Hepatic encephalopathy,defined as neuropsychiatric dysfunction secondary to liver disease,is a frequent decompensating event in cirrhosis.Its clinical impact is highlighted by a notable increase in patient mortality r...Hepatic encephalopathy,defined as neuropsychiatric dysfunction secondary to liver disease,is a frequent decompensating event in cirrhosis.Its clinical impact is highlighted by a notable increase in patient mortality rates and a concomitant reduction in overall quality of life.Systemically,liver disease,liver function failure,portosystemic shunting,and associated multi-organ dysfunction result in the increase of disease-causing neurotoxins in the circulation,which impairs cerebral homeostasis.Key circulating neurotoxins are ammonia and inflammatory mediators.In the brain,pathophysiology is less well understood,but is thought to be driven by glial cell dysfunction.Astrocytes are the only brain resident cells that have ammonia-metabolizing machinery and are therefore putatively most susceptible to ammonia elevation.Based on a large body of mostly in vitro evidence,ammonia-induced cellular and molecular disturbances include astrocyte swelling and oxidative stress.Microglia,the brain resident macrophages,have been linked to the translation of systemic inflammation to the brain microenvironment.Recent evidence from animal studies has provided novel insights into old and new downstream effects of astrocyte and microglial dysfunction such as toxin clearance disruption and myeloid cell attraction to the central nervous system parenchyma.Furthermore,state of the art research increasingly implicates neuronal dysfunction and possibly even irreversible neuronal cell death.Cell-type specific investigation in animal models highlights the need for critical revision of the contribution of astrocytes and microglia to well-established and novel cellular and molecular alterations in hepatic encephalopathy.In this review,we therefore give a current and comprehensive overview of causes,features,and consequences of astrocyte and microglial dysfunction in hepatic encephalopathy,including areas of interest for future investigation.展开更多
Background Heat stress(HS) incidence is associated with the accumulation of reactive substances, which might be associated with bone loss. N-Acetylcysteine(NAC) exhibits strong antioxidants due to its sulfhydryl group...Background Heat stress(HS) incidence is associated with the accumulation of reactive substances, which might be associated with bone loss. N-Acetylcysteine(NAC) exhibits strong antioxidants due to its sulfhydryl group and being as the precursor for endogenous glutathione synthesis. Therefore, interplay between oxidative stress and bone turnover of broilers and the effects of dietary NAC inclusion on antioxidant capability and “gut-bone” axis were evaluated during chronic HS.Results Implementing cyclic chronic HS(34 ℃ for 7 h/d) evoked reactive oxygen species excessive production and oxidant stress, which was accompanied by compromised tibia mass. The RNA-seq of proximal tibia also revealed the enrichment of oxidation–reduction process and inflammatory outbursts during HS. Although no notable alterations in the growth performance and cecal microbiota were found, the diet contained 2 g/kg NAC enhanced the antioxidant capability of heat-stressed broiler chickens by upregulating the expression of Nrf2 in the ileum, tibia, and bone marrow. Simultaneously, NAC tended to hinder NF-κB pathway activation and decreased the m RNA levels of the proinflammatory cytokines in both the ileum and bone marrow. As a result, NAC suppressed osteoclastogenesis and osteoclast activity, thereby increasing osteocyte-related gene expression. Furthermore, the inclusion of NAC tended to increase the ash content and density of the whole tibia, as well as improve cortical thickness and bone volume of the diaphysis.Conclusions These findings HS-mediated outburst of oxidant stress accelerates bone resorption and negatively regulates the bone quality of tibia, which is inhibited by NAC in broilers.展开更多
The evaluation of plant-based feedstocks is an important aspect of biorefining.Nicotiana glauca is a solanaceous,non-food crop that produces large amounts of biomass and is well adapted to grow in suboptimal condition...The evaluation of plant-based feedstocks is an important aspect of biorefining.Nicotiana glauca is a solanaceous,non-food crop that produces large amounts of biomass and is well adapted to grow in suboptimal conditions.In the present article,compatible sequential solvent extractions were applied to N.glauca leaves to enable the generation of enriched extracts containing higher metabolite content comparing to direct leaf extracts.Typically,between 60 to 100 metabolite components were identified within the fractions.The occurrence of plant fatty acids,fatty acid alcohols,alkanes,sterols and terpenoids was detected by gas liquid chromatography-mass spectrometry(GC-MS)and metabolite identification was confirmed by comparison of physico-chemical properties displayed by available authentic standards.Collectively,co-products such waxes,oils,fermentable sugars,and terpenoids were all identified and quantified.The enriched fractions of N.glauca revealed a high level of readily extractable hydrocarbons,oils and high value co-products.In addition,the saccharification yield and cell wall composition analyses in the stems revealed the potential of the residue material as a promising lignocellulosic substrate for the production of fermentable sugars.In conclusion a multifractional cascade for valuable compounds/commodities has been development,that uses N.glauca biomass.These data have enabled the evaluation of N.glauca material as a potential feedstock for biorefining.展开更多
Due to the aging of the population and despite the enormous scientific effort,Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine.Novel insights highlight the i...Due to the aging of the population and despite the enormous scientific effort,Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine.Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer's disease.Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2,but that also regulates several brain functions in health and disease.However,clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer's disease led to inconclusive results,partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1,but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials.We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer's disease patients,signaling via tumor necrosis factor receptor 1.In agreement with this,choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer's disease mouse models.Interestingly,both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer's disease-associated inflammation,choroidal morphology and cognitive functioning.Here,we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in(early) Alzheimer's disease,and the consequences this might have on the disease progression.As the main hypothesis in Alzheimer's disease clinical trials is still based on the amyloid beta-cascade,the importance of Alzheimer's disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer's disease and prevent the irreversible neurodegeneration and resulting memory decline.展开更多
The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial（CPE） cells surrounding fenestrated capillaries.These CPE cells not only form ...The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial（CPE） cells surrounding fenestrated capillaries.These CPE cells not only form an anatomical barrier,called the blood-cerebrospinal fluid barrier（BCSFB）,but also present an active interface between blood and cerebrospinal fluid（CSF）.CPE cells perform indispensable functions for the development,maintenance and functioning of the brain.Indeed,the primary role of the choroid plexus in the brain is to maintain homeostasis by secreting CSF which contains different molecules,such as nutrients,neurotrophins,and growth factors,as well as by clearing toxic and undesirable molecules from CSF.The choroid plexus also acts as a selective entry gate for leukocytes into the brain.Recent findings have revealed distinct changes in CPE cells that are associated with aging and Alzheimer＇s disease.In this review,we review some recent findings that highlight the importance of the CPE-CSF system in Alzheimer＇s disease and we summarize the recent advances in the regeneration of brain tissue through use of CPE cells as a new therapeutic strategy.展开更多
The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous template.Cartilage cells, or chondrocytes, survive, proliferate and synthesize extracellular matrix in a...The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous template.Cartilage cells, or chondrocytes, survive, proliferate and synthesize extracellular matrix in an avascular environment, but the metabolic requirements for these anabolic processes are not fully understood. Here, using metabolomics analysis and genetic in vivo models, we show that maintaining intracellular serine homeostasis is essential for chondrocyte function. De novo serine synthesis through phosphoglycerate dehydrogenase(PHGDH)-mediated glucose metabolism generates nucleotides that are necessary for chondrocyte proliferation and long bone growth. On the other hand, dietary serine is less crucial during endochondral bone formation, as serine-starved chondrocytes compensate by inducing PHGDH-mediated serine synthesis.Mechanistically, this metabolic flexibility requires ATF4, a transcriptional regulator of amino acid metabolism and stress responses.We demonstrate that both serine deprivation and PHGDH inactivation enhance ATF4 signaling to stimulate de novo serine synthesis and serine uptake, respectively, and thereby prevent intracellular serine depletion and chondrocyte dysfunction. A similar metabolic adaptability between serine uptake and de novo synthesis is observed in the cartilage callus during fracture repair.Together, the results of this study reveal a critical role for PHGDH-dependent serine synthesis in maintaining intracellular serine levels under physiological and serine-limited conditions, as adequate serine levels are necessary to support chondrocyte proliferation during endochondral ossification.展开更多
Purpose: Alteration of liver function during pro- gression of hepatocellular carcinoma (HCC) and cirrhosis affects the serum glycoprotein pattern. In this study, the changes in the N-glycome in liver tis- sue from pat...Purpose: Alteration of liver function during pro- gression of hepatocellular carcinoma (HCC) and cirrhosis affects the serum glycoprotein pattern. In this study, the changes in the N-glycome in liver tis- sue from patients with hepatocellular carcinoma and cirrhosis caused by hepatitis B virus infection were investigated to find out the relationship between this maker and liver disease. Methods: Twenty patients, 11 with cirrhosis and 9 with hepatocellular carcinoma, and 15 healthy donors were involved in this study. Liver protein N-glycans were profiled using the DSA-FACE technique developed in our laboratory. To further analyze the fucosylation status of these liver glycans Western lectin blots of total liver proteins were performed using Aspergillus oryzae lectin (AOL) as probe, which is a carbohydrate- binding protein that recognizes specifically α-1,6-fu- cosylated glycans. Results: The N-glycome of liver proteins in patients with HBV related HCC and cirrhosis was analyzed. Compared with healthy donors, the N-glycome had significantly less (p < 0.05) high mannose (M8) in both groups of patients. The total core α-1,6-fucosy-lation in total liver glycoproteins was dramatically increased during the progress of hepatocellular carcinoma and cirrhosis compared to the controls. Conclusion: These results show that fucosylation not only increases in serum proteins but also in liver tissue itself of patients with HBV related HCC and cirrhosis.展开更多
Axonal regeneration in the central nervous system is an energy-intensive process.In contrast to mammals,adult zebrafish can functionally recover from neuronal injury.This raises the question of how zebrafish can cope ...Axonal regeneration in the central nervous system is an energy-intensive process.In contrast to mammals,adult zebrafish can functionally recover from neuronal injury.This raises the question of how zebrafish can cope with this high energy demand.We previously showed that in adult zebrafish,subjected to an optic nerve crush,an antagonistic axon-dendrite interplay exists wherein the retraction of retinal ganglion cell dendrites is a prerequisite for effective axonal repair.We postulate a‘dendrites for regeneration’paradigm that might be linked to intraneuronal mitochondrial reshuffling,as ganglion cells likely have insufficient resources to maintain dendrites and restore axons simultaneously.Here,we characterized both mitochondrial distribution and mitochondrial dynamics within the different ganglion cell compartments(dendrites,somas,and axons)during the regenerative process.Optic nerve crush resulted in a reduction of mitochondria in the dendrites during dendritic retraction,whereafter enlarged mitochondria appeared in the optic nerve/tract during axonal regrowth.Upon dendritic regrowth in the retina,mitochondrial density inside the retinal dendrites returned to baseline levels.Moreover,a transient increase in mitochondrial fission and biogenesis was observed in retinal ganglion cell somas after optic nerve damage.Taken together,these findings suggest that during optic nerve injury-induced regeneration,mitochondria shift from the dendrites to the axons and back again and that temporary changes in mitochondrial dynamics support axonal and dendritic regrowth after optic nerve crush.展开更多
Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant 17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD (due to MAPT ...Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant 17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD (due to MAPT mutations) remain unknown. Here, in a series of 98 genealogically unrelated Belgian FTLD patients, we identified an ancestral 8 cM MAPT containing haplotype in two patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 [maximum summed log of the odds (LOD) score of 5.28 at D17S931]. Interestingly, the same DR2-DR8 ancestral haplotype was observed in five additional familial FTLD patients, indicative of a founder effect. In the FTLD series, the DR2-DR8 ancestral haplotype explained 7%(7 out of 98) of FTLD and 17%(7 out of 42) of familial FTLD and was seven times more frequent than MAPT mutations (1 out of 98 or 1%). Clinically, DR2-DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in one carrier the neuropathological diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, these results strongly suggest that the DR2-DR8 founder haplotype at 17q21 harbours a tau-negative FTLD causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations.展开更多
Background:Alterations in ambient temperature have been associated with multiple detrimental effects on broilers such as intestinal barrier disruption and dysbiosis resulting in systemic inflammation.Inflammation and ...Background:Alterations in ambient temperature have been associated with multiple detrimental effects on broilers such as intestinal barrier disruption and dysbiosis resulting in systemic inflammation.Inflammation and 25-hydroxycholecalciferol(25-OH-D_(3))have shown to play a negative and positive role,respectively,in the regulation of bone mass.Hence the potential of 25-OH-D_(3)in alleviating heat induced bone alterations and its mechanisms was studied.Results:Heat stress(HS)directly induced a decrease in tibia material properties and bone mass,as demonstrated by lower mineral content,and HS caused a notable increase in intestinal permeability.Treatment with dietary 25-OH-D_(3)reversed the HS-induced bone loss and barrier leak.Broilers suffering from HS exhibited dysbiosis and increased expression of inflammatory cytokines in the ileum and bone marrow,as well as increased osteoclast number and activity.The changes were prevented by dietary 25-OH-D_(3)administration.Specifically,dietary 25-OH-D_(3)addition decreased abundance of B-and T-cells in blood,and the expression of inflammatory cytokines,especially TNF-α,in both the ileum and bone marrow,but did not alter the diversity and population or composition of major bacterial phyla.With regard to bone remodeling,dietary 25-OH-D_(3)supplementation was linked to a decrease in serum C-terminal cross-linked telopeptide of type I collagen reflecting bone resorption and a concomitant decrement in osteoclast-specific marker genes expression(e.g.cathepsin K),whereas it did not apparently change serum bone formation markers during HS.Conclusions:These data underscore the damage of HS to intestinal integrity and bone health,as well as that dietary 25-OH-D_(3)supplementation was identified as a potential therapy for preventing these adverse effects.展开更多
Interleukin-3 （IL-3） deprivation of the mouse pro-B cell line Ba/F3 induces cell death that is abrogated by B-cell lymphoma 2 （Bcl-2） overexpression, but remains unaffected by the pan-caspase inhibitor carbobenzox...Interleukin-3 （IL-3） deprivation of the mouse pro-B cell line Ba/F3 induces cell death that is abrogated by B-cell lymphoma 2 （Bcl-2） overexpression, but remains unaffected by the pan-caspase inhibitor carbobenzoxy-valyl-analyl- aspartyl-[O-methyl]-fluoromethylketone （zVAD-fmk）. IL-3 withdrawal causes receptor-interacting protein （RIP）I cleavage into C-terminal fragments of 30 and 25 kDa, and only cleavage leading to the former was prevented by zVAD-fmk, siRNA experiments demonstrated that generation of the 25-kDa fragment was due to a Bcl-2-modulated release of the mitochondrial serine protease high temperature requirement protein A2 （HtrA2）/Omi. Accordingly, recombinant HtrA2/Omi efficiently cleaved mouse RIP1 in vitro, generating fragments matching those observed in IL-3-deprived Ba/F3 cells. The HtrA2/Omi cleavage site in mouse RIP1 was mapped to the intermediate domain and the corresponding N- and C-terminal fragments were impaired in their ability to activate nuclear factor-r,B, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Interestingly, knockdown of HtrA2/Omi afforded pro- tection against IL-3 withdrawal-induced death in the presence of zVAD-fmk, demonstrating a role for HtrA2/Omi in caspase-independent cell death during growth factor withdrawal by cleaving RIP1.展开更多
AIM: To investigate how t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas relate to other marginal zone lymphomas with respect to the somatic mutation pattern of the VH genes and the expression of the marker ...AIM: To investigate how t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas relate to other marginal zone lymphomas with respect to the somatic mutation pattern of the VH genes and the expression of the marker CD27. METHODS: The VH gene of 7 t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas was amplif iedby PCR using family specif ic VH primers and a consensus JH primer. PCR products were sequenced and mutation analysis of the CDR and the FR regions was performed. All cases were immunostained for CD27. RESULTS: One case showed unmutated VH genes while the others showed mutated VH genes with mutation frequencies ranging from 1.3 to 14.7% and with evidence of antigen selection in 2 cases. These data suggest that the translocation t(11;18)(q21;q21) can target either B-cells at different stages of differentiation or naive B-cells that retain the capacity to differentiate upon antigen stimulation. All cases but one displayed weak to strong CD27 expression which did not correlate with the VH gene mutation status. CONCLUSION: t(11;18)(q21;q21)-positive gastro- intestinal MALT lymphomas are heterogeneous with respect to the VH mutation status and CD27 is not a marker of somatically mutated B-cells.展开更多
Polyploidization plays a key role in plant evolution,but the forces driving the fate of homoeologs in polyploid genomes,i.e.,paralogs resulting from a whole-genome duplication(WGD)event,remain to be elucidated.Here,we...Polyploidization plays a key role in plant evolution,but the forces driving the fate of homoeologs in polyploid genomes,i.e.,paralogs resulting from a whole-genome duplication(WGD)event,remain to be elucidated.Here,we present a chromosome-scale genome assembly of tetraploid scarlet sage(Salvia splendens),one of the most diverse ornamental plants.We found evidence for three WGD events following an older WGD event shared by most eudicots(theγevent).A comprehensive,spatiotemporal,genome-wide analysis of homoeologs from the most recent WGD unveiled expression asymmetries,which could be associated with genomic rearrangements,transposable element proximity discrepancies,coding sequence variation,selection pressure,and transcription factor binding site differences.The observed differences between homoeologs may reflect the first step toward sub-and/or neofunctionalization.This assembly provides a powerful tool for understanding WGD and gene and genome evolution and is useful in developing functional genomics and genetic engineering strategies for scarlet sage and other Lamiaceae species.展开更多
Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European fami...Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors con ducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analy zed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long range PCR. Results: Ataxia occurred in combination with various CNS features,i ncluding myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions onMRI, and neuronal loss in discrete gray n uclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate induced hepatotoxicity occurred less frequently. Two patients died w ithout preceding signs of progressive external ophthalmoplegia. In muscle, typic al findings of mitochondrial disease, such as ragged red fibers and Southern blo t mtDNA abnormalities, were absent. POLG mutations were present in eight patient s, including two isolated cases, and one Finnish and two unrelated Belgian famil ies contained in total six patients. All POLG mutations were recessive, occurrin g in a homozygous state in seven patients and in a compound heterozygous state i n one patient. The novel W748S mutation was identified in five patients from thr ee unrelated families. Conclusions: The clinical spectrum of recessive POLG muta tions is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, my opathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondri al DNA also are not mandatory features associated with POLG mutations.展开更多
基金supported by grants from the Research Foundation–Flanders(11A6420N,1268823N to WC and LVH)a FWO Junior Research Project Grant(G055121N to REV)VIB.AG is a senior clinical researcher of the Research Foundation–Flanders(1805718N)。
文摘Hepatic encephalopathy,defined as neuropsychiatric dysfunction secondary to liver disease,is a frequent decompensating event in cirrhosis.Its clinical impact is highlighted by a notable increase in patient mortality rates and a concomitant reduction in overall quality of life.Systemically,liver disease,liver function failure,portosystemic shunting,and associated multi-organ dysfunction result in the increase of disease-causing neurotoxins in the circulation,which impairs cerebral homeostasis.Key circulating neurotoxins are ammonia and inflammatory mediators.In the brain,pathophysiology is less well understood,but is thought to be driven by glial cell dysfunction.Astrocytes are the only brain resident cells that have ammonia-metabolizing machinery and are therefore putatively most susceptible to ammonia elevation.Based on a large body of mostly in vitro evidence,ammonia-induced cellular and molecular disturbances include astrocyte swelling and oxidative stress.Microglia,the brain resident macrophages,have been linked to the translation of systemic inflammation to the brain microenvironment.Recent evidence from animal studies has provided novel insights into old and new downstream effects of astrocyte and microglial dysfunction such as toxin clearance disruption and myeloid cell attraction to the central nervous system parenchyma.Furthermore,state of the art research increasingly implicates neuronal dysfunction and possibly even irreversible neuronal cell death.Cell-type specific investigation in animal models highlights the need for critical revision of the contribution of astrocytes and microglia to well-established and novel cellular and molecular alterations in hepatic encephalopathy.In this review,we therefore give a current and comprehensive overview of causes,features,and consequences of astrocyte and microglial dysfunction in hepatic encephalopathy,including areas of interest for future investigation.
基金funded by the Ghent University Special Research Fund(BOF.PDO.2022.0002.01)Projects of International Cooperation of Henan Province(232102520016)National Natural Science Foundation of Henan Province(242300420159).
文摘Background Heat stress(HS) incidence is associated with the accumulation of reactive substances, which might be associated with bone loss. N-Acetylcysteine(NAC) exhibits strong antioxidants due to its sulfhydryl group and being as the precursor for endogenous glutathione synthesis. Therefore, interplay between oxidative stress and bone turnover of broilers and the effects of dietary NAC inclusion on antioxidant capability and “gut-bone” axis were evaluated during chronic HS.Results Implementing cyclic chronic HS(34 ℃ for 7 h/d) evoked reactive oxygen species excessive production and oxidant stress, which was accompanied by compromised tibia mass. The RNA-seq of proximal tibia also revealed the enrichment of oxidation–reduction process and inflammatory outbursts during HS. Although no notable alterations in the growth performance and cecal microbiota were found, the diet contained 2 g/kg NAC enhanced the antioxidant capability of heat-stressed broiler chickens by upregulating the expression of Nrf2 in the ileum, tibia, and bone marrow. Simultaneously, NAC tended to hinder NF-κB pathway activation and decreased the m RNA levels of the proinflammatory cytokines in both the ileum and bone marrow. As a result, NAC suppressed osteoclastogenesis and osteoclast activity, thereby increasing osteocyte-related gene expression. Furthermore, the inclusion of NAC tended to increase the ash content and density of the whole tibia, as well as improve cortical thickness and bone volume of the diaphysis.Conclusions These findings HS-mediated outburst of oxidant stress accelerates bone resorption and negatively regulates the bone quality of tibia, which is inhibited by NAC in broilers.
基金Open Access funding enabled and organized by Projekt DEALThe research from the MultiBioPro project leading to these results has received funding from the European Union’s Seventh Framework Programme for research,technological development and demonstration under grant agreement 311804Further funding from the BBSRC 21EBTA-Celfacto project is acknowledged by PDF.
文摘The evaluation of plant-based feedstocks is an important aspect of biorefining.Nicotiana glauca is a solanaceous,non-food crop that produces large amounts of biomass and is well adapted to grow in suboptimal conditions.In the present article,compatible sequential solvent extractions were applied to N.glauca leaves to enable the generation of enriched extracts containing higher metabolite content comparing to direct leaf extracts.Typically,between 60 to 100 metabolite components were identified within the fractions.The occurrence of plant fatty acids,fatty acid alcohols,alkanes,sterols and terpenoids was detected by gas liquid chromatography-mass spectrometry(GC-MS)and metabolite identification was confirmed by comparison of physico-chemical properties displayed by available authentic standards.Collectively,co-products such waxes,oils,fermentable sugars,and terpenoids were all identified and quantified.The enriched fractions of N.glauca revealed a high level of readily extractable hydrocarbons,oils and high value co-products.In addition,the saccharification yield and cell wall composition analyses in the stems revealed the potential of the residue material as a promising lignocellulosic substrate for the production of fermentable sugars.In conclusion a multifractional cascade for valuable compounds/commodities has been development,that uses N.glauca biomass.These data have enabled the evaluation of N.glauca material as a potential feedstock for biorefining.
基金supported by the Research Foundation Flanders(FWO)The Foundation for Alzheimer’s Research Belgium(SAO-FRA)+1 种基金European Union Cost action MouseAge(BM1402)the Baillet Latour Fund(all to SS and REV)
文摘Due to the aging of the population and despite the enormous scientific effort,Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine.Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer's disease.Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2,but that also regulates several brain functions in health and disease.However,clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer's disease led to inconclusive results,partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1,but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials.We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer's disease patients,signaling via tumor necrosis factor receptor 1.In agreement with this,choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer's disease mouse models.Interestingly,both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer's disease-associated inflammation,choroidal morphology and cognitive functioning.Here,we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in(early) Alzheimer's disease,and the consequences this might have on the disease progression.As the main hypothesis in Alzheimer's disease clinical trials is still based on the amyloid beta-cascade,the importance of Alzheimer's disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer's disease and prevent the irreversible neurodegeneration and resulting memory decline.
基金supported by the Research Foundation-Flanders (FWO)the Concerted Research Actions (GOA) of Ghent University+2 种基金the Belgian Science Policy (Interuniversity Attraction Pools-IAP7/07)the Belgain Foundation of Alzheimer's Researoh (SAO)the Ministry of Education,Science and Technological Development of the Republic of Serbia (Grant ON173056) and COST Action BM1402
文摘The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial（CPE） cells surrounding fenestrated capillaries.These CPE cells not only form an anatomical barrier,called the blood-cerebrospinal fluid barrier（BCSFB）,but also present an active interface between blood and cerebrospinal fluid（CSF）.CPE cells perform indispensable functions for the development,maintenance and functioning of the brain.Indeed,the primary role of the choroid plexus in the brain is to maintain homeostasis by secreting CSF which contains different molecules,such as nutrients,neurotrophins,and growth factors,as well as by clearing toxic and undesirable molecules from CSF.The choroid plexus also acts as a selective entry gate for leukocytes into the brain.Recent findings have revealed distinct changes in CPE cells that are associated with aging and Alzheimer＇s disease.In this review,we review some recent findings that highlight the importance of the CPE-CSF system in Alzheimer＇s disease and we summarize the recent advances in the regeneration of brain tissue through use of CPE cells as a new therapeutic strategy.
基金supported by funding from the Research Foundation-Flanders(FWO:G.0A42.16, G.0B3418 and G0C5120N)the KU Leuven (C24/17/077)supported by long-term structural funding-Methusalem Funding by the Flemish Government and the European Research Council (ERC Advanced Research Grant EU-ERC743074)
文摘The majority of the mammalian skeleton is formed through endochondral ossification starting from a cartilaginous template.Cartilage cells, or chondrocytes, survive, proliferate and synthesize extracellular matrix in an avascular environment, but the metabolic requirements for these anabolic processes are not fully understood. Here, using metabolomics analysis and genetic in vivo models, we show that maintaining intracellular serine homeostasis is essential for chondrocyte function. De novo serine synthesis through phosphoglycerate dehydrogenase(PHGDH)-mediated glucose metabolism generates nucleotides that are necessary for chondrocyte proliferation and long bone growth. On the other hand, dietary serine is less crucial during endochondral bone formation, as serine-starved chondrocytes compensate by inducing PHGDH-mediated serine synthesis.Mechanistically, this metabolic flexibility requires ATF4, a transcriptional regulator of amino acid metabolism and stress responses.We demonstrate that both serine deprivation and PHGDH inactivation enhance ATF4 signaling to stimulate de novo serine synthesis and serine uptake, respectively, and thereby prevent intracellular serine depletion and chondrocyte dysfunction. A similar metabolic adaptability between serine uptake and de novo synthesis is observed in the cartilage callus during fracture repair.Together, the results of this study reveal a critical role for PHGDH-dependent serine synthesis in maintaining intracellular serine levels under physiological and serine-limited conditions, as adequate serine levels are necessary to support chondrocyte proliferation during endochondral ossification.
文摘Purpose: Alteration of liver function during pro- gression of hepatocellular carcinoma (HCC) and cirrhosis affects the serum glycoprotein pattern. In this study, the changes in the N-glycome in liver tis- sue from patients with hepatocellular carcinoma and cirrhosis caused by hepatitis B virus infection were investigated to find out the relationship between this maker and liver disease. Methods: Twenty patients, 11 with cirrhosis and 9 with hepatocellular carcinoma, and 15 healthy donors were involved in this study. Liver protein N-glycans were profiled using the DSA-FACE technique developed in our laboratory. To further analyze the fucosylation status of these liver glycans Western lectin blots of total liver proteins were performed using Aspergillus oryzae lectin (AOL) as probe, which is a carbohydrate- binding protein that recognizes specifically α-1,6-fu- cosylated glycans. Results: The N-glycome of liver proteins in patients with HBV related HCC and cirrhosis was analyzed. Compared with healthy donors, the N-glycome had significantly less (p < 0.05) high mannose (M8) in both groups of patients. The total core α-1,6-fucosy-lation in total liver glycoproteins was dramatically increased during the progress of hepatocellular carcinoma and cirrhosis compared to the controls. Conclusion: These results show that fucosylation not only increases in serum proteins but also in liver tissue itself of patients with HBV related HCC and cirrhosis.
基金financially supported by the Katholieke Universiteit Leuven Research Council (C14/18/053)the research foundation Flanders (FWO) (G082221N)+1 种基金a personal L’Oréal/UNESCO (For Women in Science) fellowshipa personal FWO fellowship
文摘Axonal regeneration in the central nervous system is an energy-intensive process.In contrast to mammals,adult zebrafish can functionally recover from neuronal injury.This raises the question of how zebrafish can cope with this high energy demand.We previously showed that in adult zebrafish,subjected to an optic nerve crush,an antagonistic axon-dendrite interplay exists wherein the retraction of retinal ganglion cell dendrites is a prerequisite for effective axonal repair.We postulate a‘dendrites for regeneration’paradigm that might be linked to intraneuronal mitochondrial reshuffling,as ganglion cells likely have insufficient resources to maintain dendrites and restore axons simultaneously.Here,we characterized both mitochondrial distribution and mitochondrial dynamics within the different ganglion cell compartments(dendrites,somas,and axons)during the regenerative process.Optic nerve crush resulted in a reduction of mitochondria in the dendrites during dendritic retraction,whereafter enlarged mitochondria appeared in the optic nerve/tract during axonal regrowth.Upon dendritic regrowth in the retina,mitochondrial density inside the retinal dendrites returned to baseline levels.Moreover,a transient increase in mitochondrial fission and biogenesis was observed in retinal ganglion cell somas after optic nerve damage.Taken together,these findings suggest that during optic nerve injury-induced regeneration,mitochondria shift from the dendrites to the axons and back again and that temporary changes in mitochondrial dynamics support axonal and dendritic regrowth after optic nerve crush.
文摘Among patients with frontotemporal lobar degeneration (FTLD), the respective frequencies of dominant 17q21-linked tau-negative FTLD (with unidentified molecular defect) and 17q21-linked tau-positive FTLD (due to MAPT mutations) remain unknown. Here, in a series of 98 genealogically unrelated Belgian FTLD patients, we identified an ancestral 8 cM MAPT containing haplotype in two patients belonging to multiplex families DR2 and DR8, without demonstrable MAPT mutations, in which FTLD was conclusively linked to 17q21 [maximum summed log of the odds (LOD) score of 5.28 at D17S931]. Interestingly, the same DR2-DR8 ancestral haplotype was observed in five additional familial FTLD patients, indicative of a founder effect. In the FTLD series, the DR2-DR8 ancestral haplotype explained 7%(7 out of 98) of FTLD and 17%(7 out of 42) of familial FTLD and was seven times more frequent than MAPT mutations (1 out of 98 or 1%). Clinically, DR2-DR8 haplotype carriers presented with FTLD often characterized by language impairment, and in one carrier the neuropathological diagnosis was FTLD with rare tau-negative ubiquitin-positive inclusions. Together, these results strongly suggest that the DR2-DR8 founder haplotype at 17q21 harbours a tau-negative FTLD causing mutation that is a much more frequent cause of FTLD in Belgium than MAPT mutations.
基金This work was supported by the China Scholarship Council(CSC,[2019]110)The support by DSM Nutritional Products(Basel,Switzerland)for the analysis of vitamin D3 and metabolites is well appreciatedThe Ghent University Special Research Fund is acknowledged for the financial support to the UGCT Centre of Expertise(BOF.EXP.2017.0007).
文摘Background:Alterations in ambient temperature have been associated with multiple detrimental effects on broilers such as intestinal barrier disruption and dysbiosis resulting in systemic inflammation.Inflammation and 25-hydroxycholecalciferol(25-OH-D_(3))have shown to play a negative and positive role,respectively,in the regulation of bone mass.Hence the potential of 25-OH-D_(3)in alleviating heat induced bone alterations and its mechanisms was studied.Results:Heat stress(HS)directly induced a decrease in tibia material properties and bone mass,as demonstrated by lower mineral content,and HS caused a notable increase in intestinal permeability.Treatment with dietary 25-OH-D_(3)reversed the HS-induced bone loss and barrier leak.Broilers suffering from HS exhibited dysbiosis and increased expression of inflammatory cytokines in the ileum and bone marrow,as well as increased osteoclast number and activity.The changes were prevented by dietary 25-OH-D_(3)administration.Specifically,dietary 25-OH-D_(3)addition decreased abundance of B-and T-cells in blood,and the expression of inflammatory cytokines,especially TNF-α,in both the ileum and bone marrow,but did not alter the diversity and population or composition of major bacterial phyla.With regard to bone remodeling,dietary 25-OH-D_(3)supplementation was linked to a decrease in serum C-terminal cross-linked telopeptide of type I collagen reflecting bone resorption and a concomitant decrement in osteoclast-specific marker genes expression(e.g.cathepsin K),whereas it did not apparently change serum bone formation markers during HS.Conclusions:These data underscore the damage of HS to intestinal integrity and bone health,as well as that dietary 25-OH-D_(3)supplementation was identified as a potential therapy for preventing these adverse effects.
文摘Interleukin-3 （IL-3） deprivation of the mouse pro-B cell line Ba/F3 induces cell death that is abrogated by B-cell lymphoma 2 （Bcl-2） overexpression, but remains unaffected by the pan-caspase inhibitor carbobenzoxy-valyl-analyl- aspartyl-[O-methyl]-fluoromethylketone （zVAD-fmk）. IL-3 withdrawal causes receptor-interacting protein （RIP）I cleavage into C-terminal fragments of 30 and 25 kDa, and only cleavage leading to the former was prevented by zVAD-fmk, siRNA experiments demonstrated that generation of the 25-kDa fragment was due to a Bcl-2-modulated release of the mitochondrial serine protease high temperature requirement protein A2 （HtrA2）/Omi. Accordingly, recombinant HtrA2/Omi efficiently cleaved mouse RIP1 in vitro, generating fragments matching those observed in IL-3-deprived Ba/F3 cells. The HtrA2/Omi cleavage site in mouse RIP1 was mapped to the intermediate domain and the corresponding N- and C-terminal fragments were impaired in their ability to activate nuclear factor-r,B, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase. Interestingly, knockdown of HtrA2/Omi afforded pro- tection against IL-3 withdrawal-induced death in the presence of zVAD-fmk, demonstrating a role for HtrA2/Omi in caspase-independent cell death during growth factor withdrawal by cleaving RIP1.
基金Supported by A Grant of the "Belgian Cancer Association"the "Fonds voor Wetenschappelijk Onderzoek Vlaanderen"
文摘AIM: To investigate how t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas relate to other marginal zone lymphomas with respect to the somatic mutation pattern of the VH genes and the expression of the marker CD27. METHODS: The VH gene of 7 t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas was amplif iedby PCR using family specif ic VH primers and a consensus JH primer. PCR products were sequenced and mutation analysis of the CDR and the FR regions was performed. All cases were immunostained for CD27. RESULTS: One case showed unmutated VH genes while the others showed mutated VH genes with mutation frequencies ranging from 1.3 to 14.7% and with evidence of antigen selection in 2 cases. These data suggest that the translocation t(11;18)(q21;q21) can target either B-cells at different stages of differentiation or naive B-cells that retain the capacity to differentiate upon antigen stimulation. All cases but one displayed weak to strong CD27 expression which did not correlate with the VH gene mutation status. CONCLUSION: t(11;18)(q21;q21)-positive gastro- intestinal MALT lymphomas are heterogeneous with respect to the VH mutation status and CD27 is not a marker of somatically mutated B-cells.
基金This study was supported by the National Natural Science Foundation(31600527)The Fundamental Research Funds for the Central Universities in Beijing Forestry University(2018BLCB08)+2 种基金the Project of Construction of World Class Universities in Beijing Forestry University(2019XKJS0308)Y.V.d.P.acknowledges funding from the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(grant agreement no.833522)from Ghent University(Methusalem funding,BOF.MET.2021.0005.01).
文摘Polyploidization plays a key role in plant evolution,but the forces driving the fate of homoeologs in polyploid genomes,i.e.,paralogs resulting from a whole-genome duplication(WGD)event,remain to be elucidated.Here,we present a chromosome-scale genome assembly of tetraploid scarlet sage(Salvia splendens),one of the most diverse ornamental plants.We found evidence for three WGD events following an older WGD event shared by most eudicots(theγevent).A comprehensive,spatiotemporal,genome-wide analysis of homoeologs from the most recent WGD unveiled expression asymmetries,which could be associated with genomic rearrangements,transposable element proximity discrepancies,coding sequence variation,selection pressure,and transcription factor binding site differences.The observed differences between homoeologs may reflect the first step toward sub-and/or neofunctionalization.This assembly provides a powerful tool for understanding WGD and gene and genome evolution and is useful in developing functional genomics and genetic engineering strategies for scarlet sage and other Lamiaceae species.
文摘Objective: To identify POLG mutations in patients with sensory ataxia and CNS features. Methods: The authors characterized clinical, laboratory, and molecular genetic features in eight patients from five European families. The authors con ducted sequencing of coding exons of POLG, C10orf2 (Twinkle), and ANT1 and analy zed muscle mitochondrial DNA (mtDNA), including Southern blot analysis and long range PCR. Results: Ataxia occurred in combination with various CNS features,i ncluding myoclonus, epilepsy, cognitive decline, nystagmus, dysarthria, thalamic and cerebellar white matter lesions onMRI, and neuronal loss in discrete gray n uclei on autopsy. Gastrointestinal dysmotility, weight loss, cardiomyopathy, and valproate induced hepatotoxicity occurred less frequently. Two patients died w ithout preceding signs of progressive external ophthalmoplegia. In muscle, typic al findings of mitochondrial disease, such as ragged red fibers and Southern blo t mtDNA abnormalities, were absent. POLG mutations were present in eight patient s, including two isolated cases, and one Finnish and two unrelated Belgian famil ies contained in total six patients. All POLG mutations were recessive, occurrin g in a homozygous state in seven patients and in a compound heterozygous state i n one patient. The novel W748S mutation was identified in five patients from thr ee unrelated families. Conclusions: The clinical spectrum of recessive POLG muta tions is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, my opathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondri al DNA also are not mandatory features associated with POLG mutations.
