Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactiv...Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.展开更多
Dry-cured meat products are considerably popular around the world due to unique flavor.Proteolysis is one of the enzymatic reactions from which flavor substances are derived,which is affected by endogenous proteases.T...Dry-cured meat products are considerably popular around the world due to unique flavor.Proteolysis is one of the enzymatic reactions from which flavor substances are derived,which is affected by endogenous proteases.The purpose aimed to reveal the potential relationship between endogenous proteases and key flavor substances in dry-cured pork coppa in this paper.The dynamic changes of endogenous proteases activity,free amino acids,and volatiles during dry-cured pork coppa processing were characterized.The results showed that 5 kinds of free amino acids,Glu,Lys,Val,Ala,and Leu,were identified as significant contributors to taste.Meanwhile,key volatiles,such as hexanal,nonanal,octanal,benzaldehyde,3-methyl butanoic acid,2-methyl propanoic acid,and ethyl octanoate,greatly contributed to the flavor characteristics of dry-cured pork coppa.Further partial correlation analysis was performed to better elucidate the relationship among parameters.The results revealed that close relationship between endogenous proteases and key substances.RAP not only significantly affected the accumulation of key active-amino acids,but also affected the accumulation of ethyl octanoate,2,3-pentanedione,and 2,3-octanedione by regulating the accumulation of octanoic acid and Leu.In addition,cathepsin B and D,DPP II,DPP IV and RAP notably affected accumulation of hexanal.展开更多
Introduction to human endogenous retrovirus type-W(HERV-W): Genomic inheritance from the past includes retroviral sequences that have been stably incorporated into our genomes and account for up to 8% of human DNA.
BACKGROUND Competitive endogenous RNA(ceRNA)is an innovative way of gene expression modulation,which plays a crucial part in neoplasia.However,the intricacy and behavioral characteristics of the ceRNA network in hepat...BACKGROUND Competitive endogenous RNA(ceRNA)is an innovative way of gene expression modulation,which plays a crucial part in neoplasia.However,the intricacy and behavioral characteristics of the ceRNA network in hepatocellular carcinoma(HCC)remain dismal.AIM To establish a cyclin dependent kinase inhibitor 2A(CDKN2A)-related ceRNA network and recognize potential prognostic indicators for HCC.METHODS The mutation landscape of CDKN2A in HCC was first explored using the cBioPortal database.Differential expression analysis was implemented between CDKN2Ahigh and CDKN2Alow expression HCC samples.The targeted microRNAs were predicted by lncBasev3.0,and the targeted mRNAs were predicted by miRDB,and Targetscan database.The univariate and multivariate analysis were utilized to identify independent prognostic indicators.RESULTS CDKN2A was frequently mutated and deleted in HCC.The single-cell RNA-sequencing analysis revealed that CDKN2A participated in cell cycle pathways.The CDKN2A-related ceRNA network-growth arrest specific 5(GAS5)/miR-25-3p/SRY-box transcription factor 11(SOX11)was successfully established.GAS5 was recognized as an independent prognostic biomarker,whose overexpression was correlated with a poor prognosis in HCC patients.The association between GAS5 expression and methylation,immune infilt-ration was explored.Besides,traditional Chinese medicine effective components targeting GAS5 were obtained.CONCLUSION This CDKN2A-related ceRNA network provides innovative insights into the molecular mechanism of HCC formation and progression.Moreover,GAS5 might be a significant prognostic biomarker and therapeutic target in HCC.展开更多
In the article“Long non-coding RNA LINC02163 accelerates malignant tumor behaviors in breast cancer by regulating the microRNA-511-3p/HMGA2 axis as a competing endogenous RNA”(Oncology Research,2020,Vol.28,No.5,pp....In the article“Long non-coding RNA LINC02163 accelerates malignant tumor behaviors in breast cancer by regulating the microRNA-511-3p/HMGA2 axis as a competing endogenous RNA”(Oncology Research,2020,Vol.28,No.5,pp.483–495.doi:10.3727/096504020X15928179818438),there was an error in the processing of data.To further confirm our observation,we repeated multiple experiments involving in this study,including Flow Cytometry,Transwell Cell Migration and Invasion Assays,Xenograft Tumor Model,and Western Blotting.We have revised the figures to correct these errors.Corrected versions of the Figs.2,4,5,6,and 7 are provided.The corrections do not change any results or conclusion of the article.We apologize for any inconvenience caused.展开更多
Endogenous endophthalmitis is a rare condition with a poor long-term visual prognosis and significant mortality, often associated with the hematogenous spread of intravitreal infections and subsequent disruption of th...Endogenous endophthalmitis is a rare condition with a poor long-term visual prognosis and significant mortality, often associated with the hematogenous spread of intravitreal infections and subsequent disruption of the blood-ocular barrier. Its anatomical proximity to the central nervous system (CNS) poses a high risk of infection dissemination, although cases documented in the literature are rare, and endogenous endophthalmitis is typically described as secondary to neuroinfections. We report the case of an 82-year-old female patient with a history of hypertension who presented with fever, decreased visual acuity, severe headache, chemosis, and conjunctival injection. Endogenous endophthalmitis was diagnosed, and antimicrobial treatment was initiated alongside surgical intervention by the ophthalmology service. However, the patient’s condition worsened neurologically, and Streptococcus pneumoniae was identified in cerebrospinal fluid cultures. Despite intensive medical treatment, the patient’s clinical course was poor, leading to death.展开更多
Deciphering the context-specific relationship between sequence and function is a major challenge in genomics.Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limi...Deciphering the context-specific relationship between sequence and function is a major challenge in genomics.Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited.Here we present a programmable platform for long-range,locus-specific hypermutation called helicase-assisted continuous editing(HACE).HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large(>1000-base pair)genomic intervals.We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1(MEK1)that confer kinase inhibitor resistance,to dissect the impact of individual variants in splicing factor 3B subunit 1(SF3B1)-dependent missplicing,and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69.HACE provides a powerful tool for investigating coding and noncoding variants,uncovering combinatorial sequence-to-function relationships,and evolving new biological functions.展开更多
The integration of digital twin(DT)and 6G edge intelligence provides accurate forecasting for distributed resources control in smart park.However,the adverse impact of model poisoning attacks on DT model training cann...The integration of digital twin(DT)and 6G edge intelligence provides accurate forecasting for distributed resources control in smart park.However,the adverse impact of model poisoning attacks on DT model training cannot be ignored.To address this issue,we firstly construct the models of DT model training and model poisoning attacks.An optimization problem is formulated to minimize the weighted sum of the DT loss function and DT model training delay.Then,the problem is transformed and solved by the proposed Multi-timescAle endogenouS securiTy-aware DQN-based rEsouRce management algorithm(MASTER)based on DT-assisted state information evaluation and attack detection.MASTER adopts multi-timescale deep Q-learning(DQN)networks to jointly schedule local training epochs and devices.It actively adjusts resource management strategies based on estimated attack probability to achieve endogenous security awareness.Simulation results demonstrate that MASTER has excellent performances in DT model training accuracy and delay.展开更多
The objective of this study was to investigate the effects of root cutting stress on the dynamic changes of endogenous hormone content and growth characteristics of Quercus variabilis roots,and to explore the physiolo...The objective of this study was to investigate the effects of root cutting stress on the dynamic changes of endogenous hormone content and growth characteristics of Quercus variabilis roots,and to explore the physiological role of endogenous hormones in regulating root-crown interactions in the short term.The morphological characteristics and endogenous hormone contents of normal roots(no root cutting,CK)and cut roots(cut by 1/3 of the length of the main root,RP)were determined by liquid chromatography,which was combined with mass spectrometry at different levels of different developmental stages.The results showed that the root growth indexes and root endogenous hormones in the RP group were superior to those in the CK group.Through comprehensive analysis of endogenous hormones,it was found that the crosstalk of IAA,JA,ABA and SA could activate the root growth defense.After the root cutting treatment,the root growth of Quercus variabilis seedlings could compensate for the inhibition of taproot growth by promoting lateral root growth.The growth and development of compensatory lateral roots contribute to the increase the total root length of plants,thus promoting the absorption of water and nutrients.It is speculated that plant hormones may be the key factors affecting their development,but this is not only related to the content of a single hormone,but more importantly,it is the interaction between various hormones.展开更多
Age-related macular degeneration(AMD)causes irreversible blindness in people aged over 50 worldwide.The dysfunction of the retinal pigment epithelium is the primary cause of atrophic AMD.In the current study,we used t...Age-related macular degeneration(AMD)causes irreversible blindness in people aged over 50 worldwide.The dysfunction of the retinal pigment epithelium is the primary cause of atrophic AMD.In the current study,we used the ComBat and Training Distribution Matching method to integrate data obtained from the Gene Expression Omnibus database.We analyzed the integrated sequencing data by the Gene Set Enrichment Analysis.Peroxisome and tumor necrosis factor-α(TNF-α)signaling and nuclear factor kappa B(NF-κB)were among the top 10 pathways,and thus we selected them to construct AMD cell models to identify differentially expressed circular RNAs(circRNAs).We then constructed a competing endogenous RNA network,which is related to differentially expressed circRNAs.This network included seven circRNAs,15 microRNAs,and 82 mRNAs.The Kyoto Encyclopedia of Genes and Genomes analysis of mRNAs in this network showed that the hypoxia-inducible factor-1(HIF-1)signaling pathway was a common downstream event.The results of the current study may provide insights into the pathological processes of atrophic AMD.展开更多
Adoptive cell transfer(ACT)using chimeric antigen receptor(CAR)modified T cells and T cell receptor(TCR)engineered T cells has shown therapeutic efficacy in cancer treatment1,2.CAR T cells are widely applicable to tum...Adoptive cell transfer(ACT)using chimeric antigen receptor(CAR)modified T cells and T cell receptor(TCR)engineered T cells has shown therapeutic efficacy in cancer treatment1,2.CAR T cells are widely applicable to tumor patients because of their ability to directly identify tumor cells in an MHCindependent manner.展开更多
Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we ...Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.展开更多
Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblas...Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblast function.Here,we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation.As such,we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation.Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function.The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions.In vivo,conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism.Collectively,our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets,which are released via lipolysis to support cellular bioenergetic status when nutrients are limited.Perturbations in this process result in impairment of bone formation,specifically reducing ATP production and overall osteoblast function.展开更多
BACKGROUND Major depressive disorder(MDD)is a common and serious mental illness.Many novel genes in MDD have been characterized by high-throughput methods such as microarrays or sequencing.Recently,noncoding RNAs(ncRN...BACKGROUND Major depressive disorder(MDD)is a common and serious mental illness.Many novel genes in MDD have been characterized by high-throughput methods such as microarrays or sequencing.Recently,noncoding RNAs(ncRNAs)were suggested to be involved in the complicated environmental-genetic regulatory network of MDD occurrence;however,the interplay among RNA species,including protein-coding RNAs and ncRNAs,in MDD remains unclear.AIM To investigate the RNA expression datasets downloaded from a public database and construct a network based on differentially expressed long noncoding RNA(lncRNAs),microRNAs(miRNAs),and mRNAs between MDD and controls.METHODS Gene expression data were searched in NCBI Gene Expression Omnibus using the search term“major depressive disorder.”Six array datasets from humans were related to the search term:GSE19738,GSE32280,GSE38206,GSE52790,GSE76826,and GSE81152.These datasets were processed for initial assessment and subjected to quality control and differential expression analysis.Differentially expressed lncRNAs,miRNAs,and mRNAs were determined,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed,and protein-protein interaction network was generated.The results were analyzed for their association with MDD.RESULTS After analysis,3 miRNAs,12 lncRNAs,and 33 mRNAs were identified in the competing endogenous RNA network.Two of these miRNAs were earlier shown to be involved in psychiatric disorders,and differentially expressed mRNAs were found to be highly enriched in pathways related to neurogenesis and neuroplasticity as per Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The expression of hub gene fatty acid 2-hydroxylase was enriched,and the encoded protein was found to be involved in myelin formation,indicating that neurological development and signal transduction are involved in MDD pathogenesis.CONCLUSION The present study presents candidate nc RNAs involved in the neurogenesis and neuroplasticity pathways related to MDD.展开更多
Stock markets exhibit Brownian movement with random,non-linear,uncertain,evolutionary,non-parametric,nebulous,chaotic characteristics and dynamism with a high degree of complexity.Developing an algorithm to predict re...Stock markets exhibit Brownian movement with random,non-linear,uncertain,evolutionary,non-parametric,nebulous,chaotic characteristics and dynamism with a high degree of complexity.Developing an algorithm to predict returns for decision-making is a challenging goal.In addition,the choice of vari-ables that will serve as input to the model represents a non-triviality,since it is possible to observe endogeneity problems between the predictor and the predicted variables.Thus,the goal is to analyze the endogenous origin of the stock return prediction model based on technical indicators.For this,we structure a feed-for-ward neural network.We evaluate the endogenous feedback between the pre-dicted returns and technical analysis indicators based on the generated residues.It is possible to predict the return.The high accuracy of the model indicates that,during the test period,there is a hit rate close to 76%.Regarding endogeneity,the term of interest and the return are the variables that influence the largest number of indicators.The results will help investors build investment strategies based on this expert system applied to forecasting.展开更多
As drug-resistant bacterial infections escalate and antimicrobial resources become insufficient,new alternative therapies are critical.The emergence of nano drug delivery system,in addition to giving drugs sustained,t...As drug-resistant bacterial infections escalate and antimicrobial resources become insufficient,new alternative therapies are critical.The emergence of nano drug delivery system,in addition to giving drugs sustained,targeted or longer half-life characteristics,also plays an important role in improving the therapeutic effect and reducing the toxic side effects of conventional drugs.Despite its potential benefits,the traditional nanomedical drug delivery system has some practical limitations,including incomplete and slow drug release,as well as insufficient accumulation at infection sites.Stimuli responsive nanoplatforms are hence developed to overcome the disadvantages of conventional nanoparticles,which can provide several advantages like:enhancing the pharmacokinetics and biodistribution of antimicrobial drugs,increasing their effective bioavailability,reducing their dosage frequency,and improving their antimicrobial efficacy against biofilm-related infections,while slowing down the development of antimicrobial resistance,which is expected to trigger a medical revolution in the field of human health,thus bringing huge clinical benefits.In this review,we provide an extensive review of the recent progress of endogenous and exogenous stimuli-responsive nanoplatforms in the antibacterial area.Using specific infectious microenvironments(pH,enzymes,reactive oxygen species and toxins),this review systematically presents the design principles of nano delivery systems and the mechanisms by which endogenous stimuli induce changes in the morphology or properties of delivery systems to achieve programmed drug release.Furthermore,exogenous stimuli such as light,heat,and magnetic fields can also control the release of drugs.Last but not least,we discussed the challenges and opportunities for future clinical translation of stimuli-responsive nanoplatforms in bacterial infections.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81941011(to XL),31771053(to HD),31730030(to XL),31971279(to ZY),31900749(to PH),31650001(to XL),31320103903(to XL),31670988(to ZY)the Natural Science Foundation of Beijing,Nos.7222004(to HD)+1 种基金a grant from Ministry of Science and Technology of China,Nos.2017YFC1104002(to ZY),2017YFC1104001(to XL)a grant from Beihang University,No.JKF-YG-22-B001(to FH)。
文摘Attempts have been made to use cell transplantation and biomaterials to promote cell proliferation,differentiation,migration,and survival,as well as angiogenesis,in the context of brain injury.However,whether bioactive materials can repair the damage caused by ischemic stroke by activating endogenous neurogenesis and angiogenesis is still unknown.In this study,we applied chitosan gel loaded with basic fibroblast growth factor to the stroke cavity 7 days after ischemic stroke in rats.The gel slowly released basic fibroblast growth factor,which improved the local microenvironment,activated endogenous neural stem/progenitor cells,and recruited these cells to migrate toward the penumbra and stroke cavity and subsequently differentiate into neurons,while enhancing angiogenesis in the penumbra and stroke cavity and ultimately leading to partial functional recovery.This study revealed the mechanism by which bioactive materials repair ischemic strokes,thus providing a new strategy for the clinical application of bioactive materials in the treatment of ischemic stroke.
基金financially supported by the National Natural Science Foundation of China(32001728,32172248)the Taishan Industrial Experts Program+1 种基金the Guizhou High-level Innovative Talent Training Project(Qianke Cooperation Platform Talent number[2016]5662)Guizhou Science and Technology Innovation Talent Team of Ecological Characteristic Meat Products.(QKHPTRC[2020]5004)。
文摘Dry-cured meat products are considerably popular around the world due to unique flavor.Proteolysis is one of the enzymatic reactions from which flavor substances are derived,which is affected by endogenous proteases.The purpose aimed to reveal the potential relationship between endogenous proteases and key flavor substances in dry-cured pork coppa in this paper.The dynamic changes of endogenous proteases activity,free amino acids,and volatiles during dry-cured pork coppa processing were characterized.The results showed that 5 kinds of free amino acids,Glu,Lys,Val,Ala,and Leu,were identified as significant contributors to taste.Meanwhile,key volatiles,such as hexanal,nonanal,octanal,benzaldehyde,3-methyl butanoic acid,2-methyl propanoic acid,and ethyl octanoate,greatly contributed to the flavor characteristics of dry-cured pork coppa.Further partial correlation analysis was performed to better elucidate the relationship among parameters.The results revealed that close relationship between endogenous proteases and key substances.RAP not only significantly affected the accumulation of key active-amino acids,but also affected the accumulation of ethyl octanoate,2,3-pentanedione,and 2,3-octanedione by regulating the accumulation of octanoic acid and Leu.In addition,cathepsin B and D,DPP II,DPP IV and RAP notably affected accumulation of hexanal.
基金supported by the Christiane and Claudia Hempel Foundation for Regenerative Medicineby the James and Elisabeth Cloppenburg, Peek and Cloppenburg Düsseldorf Stiftung(to PK)。
文摘Introduction to human endogenous retrovirus type-W(HERV-W): Genomic inheritance from the past includes retroviral sequences that have been stably incorporated into our genomes and account for up to 8% of human DNA.
基金Supported by the Zhejiang Province Major Science and Technology Project for Medicine and Health,No.WKJ-ZJ-2329.
文摘BACKGROUND Competitive endogenous RNA(ceRNA)is an innovative way of gene expression modulation,which plays a crucial part in neoplasia.However,the intricacy and behavioral characteristics of the ceRNA network in hepatocellular carcinoma(HCC)remain dismal.AIM To establish a cyclin dependent kinase inhibitor 2A(CDKN2A)-related ceRNA network and recognize potential prognostic indicators for HCC.METHODS The mutation landscape of CDKN2A in HCC was first explored using the cBioPortal database.Differential expression analysis was implemented between CDKN2Ahigh and CDKN2Alow expression HCC samples.The targeted microRNAs were predicted by lncBasev3.0,and the targeted mRNAs were predicted by miRDB,and Targetscan database.The univariate and multivariate analysis were utilized to identify independent prognostic indicators.RESULTS CDKN2A was frequently mutated and deleted in HCC.The single-cell RNA-sequencing analysis revealed that CDKN2A participated in cell cycle pathways.The CDKN2A-related ceRNA network-growth arrest specific 5(GAS5)/miR-25-3p/SRY-box transcription factor 11(SOX11)was successfully established.GAS5 was recognized as an independent prognostic biomarker,whose overexpression was correlated with a poor prognosis in HCC patients.The association between GAS5 expression and methylation,immune infilt-ration was explored.Besides,traditional Chinese medicine effective components targeting GAS5 were obtained.CONCLUSION This CDKN2A-related ceRNA network provides innovative insights into the molecular mechanism of HCC formation and progression.Moreover,GAS5 might be a significant prognostic biomarker and therapeutic target in HCC.
文摘In the article“Long non-coding RNA LINC02163 accelerates malignant tumor behaviors in breast cancer by regulating the microRNA-511-3p/HMGA2 axis as a competing endogenous RNA”(Oncology Research,2020,Vol.28,No.5,pp.483–495.doi:10.3727/096504020X15928179818438),there was an error in the processing of data.To further confirm our observation,we repeated multiple experiments involving in this study,including Flow Cytometry,Transwell Cell Migration and Invasion Assays,Xenograft Tumor Model,and Western Blotting.We have revised the figures to correct these errors.Corrected versions of the Figs.2,4,5,6,and 7 are provided.The corrections do not change any results or conclusion of the article.We apologize for any inconvenience caused.
文摘Endogenous endophthalmitis is a rare condition with a poor long-term visual prognosis and significant mortality, often associated with the hematogenous spread of intravitreal infections and subsequent disruption of the blood-ocular barrier. Its anatomical proximity to the central nervous system (CNS) poses a high risk of infection dissemination, although cases documented in the literature are rare, and endogenous endophthalmitis is typically described as secondary to neuroinfections. We report the case of an 82-year-old female patient with a history of hypertension who presented with fever, decreased visual acuity, severe headache, chemosis, and conjunctival injection. Endogenous endophthalmitis was diagnosed, and antimicrobial treatment was initiated alongside surgical intervention by the ophthalmology service. However, the patient’s condition worsened neurologically, and Streptococcus pneumoniae was identified in cerebrospinal fluid cultures. Despite intensive medical treatment, the patient’s clinical course was poor, leading to death.
文摘Deciphering the context-specific relationship between sequence and function is a major challenge in genomics.Existing tools for inducing locus-specific hypermutation and evolution in the native genome context are limited.Here we present a programmable platform for long-range,locus-specific hypermutation called helicase-assisted continuous editing(HACE).HACE leverages CRISPR-Cas9 to target a processive helicase-deaminase fusion that incurs mutations across large(>1000-base pair)genomic intervals.We applied HACE to identify mutations in mitogen-activated protein kinase kinase 1(MEK1)that confer kinase inhibitor resistance,to dissect the impact of individual variants in splicing factor 3B subunit 1(SF3B1)-dependent missplicing,and to evaluate noncoding variants in a stimulation-dependent immune enhancer of CD69.HACE provides a powerful tool for investigating coding and noncoding variants,uncovering combinatorial sequence-to-function relationships,and evolving new biological functions.
基金supported by the Science and Technology Project of State Grid Corporation of China under Grant Number 52094021N010 (5400-202199534A-05-ZN)。
文摘The integration of digital twin(DT)and 6G edge intelligence provides accurate forecasting for distributed resources control in smart park.However,the adverse impact of model poisoning attacks on DT model training cannot be ignored.To address this issue,we firstly construct the models of DT model training and model poisoning attacks.An optimization problem is formulated to minimize the weighted sum of the DT loss function and DT model training delay.Then,the problem is transformed and solved by the proposed Multi-timescAle endogenouS securiTy-aware DQN-based rEsouRce management algorithm(MASTER)based on DT-assisted state information evaluation and attack detection.MASTER adopts multi-timescale deep Q-learning(DQN)networks to jointly schedule local training epochs and devices.It actively adjusts resource management strategies based on estimated attack probability to achieve endogenous security awareness.Simulation results demonstrate that MASTER has excellent performances in DT model training accuracy and delay.
基金funded by National Natural Science Foundation of China,Grant Number 31700549China Postdoctoral Science Foundation Project,Grant Number 2017M612401.
文摘The objective of this study was to investigate the effects of root cutting stress on the dynamic changes of endogenous hormone content and growth characteristics of Quercus variabilis roots,and to explore the physiological role of endogenous hormones in regulating root-crown interactions in the short term.The morphological characteristics and endogenous hormone contents of normal roots(no root cutting,CK)and cut roots(cut by 1/3 of the length of the main root,RP)were determined by liquid chromatography,which was combined with mass spectrometry at different levels of different developmental stages.The results showed that the root growth indexes and root endogenous hormones in the RP group were superior to those in the CK group.Through comprehensive analysis of endogenous hormones,it was found that the crosstalk of IAA,JA,ABA and SA could activate the root growth defense.After the root cutting treatment,the root growth of Quercus variabilis seedlings could compensate for the inhibition of taproot growth by promoting lateral root growth.The growth and development of compensatory lateral roots contribute to the increase the total root length of plants,thus promoting the absorption of water and nutrients.It is speculated that plant hormones may be the key factors affecting their development,but this is not only related to the content of a single hormone,but more importantly,it is the interaction between various hormones.
基金funded by the National Natural Science Foundation of China(Grant No.81970821)the Postgraduate Research Innovation Program of Jiangsu Provinc(Grant No.SJCX21_0624).
文摘Age-related macular degeneration(AMD)causes irreversible blindness in people aged over 50 worldwide.The dysfunction of the retinal pigment epithelium is the primary cause of atrophic AMD.In the current study,we used the ComBat and Training Distribution Matching method to integrate data obtained from the Gene Expression Omnibus database.We analyzed the integrated sequencing data by the Gene Set Enrichment Analysis.Peroxisome and tumor necrosis factor-α(TNF-α)signaling and nuclear factor kappa B(NF-κB)were among the top 10 pathways,and thus we selected them to construct AMD cell models to identify differentially expressed circular RNAs(circRNAs).We then constructed a competing endogenous RNA network,which is related to differentially expressed circRNAs.This network included seven circRNAs,15 microRNAs,and 82 mRNAs.The Kyoto Encyclopedia of Genes and Genomes analysis of mRNAs in this network showed that the hypoxia-inducible factor-1(HIF-1)signaling pathway was a common downstream event.The results of the current study may provide insights into the pathological processes of atrophic AMD.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82150108,31991171,and 81830002 to W.H.,and Grant No.82102892 to C.T.)。
文摘Adoptive cell transfer(ACT)using chimeric antigen receptor(CAR)modified T cells and T cell receptor(TCR)engineered T cells has shown therapeutic efficacy in cancer treatment1,2.CAR T cells are widely applicable to tumor patients because of their ability to directly identify tumor cells in an MHCindependent manner.
基金supported by the National Natural Science Foundations of China 82230030 and 81871492(Y.L.),82201020(Y.W),and 82100980(S.S.J)the Beijing Natural Science Foundation JL23002(Y.L.)and 7214305(S.S.J)+6 种基金the Beijing International Science and Technology Cooperation Project Z221100002722003(Y.L.)the Innovative Research Team of High-level Local Universities in Shanghai SHSMU-ZLCX20212402(Y.L.)Ten-Thousand Talents Program QNBJ2019-2(Y.L.)the Key R&D Plan of Ningxia Hui Autonomous Region 2020BCG01001(Y.L.)Beijing Nova Program Z211100002121043(Y.W.)China National Postdoctoral Program for Innovative Talents BX2021022(Y.W.),BX20200020(S.S.J)China Postdoctoral Science Foundation 2021M700281(Y.W.)。
文摘Adult tendon stem/progenitor cells(TSPCs)are essential for tendon maintenance,regeneration,and repair,yet they become susceptible to senescence with age,impairing the self-healing capacity of tendons.In this study,we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness.The top-ranked candidate,prim-O-glucosylcimifugin(POG),a saposhnikovia root extract,could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans,as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs.In vivo,the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals.Mechanistically,POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy.Thus,the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.
基金supported by National Institutes of Health(NIH),the National Institute of Arthritis and Musculoskeletal and Skin Diseases(NIAMS)Grant K01AR072123(ER-R)the American Society of Bone and Mineral Research(ASBMR)Rising Star awardprovided by NIH-National Institute of Diabetes and Digestive and Kidney Disease(NIDDK)Grant DK116056(MPC)。
文摘Bone formation is a highly energy-demanding process that can be impacted by metabolic disorders.Glucose has been considered the principal substrate for osteoblasts,although fatty acids are also important for osteoblast function.Here,we report that osteoblasts can derive energy from endogenous fatty acids stored in lipid droplets via lipolysis and that this process is critical for bone formation.As such,we demonstrate that osteoblasts accumulate lipid droplets that are highly dynamic and provide the molecular mechanism by which they serve as a fuel source for energy generation during osteoblast maturation.Inhibiting cytoplasmic lipolysis leads to both an increase in lipid droplet size in osteoblasts and an impairment in osteoblast function.The fatty acids released by lipolysis from these lipid droplets become critical for cellular energy production as cellular energetics shifts towards oxidative phosphorylation during nutrient-depleted conditions.In vivo,conditional deletion of the ATGL-encoding gene Pnpla2 in osteoblast progenitor cells reduces cortical and trabecular bone parameters and alters skeletal lipid metabolism.Collectively,our data demonstrate that osteoblasts store fatty acids in the form of lipid droplets,which are released via lipolysis to support cellular bioenergetic status when nutrients are limited.Perturbations in this process result in impairment of bone formation,specifically reducing ATP production and overall osteoblast function.
基金Supported by the National Key Research and Development Program of China,No.2020YFC2005500。
文摘BACKGROUND Major depressive disorder(MDD)is a common and serious mental illness.Many novel genes in MDD have been characterized by high-throughput methods such as microarrays or sequencing.Recently,noncoding RNAs(ncRNAs)were suggested to be involved in the complicated environmental-genetic regulatory network of MDD occurrence;however,the interplay among RNA species,including protein-coding RNAs and ncRNAs,in MDD remains unclear.AIM To investigate the RNA expression datasets downloaded from a public database and construct a network based on differentially expressed long noncoding RNA(lncRNAs),microRNAs(miRNAs),and mRNAs between MDD and controls.METHODS Gene expression data were searched in NCBI Gene Expression Omnibus using the search term“major depressive disorder.”Six array datasets from humans were related to the search term:GSE19738,GSE32280,GSE38206,GSE52790,GSE76826,and GSE81152.These datasets were processed for initial assessment and subjected to quality control and differential expression analysis.Differentially expressed lncRNAs,miRNAs,and mRNAs were determined,Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed,and protein-protein interaction network was generated.The results were analyzed for their association with MDD.RESULTS After analysis,3 miRNAs,12 lncRNAs,and 33 mRNAs were identified in the competing endogenous RNA network.Two of these miRNAs were earlier shown to be involved in psychiatric disorders,and differentially expressed mRNAs were found to be highly enriched in pathways related to neurogenesis and neuroplasticity as per Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses.The expression of hub gene fatty acid 2-hydroxylase was enriched,and the encoded protein was found to be involved in myelin formation,indicating that neurological development and signal transduction are involved in MDD pathogenesis.CONCLUSION The present study presents candidate nc RNAs involved in the neurogenesis and neuroplasticity pathways related to MDD.
文摘Stock markets exhibit Brownian movement with random,non-linear,uncertain,evolutionary,non-parametric,nebulous,chaotic characteristics and dynamism with a high degree of complexity.Developing an algorithm to predict returns for decision-making is a challenging goal.In addition,the choice of vari-ables that will serve as input to the model represents a non-triviality,since it is possible to observe endogeneity problems between the predictor and the predicted variables.Thus,the goal is to analyze the endogenous origin of the stock return prediction model based on technical indicators.For this,we structure a feed-for-ward neural network.We evaluate the endogenous feedback between the pre-dicted returns and technical analysis indicators based on the generated residues.It is possible to predict the return.The high accuracy of the model indicates that,during the test period,there is a hit rate close to 76%.Regarding endogeneity,the term of interest and the return are the variables that influence the largest number of indicators.The results will help investors build investment strategies based on this expert system applied to forecasting.
基金the Natural Science Foundation of Hubei Province,China(2021CFB468)Sci-tech Innovation Foundation of Huazhong Agriculture University(2662020LXPY007)National Key Research and Development Program of China(2021YFD1400800).
文摘As drug-resistant bacterial infections escalate and antimicrobial resources become insufficient,new alternative therapies are critical.The emergence of nano drug delivery system,in addition to giving drugs sustained,targeted or longer half-life characteristics,also plays an important role in improving the therapeutic effect and reducing the toxic side effects of conventional drugs.Despite its potential benefits,the traditional nanomedical drug delivery system has some practical limitations,including incomplete and slow drug release,as well as insufficient accumulation at infection sites.Stimuli responsive nanoplatforms are hence developed to overcome the disadvantages of conventional nanoparticles,which can provide several advantages like:enhancing the pharmacokinetics and biodistribution of antimicrobial drugs,increasing their effective bioavailability,reducing their dosage frequency,and improving their antimicrobial efficacy against biofilm-related infections,while slowing down the development of antimicrobial resistance,which is expected to trigger a medical revolution in the field of human health,thus bringing huge clinical benefits.In this review,we provide an extensive review of the recent progress of endogenous and exogenous stimuli-responsive nanoplatforms in the antibacterial area.Using specific infectious microenvironments(pH,enzymes,reactive oxygen species and toxins),this review systematically presents the design principles of nano delivery systems and the mechanisms by which endogenous stimuli induce changes in the morphology or properties of delivery systems to achieve programmed drug release.Furthermore,exogenous stimuli such as light,heat,and magnetic fields can also control the release of drugs.Last but not least,we discussed the challenges and opportunities for future clinical translation of stimuli-responsive nanoplatforms in bacterial infections.
