Macaques,particularly rhesus(Macaca mulatta) and cynomolgus(M.fascicularis) monkeys,are widely utilized in biomedical and toxicological research.Despite their critical role,effective vaccines against many viral pathog...Macaques,particularly rhesus(Macaca mulatta) and cynomolgus(M.fascicularis) monkeys,are widely utilized in biomedical and toxicological research.Despite their critical role,effective vaccines against many viral pathogens affecting these primates remain limited,and vaccination is generally avoided in experimental populations to prevent potential confounding outcomes.Consequently,maintaining viral control within macaque colonies depends on stringent surveillance,systematic diagnostic testing,and rigorously enforced quarantine protocols.Accurate and early detection of viral infections is therefore essential for colony management and research integrity.This review synthesizes current knowledge on 10major viruses affecting macaque colonies,outlining their biological characteristics and diagnostic methodologies,and further assesses recent technological advances in viral detection.Drawing upon five years of surveillance data collected by VRL-Asia from breeding facilities across China,this review highlights the prevalence patterns of viral infections among breeding macaques and identifies critical epidemiological trends.These insights provide a valuable reference for researchers,veterinarians,and laboratory personnel seeking to strengthen biosecurity frameworks and ensure the reliability of research involving macaques.展开更多
It is generally accepted that climate has changed greatly on a global scale, and that the earth＇s climate has already wanned by some degrees over the past century. Ample evidence shows that there have been apparent c...It is generally accepted that climate has changed greatly on a global scale, and that the earth＇s climate has already wanned by some degrees over the past century. Ample evidence shows that there have been apparent changes in avian population dynamics, life-history traits and geographic ranges in response to global climate change. This paper briefly reviews the possible effects of climate change on avian biology and ecology all over the world, with emphasis on new findings from several long-term studies in Europe and North America, which provide unique opportunities to investigate how long-term changes in climate affect birds at both individual and population levels. The implications of such long-term studies for future bird studies in China is discussed with hope that this review can contribute to the preparation and plan for studies of climatic effects on birds in China in the future.展开更多
Osteoarthritis(OA)is a degenerative articular disorder manifested by cartilage destruction,subchondral sclerosis,osteophytes,and synovitis,resulting in chronic joint pain and physical disability in the elderly.The pur...Osteoarthritis(OA)is a degenerative articular disorder manifested by cartilage destruction,subchondral sclerosis,osteophytes,and synovitis,resulting in chronic joint pain and physical disability in the elderly.The purpose of this study was to investigate mitochondrial DNA copy number(mtDNACN)and inflammatory cytokines in primary knee OA patients and healthy volunteers.A total of 204 knee OA patients and 169 age-matched healthy volunteers were recruited.Their relative blood leukocyte mtDNACN was assessed by quantitative real-time polymerase chain reaction(qRT-PCR),and ten inflammatory cytokines in their plasma were detected by multiplex immunoassay.Blood leukocyte mtDNACN in the OA group was significantly lower than that in the control group.Leukocyte mtDNACN in the control group was negatively correlated with their age(r=−0.380,P<0.0001),whereas mtDNACN in the OA group was positively correlated with their age(r=0.198,P<0.001).Plasma interleukin-4(IL-4)and IL-6 were significantly higher in the knee OA group than in the control group.The plasma IL-6 level was positively correlated with blood leukocyte mtDNACN in the OA group(r=0.547,P=0.0014).IL-5 showed as a major factor(coefficient 0.69)in the second dimension of principle components analysis(PCA)-transformed data and was significantly higher in the OA group(P<0.001)as well as negatively correlated with mtDNACN(r=−0.577,P<0.001).These findings suggest that elevation of plasma IL-4 and IL-6 and a relative reduction in mtDNACN might be effective biomarkers for knee OA.IL-5 is a plausible factor responsible for decreasing blood leukocyte mtDNACN in knee OA patients.展开更多
Climate change is increasing the frequency and severity of short-term heat shocks that threaten the persistence of natural populations.However,most work addressing the evolutionary consequences of anthropogenic enviro...Climate change is increasing the frequency and severity of short-term heat shocks that threaten the persistence of natural populations.However,most work addressing the evolutionary consequences of anthropogenic environmental change has focused on natural selection,with less attention paid to the impacts on sexual selection.The conditions under which sexual selection operates is a topic of debate,but a generally observed pattern is that the oper-ational sex ratio(OSR)of a population is key to determining both the extent of competition for fertilizations and the scope for mate choice(Weir et al.2011)展开更多
The fungal communities in mushroom compost phase Ⅱ was assessed using a combination of PCR amplification and sequencing of 18S rDNA from fungal isolates and “nested” PCR TGGE analysis on the basis of DNA directly e...The fungal communities in mushroom compost phase Ⅱ was assessed using a combination of PCR amplification and sequencing of 18S rDNA from fungal isolates and “nested” PCR TGGE analysis on the basis of DNA directly extracted from compost samples. The diversity of cultivated fungi isolated from compost samples was low. A total of 11 isolates were related to only 2 different species. One species, Chaetomium elatum, was identified within 10 isolates, and the other, with high similarity belonged to Penicillium expansum. The fungal flora associated with mushroom compost was then monitored with “nested” PCR TGGE. The patterns obtained revealed the more complex existence of fungal communities from the original compost samples than from thoses enriched with food waste and cow slurry.展开更多
The pharmaceutical and anticoagulant agent heparin,a member of the glycosaminoglycan family of carbohydrates,has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target,the primary n...The pharmaceutical and anticoagulant agent heparin,a member of the glycosaminoglycan family of carbohydrates,has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target,the primary neuronalβ-secretase,β-site amyloid precursor protein cleaving enzyme 1(BACE1).The anticoagulant activity of heparin has,however,precluded the repurposing of this widely used pharmaceutical as an Alzheimer’s disease therapeutic.Here,a glycosaminoglycan extract,composed predominantly of 4-sulfated chondroitin sulfate,has been isolated from Sardina pilchardus,which possess the ability to inhibit BACE1(IC50[half maximal inhibitory concentration]=4.8μg/mL),while displaying highly attenuated anticoagulant activities(activated partial thromboplastin time EC50[median effective concentration]=403.8μg/mL,prothrombin time EC50=1.3 mg/mL).The marine-derived,chondroitin sulfate extract destabilizes BACE1,determined via differential scanning fluorimetry(ΔTm–5°C),to a similar extent as heparin,suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action,which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease.展开更多
BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms...BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood.Recently,the TLR4-MyD88 signaling pathway has been reported to contribute to fibrosis.Extracellular histones are ligands of TLR4 but their roles in liver fibrosis have not been investigated.AIM To investigate the roles and potential mechanisms of extracellular histones in liver fibrosis.METHODS In vitro,LX2 human hepatic stellate cells(HSCs)were treated with histones in the presence or absence of non-anticoagulant heparin(NAHP)for neutralizing histones or TLR4-blocking antibody.The resultant cellular expression of collagen I was detected using western blotting and immunofluorescent staining.In vivo,the CCl4-induced liver fibrosis model was generated in male 6-week-old ICR mice and in TLR4 or MyD88 knockout and parental mice.Circulating histones were detected and the effect of NAHP was evaluated.RESULTS Extracellular histones strongly stimulated LX2 cells to produce collagen I.Histone-enhanced collagen expression was significantly reduced by NAHP and TLR4-blocking antibody.In CCl4-treated wild type mice,circulating histones were dramatically increased and maintained high levels during the duration of fibrosisinduction.Injection of NAHP not only reduced alanine aminotransferase and liver injury scores,but also significantly reduced fibrogenesis.Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC,the CCl4 model with TLR4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signaling pathway in CCl4-induced liver fibrosis.The levels of liver fibrosis were indeed significantly reduced in knockout mice compared to wild type parental mice.CONCLUSION Extracellular histones potentially enhance fibrogenesis via the TLR4–MyD88 signaling pathway and NAHP has therapeutic potential by detoxifying extracellular histones.展开更多
Proteinaceous infectious particles(prions) are unique pathogens as they are devoid of any coding nucleic acid.Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein...Proteinaceous infectious particles(prions) are unique pathogens as they are devoid of any coding nucleic acid.Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed.展开更多
The pH values of soils collected from 30 different districts of Al-Madinah Al-Munawarah province were measured using an Electric pH meter. The pH values revealed （27%） a slight to （60%） medium alkalinity ranged be...The pH values of soils collected from 30 different districts of Al-Madinah Al-Munawarah province were measured using an Electric pH meter. The pH values revealed （27%） a slight to （60%） medium alkalinity ranged between： 7.17-9.45 （pH 8.13 ± 0.13） The alkalinity is attributed to scanty rainfall and deep underground waters as well as deposition of high air pollution contents at Al-Madinah Al-Munawarah. Such soil alkalinity is not optimum to growth of arable/lea-grassland but only for limited cultivation i.e. date palms in comparison with Northwestern and Southwestern sectors of KSA. It is recommended to carry out similar soil evaluation of other parts of KSA involving more measurements i.e. ionic concentration, nutrient levels, micro-flora and to laundry these lands to lower soil＇spHs and to increase its fertility.展开更多
DEE （diesel exhaust emitted） and fossil fuel do contribute to the pollution of ecosystem while very little is known about their toxic effects on pulmonary tissue in the short-term. Ten male Guinea pigs exposed to DE...DEE （diesel exhaust emitted） and fossil fuel do contribute to the pollution of ecosystem while very little is known about their toxic effects on pulmonary tissue in the short-term. Ten male Guinea pigs exposed to DEE in an open system experiment at different time schemes and their tracheas and lungs were processed for routine Histology, Immunohistochemsitry and TEM （transmission Electron Microscopy） techniques. The results revealed early toxicological effects of DEE on pulmonary tissue involved cellular damages to the mucosa of trachea and bronchial tree, rupture of alveolar walls, disintegration of pneumocytes, development of mucous secretions, swellings in the alveolar network, hemorrhage and lymphatic infiltration all over the parenchyma starting from the early hours of exposure to DEE. Ultrastructural changes confirmed the ruptures to the alveolar walls, infiltration of various WBC （white blood cells）, development of vacuoles inside the cytoplasmic organelles of pnemocytes, distortion in morphology of both RBCs （Red Blood corpuscles） which all had begun as early as 1 h following the exposure to the DEE. Activation of the immune system was noted via the increase in size of lymph nodules to confront the invaded particulates. These results indicate blockage of the respiratory leading to suffocation and do alert the expected acute cellular harms to the pulmonary tissues following exposure to the DEE of mechanics work in vicinity of DEE who spend most daily hours in semi-closed areas.展开更多
Rubisco(ribulose-1,5-bisphosphate carboxylase/oxygenase)is the central enzyme for conversion of atmospheric CO_(2)into organic molecules,playing a crucial role in the global carbon cycle.In cyanobacteria and some chem...Rubisco(ribulose-1,5-bisphosphate carboxylase/oxygenase)is the central enzyme for conversion of atmospheric CO_(2)into organic molecules,playing a crucial role in the global carbon cycle.In cyanobacteria and some chemoautotrophs,Rubisco complexes,together with carbonic anhydrase,are enclosed within specific proteinaceous microcompartments known as carboxysomes.The polyhedral carboxysome shell ensures the dense packaging of Rubisco and creates a high-CO_(2)internal environment to facilitate CO_(2)fixation.Rubisco and carboxysomes have been popular targets for bioengineering,with the intent of enhancing plant photosynthesis,crop yields,and biofuel production.However,efficient generation of Form 1B Rubisco and cyanobacterial b-carboxysomes in heterologous systems remains a challenge.Here,we developed genetic systems to efficiently engineer functional cyanobacterial Form 1B Rubisco in Escherichia coli by incorporating Rubisco assembly factor Raf1 and modulating the RbcL/S stoichiometry.We then reconstituted catalytically active b-carboxysomes in E.coli with cognate Form 1B Rubisco by fine-tuning the expression levels of individual b-carboxysome components.In addition,we investigated the mechanism of Rubisco encapsulation into carboxysomes by constructing hybrid carboxysomes;this was achieved by creating a chimeric encapsulation peptide incorporating small sub-unit-like domains,which enabled the encapsulation of Form 1B Rubisco into a-carboxysome shells.Our study provides insights into the assembly mechanisms of plant-like Form 1B Rubisco and the principles of its encapsulation in both b-carboxysomes and hybrid carboxysomes,highlighting the inherent modularity of carboxysome structures.These findings lay the framework for rational design and repurposing of CO_(2)-fixing modules in bioengineering applications,e.g.,crop engineering,biocatalyst production,and molecule delivery.展开更多
Model validation is the most important part of building a supervised model.For building a model with good generalization performance one must have a sensible data splitting strategy,and this is crucial for model valid...Model validation is the most important part of building a supervised model.For building a model with good generalization performance one must have a sensible data splitting strategy,and this is crucial for model validation.In this study,we con-ducted a comparative study on various reported data splitting methods.The MixSim model was employed to generate nine simulated datasets with different probabilities of mis-classification and variable sample sizes.Then partial least squares for discriminant analysis and support vector machines for classification were applied to these datasets.Data splitting methods tested included variants of cross-validation,bootstrapping,bootstrapped Latin partition,Kennard-Stone algorithm(K-S)and sample set partitioning based on joint X-Y distances algorithm(SPXY).These methods were employed to split the data into training and validation sets.The estimated generalization performances from the validation sets were then compared with the ones obtained from the blind test sets which were generated from the same distribution but were unseen by the train-ing/validation procedure used in model construction.The results showed that the size of the data is the deciding factor for the qualities of the generalization performance estimated from the validation set.We found that there was a significant gap between the performance estimated from the validation set and the one from the test set for the all the data splitting methods employed on small datasets.Such disparity decreased when more samples were available for training/validation,and this is because the models were then moving towards approximations of the central limit theory for the simulated datasets used.We also found that having too many or too few samples in the training set had a negative effect on the estimated model performance,suggesting that it is necessary to have a good balance between the sizes of training set and validation set to have a reliable estimation of model performance.We also found that systematic sampling method such as K-S and SPXY generally had very poor estimation of the model performance,most likely due to the fact that they are designed to take the most representative samples first and thus left a rather poorly representative sample set for model performance estimation.展开更多
The equilibrium temperature and pressure of both spinel and garnet peridotite xenolithsfrom eastern China have been estimated by using different geothermobarometers that are currentlyconsidered to be reliable.Based on...The equilibrium temperature and pressure of both spinel and garnet peridotite xenolithsfrom eastern China have been estimated by using different geothermobarometers that are currentlyconsidered to be reliable.Based on these data,the upper mantle geotherm for eastern China has beenconstructed.The obtained geotherm is higher than that for old craton regions,but is similar to that for southeasternAustralia.The most prominent feature of the geotherm is that there is a slight gradient at about 60 kmdepth,and the inflection of the geotherm just passes through the transition line between spinel and garnetfacies.It is likely that the inflection represents the botmdary between the lithosphere and asthenosphere.Thestructures of the upper mantle beneath eastern China have also been discussed by combining the results ofpetrologic,rheological and dynamical studies of the upper mantle.展开更多
As the most pervasive epigenetic marker present on mRNAs and long non-coding RNAs(lncRNAs),N6-methyladenosine(m^(6)A)RNA methylation has been shown to participate in essential biological processes.Recent studies have ...As the most pervasive epigenetic marker present on mRNAs and long non-coding RNAs(lncRNAs),N6-methyladenosine(m^(6)A)RNA methylation has been shown to participate in essential biological processes.Recent studies have revealed the distinct patterns of m^(6)A methylome across human tissues,and a major challenge remains in elucidating the tissue-specific presence and circuitry of m^(6)A methylation.We present here a comprehensive online platform,m^(6)A-TSHub,for unveiling the context-specific m^(6)A methylation and genetic mutations that potentially regulate m^(6)A epigenetic mark.m^(6)A-TSHub consists of four core components,including(1)m^(6)A-TSDB,a comprehensive database of 184,554 functionally annotated m^(6)A sites derived from 23 human tissues and 499,369 m^(6)A sites from 25 tumor conditions,respectively;(2)m^(6)A-TSFinder,a web server for high-accuracy prediction of m^(6)A methylation sites within a specific tissue from RNA sequences,which was constructed using multi-instance deep neural networks with gated attention;(3)m^(6)ATSVar,a web server for assessing the impact of genetic variants on tissue-specific m^(6)A RNA modifications;and(4)m^(6)A-CAVar,a database of 587,983 The Cancer Genome Atlas(TCGA)cancer mutations(derived from 27 cancer types)that were predicted to affect m^(6)A modifications in the primary tissue of cancers.The database should make a useful resource for studying the m^(6)A methylome and the genetic factors of epitranscriptome disturbance in a specific tissue(or cancer type).m^(6)A-TSHub is accessible at www.xjtlu.edu.cn/biologicalsciences/m^(6)ats.展开更多
基金supported by the Postgraduate Research Scholarship fund of Xi’an Jiaotong-Liverpool University (FOSA2212023 to R.R.)Research Development Fund of Xi’an Jiaotong-Liverpool University (RDF-22-01-045) to Z.L.L.)。
文摘Macaques,particularly rhesus(Macaca mulatta) and cynomolgus(M.fascicularis) monkeys,are widely utilized in biomedical and toxicological research.Despite their critical role,effective vaccines against many viral pathogens affecting these primates remain limited,and vaccination is generally avoided in experimental populations to prevent potential confounding outcomes.Consequently,maintaining viral control within macaque colonies depends on stringent surveillance,systematic diagnostic testing,and rigorously enforced quarantine protocols.Accurate and early detection of viral infections is therefore essential for colony management and research integrity.This review synthesizes current knowledge on 10major viruses affecting macaque colonies,outlining their biological characteristics and diagnostic methodologies,and further assesses recent technological advances in viral detection.Drawing upon five years of surveillance data collected by VRL-Asia from breeding facilities across China,this review highlights the prevalence patterns of viral infections among breeding macaques and identifies critical epidemiological trends.These insights provide a valuable reference for researchers,veterinarians,and laboratory personnel seeking to strengthen biosecurity frameworks and ensure the reliability of research involving macaques.
文摘It is generally accepted that climate has changed greatly on a global scale, and that the earth＇s climate has already wanned by some degrees over the past century. Ample evidence shows that there have been apparent changes in avian population dynamics, life-history traits and geographic ranges in response to global climate change. This paper briefly reviews the possible effects of climate change on avian biology and ecology all over the world, with emphasis on new findings from several long-term studies in Europe and North America, which provide unique opportunities to investigate how long-term changes in climate affect birds at both individual and population levels. The implications of such long-term studies for future bird studies in China is discussed with hope that this review can contribute to the preparation and plan for studies of climatic effects on birds in China in the future.
基金Project supported by the 90th Anniversary of Chulalongkorn University(No.RA61/104)the Research Chair Grant from the National Science and Technology Development Agency+1 种基金the 100th Anniversary of Chulalongkorn University Fund for Doctoral Scholarshipthe Overseas Research Experience Scholarship for Graduate Student,Thailand and China Scholarship Council,China
文摘Osteoarthritis(OA)is a degenerative articular disorder manifested by cartilage destruction,subchondral sclerosis,osteophytes,and synovitis,resulting in chronic joint pain and physical disability in the elderly.The purpose of this study was to investigate mitochondrial DNA copy number(mtDNACN)and inflammatory cytokines in primary knee OA patients and healthy volunteers.A total of 204 knee OA patients and 169 age-matched healthy volunteers were recruited.Their relative blood leukocyte mtDNACN was assessed by quantitative real-time polymerase chain reaction(qRT-PCR),and ten inflammatory cytokines in their plasma were detected by multiplex immunoassay.Blood leukocyte mtDNACN in the OA group was significantly lower than that in the control group.Leukocyte mtDNACN in the control group was negatively correlated with their age(r=−0.380,P<0.0001),whereas mtDNACN in the OA group was positively correlated with their age(r=0.198,P<0.001).Plasma interleukin-4(IL-4)and IL-6 were significantly higher in the knee OA group than in the control group.The plasma IL-6 level was positively correlated with blood leukocyte mtDNACN in the OA group(r=0.547,P=0.0014).IL-5 showed as a major factor(coefficient 0.69)in the second dimension of principle components analysis(PCA)-transformed data and was significantly higher in the OA group(P<0.001)as well as negatively correlated with mtDNACN(r=−0.577,P<0.001).These findings suggest that elevation of plasma IL-4 and IL-6 and a relative reduction in mtDNACN might be effective biomarkers for knee OA.IL-5 is a plausible factor responsible for decreasing blood leukocyte mtDNACN in knee OA patients.
基金B.S.W.was funded by the“Adapting to the Challenges of a Changing Environment”(ACCE)Doctoral Training Partnershipwhich is itself funded by the Natural Environment Research Council(NERC)[NERC grant NE/P002692/1 to T.A.R.P.].
文摘Climate change is increasing the frequency and severity of short-term heat shocks that threaten the persistence of natural populations.However,most work addressing the evolutionary consequences of anthropogenic environmental change has focused on natural selection,with less attention paid to the impacts on sexual selection.The conditions under which sexual selection operates is a topic of debate,but a generally observed pattern is that the oper-ational sex ratio(OSR)of a population is key to determining both the extent of competition for fertilizations and the scope for mate choice(Weir et al.2011)
文摘The fungal communities in mushroom compost phase Ⅱ was assessed using a combination of PCR amplification and sequencing of 18S rDNA from fungal isolates and “nested” PCR TGGE analysis on the basis of DNA directly extracted from compost samples. The diversity of cultivated fungi isolated from compost samples was low. A total of 11 isolates were related to only 2 different species. One species, Chaetomium elatum, was identified within 10 isolates, and the other, with high similarity belonged to Penicillium expansum. The fungal flora associated with mushroom compost was then monitored with “nested” PCR TGGE. The patterns obtained revealed the more complex existence of fungal communities from the original compost samples than from thoses enriched with food waste and cow slurry.
基金financially supported by grants from the Engineering and Physical Sciences Research Council,UK,the Biotechnology and Biological Sciences Research Council,UK,the Medical Research Council,UK,Intellihep Ltd.,UK,MI Engineering Ltd.,UK and Financiadora de Estudos e Projetos
文摘The pharmaceutical and anticoagulant agent heparin,a member of the glycosaminoglycan family of carbohydrates,has previously been identified as a potent inhibitor of a key Alzheimer’s disease drug target,the primary neuronalβ-secretase,β-site amyloid precursor protein cleaving enzyme 1(BACE1).The anticoagulant activity of heparin has,however,precluded the repurposing of this widely used pharmaceutical as an Alzheimer’s disease therapeutic.Here,a glycosaminoglycan extract,composed predominantly of 4-sulfated chondroitin sulfate,has been isolated from Sardina pilchardus,which possess the ability to inhibit BACE1(IC50[half maximal inhibitory concentration]=4.8μg/mL),while displaying highly attenuated anticoagulant activities(activated partial thromboplastin time EC50[median effective concentration]=403.8μg/mL,prothrombin time EC50=1.3 mg/mL).The marine-derived,chondroitin sulfate extract destabilizes BACE1,determined via differential scanning fluorimetry(ΔTm–5°C),to a similar extent as heparin,suggesting that BACE1 inhibition by glycosaminoglycans may occur through a common mode of action,which may assist in the screening of glycan-based BACE1 inhibitors for Alzheimer’s disease.
基金Supported by Key R&D Program of Jiangsu Province,No.BE2019712British Heart Foundation,No.PG/14/19/30751 and No.PG/16/65/32313.
文摘BACKGROUND Liver fibrosis progressing to liver cirrhosis and hepatic carcinoma is very common and causes more than one million deaths annually.Fibrosis develops from recurrent liver injury but the molecular mechanisms are not fully understood.Recently,the TLR4-MyD88 signaling pathway has been reported to contribute to fibrosis.Extracellular histones are ligands of TLR4 but their roles in liver fibrosis have not been investigated.AIM To investigate the roles and potential mechanisms of extracellular histones in liver fibrosis.METHODS In vitro,LX2 human hepatic stellate cells(HSCs)were treated with histones in the presence or absence of non-anticoagulant heparin(NAHP)for neutralizing histones or TLR4-blocking antibody.The resultant cellular expression of collagen I was detected using western blotting and immunofluorescent staining.In vivo,the CCl4-induced liver fibrosis model was generated in male 6-week-old ICR mice and in TLR4 or MyD88 knockout and parental mice.Circulating histones were detected and the effect of NAHP was evaluated.RESULTS Extracellular histones strongly stimulated LX2 cells to produce collagen I.Histone-enhanced collagen expression was significantly reduced by NAHP and TLR4-blocking antibody.In CCl4-treated wild type mice,circulating histones were dramatically increased and maintained high levels during the duration of fibrosisinduction.Injection of NAHP not only reduced alanine aminotransferase and liver injury scores,but also significantly reduced fibrogenesis.Since the TLR4-blocking antibody reduced histone-enhanced collagen I production in HSC,the CCl4 model with TLR4 and MyD88 knockout mice was used to demonstrate the roles of the TLR4-MyD88 signaling pathway in CCl4-induced liver fibrosis.The levels of liver fibrosis were indeed significantly reduced in knockout mice compared to wild type parental mice.CONCLUSION Extracellular histones potentially enhance fibrogenesis via the TLR4–MyD88 signaling pathway and NAHP has therapeutic potential by detoxifying extracellular histones.
基金Supported by Alberta Prion Research Institute,Canada(Project title:"Comprehensive Risk Assessment of CWD Transmission to Humans Using Non-human Primates")European Metrology Research Programme(EMRP)Researcher Grant:HLT10-Bi Origin(Metrology for the Biomolecular Origin of Disease)
文摘Proteinaceous infectious particles(prions) are unique pathogens as they are devoid of any coding nucleic acid.Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed.
文摘The pH values of soils collected from 30 different districts of Al-Madinah Al-Munawarah province were measured using an Electric pH meter. The pH values revealed （27%） a slight to （60%） medium alkalinity ranged between： 7.17-9.45 （pH 8.13 ± 0.13） The alkalinity is attributed to scanty rainfall and deep underground waters as well as deposition of high air pollution contents at Al-Madinah Al-Munawarah. Such soil alkalinity is not optimum to growth of arable/lea-grassland but only for limited cultivation i.e. date palms in comparison with Northwestern and Southwestern sectors of KSA. It is recommended to carry out similar soil evaluation of other parts of KSA involving more measurements i.e. ionic concentration, nutrient levels, micro-flora and to laundry these lands to lower soil＇spHs and to increase its fertility.
文摘DEE （diesel exhaust emitted） and fossil fuel do contribute to the pollution of ecosystem while very little is known about their toxic effects on pulmonary tissue in the short-term. Ten male Guinea pigs exposed to DEE in an open system experiment at different time schemes and their tracheas and lungs were processed for routine Histology, Immunohistochemsitry and TEM （transmission Electron Microscopy） techniques. The results revealed early toxicological effects of DEE on pulmonary tissue involved cellular damages to the mucosa of trachea and bronchial tree, rupture of alveolar walls, disintegration of pneumocytes, development of mucous secretions, swellings in the alveolar network, hemorrhage and lymphatic infiltration all over the parenchyma starting from the early hours of exposure to DEE. Ultrastructural changes confirmed the ruptures to the alveolar walls, infiltration of various WBC （white blood cells）, development of vacuoles inside the cytoplasmic organelles of pnemocytes, distortion in morphology of both RBCs （Red Blood corpuscles） which all had begun as early as 1 h following the exposure to the DEE. Activation of the immune system was noted via the increase in size of lymph nodules to confront the invaded particulates. These results indicate blockage of the respiratory leading to suffocation and do alert the expected acute cellular harms to the pulmonary tissues following exposure to the DEE of mechanics work in vicinity of DEE who spend most daily hours in semi-closed areas.
基金supported by the National Key R&D Program of China(2023YFA0914600 and 2021YFA0909600)the National Natural Science Foundation of China(32070109)+5 种基金Biotechnology and Biological Sciences Research Council Grants(BB/Y01135X/1,BB/V009729/1,BB/Y008308/1,and BB/S003339/1)the Leverhulme Trust(RPG-2021-286 and RPG-2019-300)the Natural Environment Research Council Grant(NE/Z00019X/1)the Royal Society(URF\R\180030 and RGF\EA\181061),the ERC Advanced Grant(101021133)the Wellcome Trust Investigator Award(206422/Z/17/Z).support of the cryo-EM facilities at the UK National electron Bio-Imaging Centre(eBIC),proposal NT21004.
文摘Rubisco(ribulose-1,5-bisphosphate carboxylase/oxygenase)is the central enzyme for conversion of atmospheric CO_(2)into organic molecules,playing a crucial role in the global carbon cycle.In cyanobacteria and some chemoautotrophs,Rubisco complexes,together with carbonic anhydrase,are enclosed within specific proteinaceous microcompartments known as carboxysomes.The polyhedral carboxysome shell ensures the dense packaging of Rubisco and creates a high-CO_(2)internal environment to facilitate CO_(2)fixation.Rubisco and carboxysomes have been popular targets for bioengineering,with the intent of enhancing plant photosynthesis,crop yields,and biofuel production.However,efficient generation of Form 1B Rubisco and cyanobacterial b-carboxysomes in heterologous systems remains a challenge.Here,we developed genetic systems to efficiently engineer functional cyanobacterial Form 1B Rubisco in Escherichia coli by incorporating Rubisco assembly factor Raf1 and modulating the RbcL/S stoichiometry.We then reconstituted catalytically active b-carboxysomes in E.coli with cognate Form 1B Rubisco by fine-tuning the expression levels of individual b-carboxysome components.In addition,we investigated the mechanism of Rubisco encapsulation into carboxysomes by constructing hybrid carboxysomes;this was achieved by creating a chimeric encapsulation peptide incorporating small sub-unit-like domains,which enabled the encapsulation of Form 1B Rubisco into a-carboxysome shells.Our study provides insights into the assembly mechanisms of plant-like Form 1B Rubisco and the principles of its encapsulation in both b-carboxysomes and hybrid carboxysomes,highlighting the inherent modularity of carboxysome structures.These findings lay the framework for rational design and repurposing of CO_(2)-fixing modules in bioengineering applications,e.g.,crop engineering,biocatalyst production,and molecule delivery.
基金YX and RG thank Wellcome Trust for funding MetaboFlow(Grant 202952/Z/16/Z).
文摘Model validation is the most important part of building a supervised model.For building a model with good generalization performance one must have a sensible data splitting strategy,and this is crucial for model validation.In this study,we con-ducted a comparative study on various reported data splitting methods.The MixSim model was employed to generate nine simulated datasets with different probabilities of mis-classification and variable sample sizes.Then partial least squares for discriminant analysis and support vector machines for classification were applied to these datasets.Data splitting methods tested included variants of cross-validation,bootstrapping,bootstrapped Latin partition,Kennard-Stone algorithm(K-S)and sample set partitioning based on joint X-Y distances algorithm(SPXY).These methods were employed to split the data into training and validation sets.The estimated generalization performances from the validation sets were then compared with the ones obtained from the blind test sets which were generated from the same distribution but were unseen by the train-ing/validation procedure used in model construction.The results showed that the size of the data is the deciding factor for the qualities of the generalization performance estimated from the validation set.We found that there was a significant gap between the performance estimated from the validation set and the one from the test set for the all the data splitting methods employed on small datasets.Such disparity decreased when more samples were available for training/validation,and this is because the models were then moving towards approximations of the central limit theory for the simulated datasets used.We also found that having too many or too few samples in the training set had a negative effect on the estimated model performance,suggesting that it is necessary to have a good balance between the sizes of training set and validation set to have a reliable estimation of model performance.We also found that systematic sampling method such as K-S and SPXY generally had very poor estimation of the model performance,most likely due to the fact that they are designed to take the most representative samples first and thus left a rather poorly representative sample set for model performance estimation.
基金the National Natural Scienoe Foundation of ChinaChina-France-Canada cooperation research project+2 种基金the State Seismological Bureau of ChinaInstitute National des Science des Univ.,FranceNational Science and Engineering Research Council of Canada
文摘The equilibrium temperature and pressure of both spinel and garnet peridotite xenolithsfrom eastern China have been estimated by using different geothermobarometers that are currentlyconsidered to be reliable.Based on these data,the upper mantle geotherm for eastern China has beenconstructed.The obtained geotherm is higher than that for old craton regions,but is similar to that for southeasternAustralia.The most prominent feature of the geotherm is that there is a slight gradient at about 60 kmdepth,and the inflection of the geotherm just passes through the transition line between spinel and garnetfacies.It is likely that the inflection represents the botmdary between the lithosphere and asthenosphere.Thestructures of the upper mantle beneath eastern China have also been discussed by combining the results ofpetrologic,rheological and dynamical studies of the upper mantle.
基金supported by the National Natural Science Foundation of China(Grant Nos.32100519 and 31671373)the Scientific Research Foundation for Advanced Talents of Fujian Medical University(Grant No.XRCZX2021019)the XJTLU Key Program Special Fund(Grant Nos.KSF-T-01,KSF-E-51,and KSF-P-02),China.
文摘As the most pervasive epigenetic marker present on mRNAs and long non-coding RNAs(lncRNAs),N6-methyladenosine(m^(6)A)RNA methylation has been shown to participate in essential biological processes.Recent studies have revealed the distinct patterns of m^(6)A methylome across human tissues,and a major challenge remains in elucidating the tissue-specific presence and circuitry of m^(6)A methylation.We present here a comprehensive online platform,m^(6)A-TSHub,for unveiling the context-specific m^(6)A methylation and genetic mutations that potentially regulate m^(6)A epigenetic mark.m^(6)A-TSHub consists of four core components,including(1)m^(6)A-TSDB,a comprehensive database of 184,554 functionally annotated m^(6)A sites derived from 23 human tissues and 499,369 m^(6)A sites from 25 tumor conditions,respectively;(2)m^(6)A-TSFinder,a web server for high-accuracy prediction of m^(6)A methylation sites within a specific tissue from RNA sequences,which was constructed using multi-instance deep neural networks with gated attention;(3)m^(6)ATSVar,a web server for assessing the impact of genetic variants on tissue-specific m^(6)A RNA modifications;and(4)m^(6)A-CAVar,a database of 587,983 The Cancer Genome Atlas(TCGA)cancer mutations(derived from 27 cancer types)that were predicted to affect m^(6)A modifications in the primary tissue of cancers.The database should make a useful resource for studying the m^(6)A methylome and the genetic factors of epitranscriptome disturbance in a specific tissue(or cancer type).m^(6)A-TSHub is accessible at www.xjtlu.edu.cn/biologicalsciences/m^(6)ats.
