variations and pathophysiologic alterations. Specific single markers have gained con-siderable attention recently, among them markers related to hepatic pathophysiology, inflammation, adipocytokines and so forth. But, it seems that no single marker is sufficient for diagnosis and staging of the disease, and applying a panel including different types of tests may be more useful.展开更多
To estimate essential fatty acid (FA) and long-chain polyunsaturated fatty acid (LCPUFA) concentrations in early breast milk (BM) in relation to habitual fish intake. BM was collected within 72-hours after delivery fr...To estimate essential fatty acid (FA) and long-chain polyunsaturated fatty acid (LCPUFA) concentrations in early breast milk (BM) in relation to habitual fish intake. BM was collected within 72-hours after delivery from consecutively included mothers, 60 in Guilan (coastal) and 60 in Kermanshah (inland) provinces. Mothers were interviewed to com-plete a food frequency questionnaire. The FA composition was measured with gas chromatography. Mothers in the coastal area had higher intake of fish/seafood. Consumption of saturated fat was higher in Kermanshah and olive intake was higher in Guilan. High fish/seafood intake was associated with higher docosahexaenoic acid (DHA) and lower arachidonic acid (AA)/DHA ratio in BM. There were no differences in linoleic and α-linolenic acid concentrations in BM between the provinces. N-3 FA and DHA concentration were significantly higher in Guilan than Kermanshah, but total n-6 FAs and AA did not differ and were high in both provinces. The ratios of total n-6/n-3 and AA/DHA in BM of mothers from Guilan were significantly lower than those in Kermanshah. The LCPUFA status in BM in two Iranian provinces was generally good and DHA was higher and the AA/DHA was significantly lower in mothers with high fish intake.展开更多
The liver X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the ...The liver X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the zebrafish model. By in situ hybridization we showed distinct expression of lxr in the brain and the retina in the developing and adult zebrafish. Lxr ligand activation affected the expression of genes involved in lipid metabolism in zebrafish adult brain and eye as well as in zebrafish embryos. Morpholino knock down of lxr resulted in an overall impaired lipid deposition as determined by oil red O staining particularly in the head and around the eyes, and to significantly elevated levels of both total and free cholesterol in the yolk of lxr morphant embryos. The expression of genes involved in lipid and cholesterol metabolism was also changed in the lxr morphants. Furthermore, alcian blue staining revealed malformation of the pharyngeal skeleton in the lxr morphant. Our data show that lxr is an important component of the regulatory network governing the lipid homeostasis during zebrafish development, which in turn may support a role of lxr for normal development of the central nervous sytem, including the retina.展开更多
Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence sugge...Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence suggesting that microglia-released galectin-3(gal3)plays a pivotal role by amplifying neuroinflammation in AD.However,the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.Methods Here,we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo(20-80 Hz)by performing electrophysiological recordings in the hippocampal CA3 area of wild-type(WT)mice and of the 5×FAD mouse model of AD.In addition,the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes,and amyloid-β(Aβ)plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout(KO).Results Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner,which was accompanied by impairment of cellular dynamics in fast-spiking interneurons(FSNs)and pyramidal cells.We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139,which also prevented Aβ42-induced degradation of gamma oscillations.Further-more,the 5×FAD mice lacking gal3(5×FAD-Gal3KO)exhibited WT-like gamma network dynamics and decreased Aβplaque load.Conclusions We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs,inducing a network performance collapse.Moreover,our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.展开更多
Dear Editor, Heat shock factors （HSFs） constitute a transcription factor family playing regulatory roles in maintaining cellular protein homeostasis or mediating cell differentiation and develop- ment （Akerfelt et ...Dear Editor, Heat shock factors （HSFs） constitute a transcription factor family playing regulatory roles in maintaining cellular protein homeostasis or mediating cell differentiation and develop- ment （Akerfelt et al., 2010, Bjork and Sistonen 2010, Westerheide et al., 2012）. Some human diseases such as cancer and neurodegeneration are often linked with mal- function of HSFs （Dai et al., 2007, Neef et al., 2011, Scherz- Shouval et al., 2014）. The human HSF family consists four members： HSF1-4, which exhibit tissue-specific expression profiles and possess unique but overlapping functions. HSF1 is the major regulator of the heat shock response.展开更多
Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesi...Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated manners.Other than BM,extramedullary hematopoiesis is discovered in various pathophysiological settings.However,whether tumors can contribute to hematopoiesis is completely unknown.Accumulating evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other cells.Here,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis.Methods:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived pericytes.Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo.Fluorescence-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological studies.The production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and immunohistochemistry.To investigate BM function in tumor erythropoiesis,BM transplantation mouse models were employed.Results:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage.PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates erythropoiesis.FACS analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells.Single-cell sequencing and colony formation assays validated the fact that,upon PDGF-B stimulation,NG2+cells isolated from tumors acted as erythroblast progenitor cells,which were distinctive from the canonical BM hematopoietic stem cells.Conclusions:Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME.Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.展开更多
Immunology has become as an attractive discipline of biomedical science in the 21st century,integrated with the rapid development of molecular biology,cell biology,structural biology,genetics and other branches in lif...Immunology has become as an attractive discipline of biomedical science in the 21st century,integrated with the rapid development of molecular biology,cell biology,structural biology,genetics and other branches in life sciences.A special issue of Sci China Life Sci was published in February 2010 to highlight recent progresses in immunology.Six review articles focusing on various specific topics were contributed by leading scientists who work in respective fields of immunology.Some progresses of immunology research in China are also described.展开更多
In a recent study published in Nature,Suryawanshi et al.showed that primary Omicron infection only elicits a mild humoral immune response and limited cross-variant neutralization in non-vaccinated individuals.1On the ...In a recent study published in Nature,Suryawanshi et al.showed that primary Omicron infection only elicits a mild humoral immune response and limited cross-variant neutralization in non-vaccinated individuals.1On the other hand,vaccinated individuals developed high neutralizing antibody titers against all variants of concern(VOCs)following breakthrough Omicron infections.Hence,Omicron infection can enhance existing immunity induced by vaccination but may not prevent reinfection by other VOCs in non-vaccinated individuals.展开更多
基金supported by grants from the Alzheimer’s Association Research Grant(to GC)Olle Engkvists Stiftelse(to GC)+10 种基金the Petrus and Augusta Hedlunds Stiftelse(to GC)Ake Wibergs stiftelse(to GC)the Swedish Alzheimer foundation(to GC)the Ahlén Stiftelsens(to GC)Karolinska Institutet Research Foundation Grant(to GC)the Stiftelsen for Gamla Tjanarinnor(to GC)the Stiftelsen Sigurd och Elsa Goljes Minne(to GC)the Loo and Hans Osterman Foundation(to GC)Geriatric Diseases Foundation at Karolinska Institutet(to GC)the Gun and Bertil Stohne’s Foundation(to GC)the Magnus Bergvall Foundation(to GC).
文摘Alzheimer’s disease(AD)is the most prevalent form of dementia,i.e.,progressive memory loss and profound cognitive dysfunction,resulting in a considerable societal burden.At the neuropathological level,the brains of AD patients exhibit amyloid-β(Aβ)plaques,neurofibrillary tangles,and neuroinflammation(Sala Frigerio and De Strooper,2016).
基金supported by the China Scholarship Council(to YW)the Swedish Research Council,No.2018-02601(to MS)+7 种基金the Alzheimer Foundation,No.AF-980695(to MS)the Stockholm County Council,No.RS2020-0731(to MS)the Foundation of Old Servants(to MS)the Gun and Bertil Stohne Foundation(to MS)the?hlén Foundation,No.233055(to MS)The Swedish Fund for Research without Animal Experiments(to MS)the Swedish Dementia Foundation(to MS)the Brain foundation,No.FO2022-0131(to MS)。
文摘Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.
文摘The present study aimed at determining whether short-term exposure to art in shared common areas in congregate housing units could affect health and health determinants among the residents. Ten residents (mean age 80.4 years) at one block were exposed to visual art environmental enrichment in common areas over a period of three months. Thirteen persons (mean age 86.6 years) living in another block played in-house boule. Cornell’s test, Mini-Mental tests (MMT), and face recognition test were performed to assess depression, cognition, and episodic memory, respectively before and after the intervention. The results show that visual art environmental enrichment in common areas and lack of stimulating and guiding dialogues show a change in depression scores in the intervention group (p = 0.018) and the control group (p = 0.009). MMT scores improved only in the control group (p = 0.003). No changes in episodic memory in any of the groups were observed. It could be concluded that in order to obtain a positive result of short term visual art environmental enrichment, guiding art dialogues conducted by nurses, as described in previous research, should be added to visual art environmental enrichment in healthcare settings.
基金CAMS Innovation Fund for Medical Sciences(2021‐I2M‐1‐017),the National Natural Science Foundation of China(81970107),State Key Laboratory of Experimental Hematology Research Grant(Z22‐02)和Tianjin“131”Science Fund for Creative Research Groups(2021)基金支持Yihai Cao获得the Swed is h Research Counc i l(2016‐02215,2019‐01502,2020‐06121,2021‐06122),National Key R&D Program of China(2020YFC0846600)+6 种基金the Hong Kong Centre for Cerebro‐cardiovascular Health Engineering,the Swedish Cancer Foundation(200734PjF),the Swedish Children's Cancer Foundation(PR2018‐0107)the Strategic Research Areas(SFO)‐Stem Cell and Regenerative Medicine Foundation,the Karolinska Institute Foundation(2020‐02080)the Karolinska Institute distinguished professor award,and the Karolinska Institute Foundation(2020‐02588)基金支持Kayoko Hosaka获得the Karolinska Institute Foundation基金支持Takahiro Seki获得the Scandinavia‐Japan Sasakawa Foundation基金支持Xu Jing获得the National Natural Science Foundation of China(81801163)and Doctor Fund of Shandong Natural Science Foundation(ZR201807060846)基金支持Masahito Yoshihara获得the Japan Society for the Promotion of Science(JSPS)Overseas Research Fellowships基金支持。
基金supported by ANID-FONDECYT 1170033(to JSA)ANID-STINT-CONICYT CS2018-7940(to JSA,IN,JI,MV)Swedish Research Council grant 2015-04222 to BM.
文摘Astrocytes protect neurons by modulating neuronal function and survival.Astrocytes support neurons in several ways.They provide energy through the astrocyte-neuron lactate shuttle,protect neurons from excitotoxicity,and internalize neuronal lipid droplets to degrade fatty acids for neuronal metabolic and synaptic support,as well as by their high capacity for glutamate uptake and the conversion of glutamate to glutamine.A recent reported astrocyte system for protection of dopamine neurons against the neurotoxic products of dopamine,such as aminochrome and other o-quinones,were generated under neuromelanin synthesis by oxidizing dopamine catechol structure.Astrocytes secrete glutathione transferase M2-2 through exosomes that transport this enzyme into dopaminergic neurons to protect these neurons against aminochrome neurotoxicity.The role of this new astrocyte protective mechanism in Parkinson´s disease is discussed.
文摘Nonalcoholic fatty liver disease is a common medical condition worldwide and its prevalence has increased notably in the past few years due to the increases in prevalence of obesity and metabolic syndrome. However, diagnosis of this disease is still a matter of debate because of disease variations and pathophysiologic alterations. Specific single markers have gained con-siderable attention recently, among them markers related to hepatic pathophysiology, inflammation, adipocytokines and so forth. But, it seems that no single marker is sufficient for diagnosis and staging of the disease, and applying a panel including different types of tests may be more useful.
文摘To estimate essential fatty acid (FA) and long-chain polyunsaturated fatty acid (LCPUFA) concentrations in early breast milk (BM) in relation to habitual fish intake. BM was collected within 72-hours after delivery from consecutively included mothers, 60 in Guilan (coastal) and 60 in Kermanshah (inland) provinces. Mothers were interviewed to com-plete a food frequency questionnaire. The FA composition was measured with gas chromatography. Mothers in the coastal area had higher intake of fish/seafood. Consumption of saturated fat was higher in Kermanshah and olive intake was higher in Guilan. High fish/seafood intake was associated with higher docosahexaenoic acid (DHA) and lower arachidonic acid (AA)/DHA ratio in BM. There were no differences in linoleic and α-linolenic acid concentrations in BM between the provinces. N-3 FA and DHA concentration were significantly higher in Guilan than Kermanshah, but total n-6 FAs and AA did not differ and were high in both provinces. The ratios of total n-6/n-3 and AA/DHA in BM of mothers from Guilan were significantly lower than those in Kermanshah. The LCPUFA status in BM in two Iranian provinces was generally good and DHA was higher and the AA/DHA was significantly lower in mothers with high fish intake.
基金the Swedish Research Council (1213-45762)Karolinska Institutet
文摘The liver X-receptors (LXRs) act as cholesterol sensors and participate in the regulation of lipid and cholesterol metabolism. The objective of this study was to determine the role of LXR during development using the zebrafish model. By in situ hybridization we showed distinct expression of lxr in the brain and the retina in the developing and adult zebrafish. Lxr ligand activation affected the expression of genes involved in lipid metabolism in zebrafish adult brain and eye as well as in zebrafish embryos. Morpholino knock down of lxr resulted in an overall impaired lipid deposition as determined by oil red O staining particularly in the head and around the eyes, and to significantly elevated levels of both total and free cholesterol in the yolk of lxr morphant embryos. The expression of genes involved in lipid and cholesterol metabolism was also changed in the lxr morphants. Furthermore, alcian blue staining revealed malformation of the pharyngeal skeleton in the lxr morphant. Our data show that lxr is an important component of the regulatory network governing the lipid homeostasis during zebrafish development, which in turn may support a role of lxr for normal development of the central nervous sytem, including the retina.
基金funding provided by Karolinska Institute.This work was supported by the Swedish Research Council,the Swedish Brain Foundation,the Swedish Alzheimer Foundation,theÅhlén Foundation(AF),the Berger Foundation(TD),the Olle Engkvist Foundation(TD),G&K Kock Foundation(TD),the Strategic Research Area MultiPark at Lund University(TD),the Foundation for Geriatric Diseases at Karolinska Institutet,theÅhlén Foundation(YAT),Consejo Nacional de Ciencia y Tecnología(CONACYT)postdoctoral fellowships and StratNeuro program at Karolinska Institutet(LEAG),Lindhés Advokabyra AB Grant and Stohnes Stiftelse(LEAG,YAT)the Spanish Ministerio de Ciencia e Innovación(MICIN/AEI/FEDER:PID2019-107677 GB-I00,ARM).
文摘Background Alzheimer’s disease(AD)is a progressive multifaceted neurodegenerative disorder for which no disease-modifying treatment exists.Neuroinflammation is central to the pathology progression,with evidence suggesting that microglia-released galectin-3(gal3)plays a pivotal role by amplifying neuroinflammation in AD.However,the possible involvement of gal3 in the disruption of neuronal network oscillations typical of AD remains unknown.Methods Here,we investigated the functional implications of gal3 signaling on experimentally induced gamma oscillations ex vivo(20-80 Hz)by performing electrophysiological recordings in the hippocampal CA3 area of wild-type(WT)mice and of the 5×FAD mouse model of AD.In addition,the recorded slices from WT mice under acute gal3 application were analyzed with RT-qPCR to detect expression of some neuroinflammation-related genes,and amyloid-β(Aβ)plaque load was quantified by immunostaining in the CA3 area of 6-month-old 5×FAD mice with or without Gal3 knockout(KO).Results Gal3 application decreased gamma oscillation power and rhythmicity in an activity-dependent manner,which was accompanied by impairment of cellular dynamics in fast-spiking interneurons(FSNs)and pyramidal cells.We found that the gal3-induced disruption was mediated by the gal3 carbohydrate-recognition domain and prevented by the gal3 inhibitor TD139,which also prevented Aβ42-induced degradation of gamma oscillations.Further-more,the 5×FAD mice lacking gal3(5×FAD-Gal3KO)exhibited WT-like gamma network dynamics and decreased Aβplaque load.Conclusions We report for the first time that gal3 impairs neuronal network dynamics by spike-phase uncoupling of FSNs,inducing a network performance collapse.Moreover,our findings suggest gal3 inhibition as a potential therapeutic strategy to counteract the neuronal network instability typical of AD and other neurological disorders encompassing neuroinflammation and cognitive decline.
文摘Dear Editor, Heat shock factors （HSFs） constitute a transcription factor family playing regulatory roles in maintaining cellular protein homeostasis or mediating cell differentiation and develop- ment （Akerfelt et al., 2010, Bjork and Sistonen 2010, Westerheide et al., 2012）. Some human diseases such as cancer and neurodegeneration are often linked with mal- function of HSFs （Dai et al., 2007, Neef et al., 2011, Scherz- Shouval et al., 2014）. The human HSF family consists four members： HSF1-4, which exhibit tissue-specific expression profiles and possess unique but overlapping functions. HSF1 is the major regulator of the heat shock response.
基金CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-017National Natural Science Foundation of China,Grant/Award Number:81970107+12 种基金State Key Laboratory of Experimental Hematology Research,Grant/Award Number:Z22-02Tianjin“131”Science Fund for Creative Research Groups,Grant/Award Number:2021Swedish Research Council,Grant/Award Numbers:2016-02215,2019-01502,2020-06121,2021-06122National Key R&D Program of China,Grant/Award Number:2020YFC0846600Hong Kong Centre for Cerebro-cardiovascular Health EngineeringSwedish Cancer Foundation,Grant/Award Number:200734PjFSwedish Children’s Cancer Foundation,Grant/Award Number:PR2018-0107Strategic Research Areas(SFO)-Stem Cell and Regenerative Medicine FoundationKarolinska Institute distinguished professor awardKarolinska Institute FoundationScandinavia-Japan Sasakawa Foundation,Grant/Award Number:81801163Doctor Fund of Shandong Natural Science Foundation,Grant/Award Number:ZR201807060846Japan Society for the Promotion of Science(JSPS)Overseas Research Fellowships。
文摘Background:Tumors possess incessant growth features,and expansion of their masses demands sufficient oxygen supply by red blood cells(RBCs).In adult mammals,the bone marrow(BM)is the main organ regulating hematopoiesis with dedicated manners.Other than BM,extramedullary hematopoiesis is discovered in various pathophysiological settings.However,whether tumors can contribute to hematopoiesis is completely unknown.Accumulating evidence shows that,in the tumor microenvironment(TME),perivascular localized cells retain progenitor cell properties and can differentiate into other cells.Here,we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis.Methods:To test if vascular cells can differentiate into RBCs,genome-wide expression profiling was performed using mouse-derived pericytes.Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo.Fluorescence-activated cell sorting(FACS),single-cell sequencing,and colony formation assays were applied for biological studies.The production of erythroid differentiationspecific cytokine,erythropoietin(EPO),in TME was checked using quantitative polymerase chain reaction(qPCR),enzyme-linked immunosorbent assay(ELISA,magnetic-activated cell sorting and immunohistochemistry.To investigate BM function in tumor erythropoiesis,BM transplantation mouse models were employed.Results:Genome-wide expression profiling showed that in response to plateletderived growth factor subunit B(PDGF-B),neural/glial antigen 2(NG2)+perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage.PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO,a crucial hormone that necessitates erythropoiesis.FACS analysis using genetic tracing of NG2+cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells.Single-cell sequencing and colony formation assays validated the fact that,upon PDGF-B stimulation,NG2+cells isolated from tumors acted as erythroblast progenitor cells,which were distinctive from the canonical BM hematopoietic stem cells.Conclusions:Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME.Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.
文摘Immunology has become as an attractive discipline of biomedical science in the 21st century,integrated with the rapid development of molecular biology,cell biology,structural biology,genetics and other branches in life sciences.A special issue of Sci China Life Sci was published in February 2010 to highlight recent progresses in immunology.Six review articles focusing on various specific topics were contributed by leading scientists who work in respective fields of immunology.Some progresses of immunology research in China are also described.
基金H.M,L.H,and Q.P.H.are supported by the European Union's Horizon 2020 research and innovation program under grant agreement No 101003650(ATAC)the Swedish Research Council,and the Knut and Alice Wallenberg Foundation(KAW).
文摘In a recent study published in Nature,Suryawanshi et al.showed that primary Omicron infection only elicits a mild humoral immune response and limited cross-variant neutralization in non-vaccinated individuals.1On the other hand,vaccinated individuals developed high neutralizing antibody titers against all variants of concern(VOCs)following breakthrough Omicron infections.Hence,Omicron infection can enhance existing immunity induced by vaccination but may not prevent reinfection by other VOCs in non-vaccinated individuals.
