Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RP...Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RPL19-TRAP^(KI)-seq method,combining CRISPR/Cas9 and TRAP technologies,to investigate these mechanisms.We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP,selecting RPL19 for its high enrichment.We successfully established a stable cell line expressing EGFP-RPL19 using CRISPR knock-in and verified its efficiency and specificity in enriching ribosomes and translating mRNA.Integrated with next-generation sequencing,this method allows precise detection of translating mRNA.We validated RPL19-TRAP^(KI)-seq by investigating rapamycin,an mTOR inhibitor,yielding results consistent with previous reports.This optimized TRAP technology provides an accurate representation of translating mRNA,closely reflecting protein expression levels.Furthermore,we investigated SBF-1,a 23-oxa-analog of natural saponin OSW-1 with significant anti-tumor activity but an unclear mechanism.Using RPL19-TRAP^(KI)-seq,we found that SBF-1 exerts its cytotoxic effects on tumor cells by disturbing cellular oxidative phosphorylation.In conclusion,our method has been proven to be a promising tool that can reveal the mechanisms of small molecules with greater accuracy,setting the stage for future exploration of small molecules and advancing the fields of pharmacology and therapeutic development.展开更多
BACKGROUND Colorectal polyps,which are characterized by a high recurrence rate,represent preneoplastic conditions of the intestine.Due to unclear mechanisms of pathogenesis,first-line therapies for non-hereditary recu...BACKGROUND Colorectal polyps,which are characterized by a high recurrence rate,represent preneoplastic conditions of the intestine.Due to unclear mechanisms of pathogenesis,first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection.Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps,the exact compositions and roles of bacteria in the mucosa around the lesions,rather than feces,remain unsettled.AIM To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps.METHODS Mucosal samples were collected from four patients consistently with adenomatous polyps(Ade),seven consistently with non-Ade(Pol),ten with current Pol but previous Ade,and six healthy individuals,and bacterial patterns were evaluated by 16S rDNA sequencing.Linear discriminant analysis and Student’s t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes.Pearson’s correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators.RESULTS The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals.These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps,but also existed in histologically normal tissue 10 cm distal from the lesions.Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions,Pol,and Ade.Increased abundance of Gram-negative bacteria,including Klebsiella,Plesiomonas,and Cronobacter,was observed in Pol group and Ade group,suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment.Meanwhile,age and gender were linked to bacteria changes,indicating the potential involvement of sex hormones.CONCLUSION These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps,especially adenoma.Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.展开更多
The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with th...The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with the lignin oligomers,were adopted to study their effects during solvent shifting process for LNPs’production.The lignin oligomers with widely distributed molecular weight and abundant guaiacyl units were extracted from wood waste(mainly consists of pine wood),exerting outstanding self-assembly capability.Uniform and spherical LNPs were generated in H_(2)O-n-propanol cosolvent,whereas irregular LNPs were obtained in H_(2)O-methanol cosolvent.The unsatisfactory self-assembly performance of the lignin oligomers in H_(2)O-methanol cosolvent could be attributed to two aspects.On one hand,for the initial dissolution state,the distinguishing Hansen solubility parameter and polarity between methanol solvent and lignin oligomers resulted in the poor dispersion of the lignin oligomers.On the other hand,strong hydrogen bonds between methanol solvent and lignin oligomers during solvent shifting process,hindered the interactions among the lignin oligomers for self-assembly.展开更多
Multilayer paper-based cell culture,as an in vitro three-dimensional(3D)cell culture method,has been frequently used to research drug bioavailability,therapeutic efficacy,and dose-limiting toxicity in malignant tumors...Multilayer paper-based cell culture,as an in vitro three-dimensional(3D)cell culture method,has been frequently used to research drug bioavailability,therapeutic efficacy,and dose-limiting toxicity in malignant tumors.This paper proposes a heterogenous multilayer paper stacking co-culture system to establish a model of natural killer(NK)cells moving through the endothelium layer and attacking tumor spheroids.This system consists of three layers:a bottom tumor-spheroid layer,a middle invasion layer,and a top endothelium layer.NK-92 cells were placed in the supernatant on top of the three layers.After two days of co-culture,the attack of tumor spheroids by NK cells was observed.We additionally examined the infiltration of NK-92 cells within the tumor spheroids at different Z-axis depths using a confocal microscope,and the results suggested that the system successfully realizes NK cells traveling cross the endothelium layer to form tumor-infiltrating NK cells(TINKs).The potential application of multilayer paper for co-culture models involving cancer cells and immune cells holds great promise for exploring the interaction dynamics of these two cell types.展开更多
Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical trea...Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.展开更多
Tbx18,Wt1,and Tcf21 have been identified as epicardial markers during the early embryonic stage.However,the gene markers of mature epicardial cells remain unclear.Single-cell transcriptomic analysis was performed with...Tbx18,Wt1,and Tcf21 have been identified as epicardial markers during the early embryonic stage.However,the gene markers of mature epicardial cells remain unclear.Single-cell transcriptomic analysis was performed with the Seurat,Monocle,and CellphoneDB packages in R software with standard procedures.Spatial transcriptomics was performed on chilled Visium Tissue Optimization Slides(10x Genomics)and Visium Spatial Gene Expression Slides(10x Genomics).Spatial transcriptomics analysis was performed with Space Ranger software and R software.Immunofluorescence,whole-mount RNA in situ hybridization and X-gal staining were performed to validate the analysis results.Spatial transcriptomics analysis revealed distinct transcriptional profiles and functions between epicardial tissue and non-epicardial tissue.Several gene markers specific to postnatal epicardial tissue were identified,including Msln,C3,Efemp1,and Upk3b.Single-cell transcriptomic analysis revealed that cardiac cells from wildtype mouse hearts(from embryonic day 9.5 to postnatal day 9)could be categorized into six major cell types,which included epicardial cells.Throughout epicardial development,Wt1,Tbx18,and Upk3b were consistently expressed,whereas genes including Msln,C3,and Efemp1 exhibited increased expression during the mature stages of development.Pseudotime analysis further revealed two epicardial cell fates during maturation.Moreover,Upk3b,Msln,Efemp1,and C3 positive epicardial cells were enriched in extracellular matrix signaling.Our results suggested Upk3b,Efemp1,Msln,C3,and other genes were mature epicardium markers.Extracellular matrix signaling was found to play a critical role in the mature epicardium,thus suggesting potential therapeutic targets for heart regeneration in future clinical practice.展开更多
After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrat...After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.展开更多
The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epitheli...The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation,the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood.In this study,by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways,we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids.These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues.Specifically,BMP4 signaling stimulates pit cell and parietal cell differentiation.Furthermore,BMP4 and EGF signaling cooperate to enhance pit cell differentiation,whereas inhibition of TGF-βand BMP4 signaling promotes chief cell differentiation.We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation.In addition,BMP4,together with the small molecule Isoxazole 9,promotes parietal and enteroendocrine cell differentiation.Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human.Together,our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human,laying a foundation for future investigation and potential clinical use of gastric organoids.展开更多
Tumor metastasis is the primary cause of mortality in cancer patients,yet its mechanism remains poorly understood.Among the known cancer-related factors,lifestyle and environmental influences such as tobacco use,diet,...Tumor metastasis is the primary cause of mortality in cancer patients,yet its mechanism remains poorly understood.Among the known cancer-related factors,lifestyle and environmental influences such as tobacco use,diet,and viral infections have been considered“stressors”.Prolonged exposure to these stresses significantly increases the risk of tumor formation.Yet,the impact of these environmental factors on tumor metastasis remains an intriguing and open question.展开更多
The ketogenic diet(KD)has attracted attention in recent years for its potential anticancer effects.KD is a dietary structure of high fat,moderate protein,and extremely low carbohydrate content.Originally introduced as...The ketogenic diet(KD)has attracted attention in recent years for its potential anticancer effects.KD is a dietary structure of high fat,moderate protein,and extremely low carbohydrate content.Originally introduced as a treatment for epilepsy,KD has been widely applied in weight loss programs and the management of metabolic diseases.Previous studies have shown that KD can potentially inhibit the growth and spread of cancer by limiting energy supply to tumor cells,thereby inhibiting tumor angiogenesis,reducing oxidative stress in normal cells,and affecting cancer cell signaling and other processes.Moreover,KD has been shown to influence T-cell-mediated immune responses and inflammation by modulating the gut microbiota,enhance the efficacy of standard cancer treatments,and mitigate the complications of chemotherapy.However,controversies and uncertainties remain regarding the specific mechanisms and clinical effects of KD as an adjunctive therapy for cancer.Therefore,this review summarizes the existing research and explores the intricate relationships between KD and cancer treatment.展开更多
Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting th...Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting the need for the development of novel therapeutics.Sodium taurocholate cotransporting polypeptide(NTCP)was identified as a functional receptor for HBV entry,making it a promising therapeutic target for developing novel anti-HBV agents.展开更多
Intestinal homeostasis is sustained by self-renewal of intestinal stem cells(ISCs),which continuously divide and produce proliferative transit-amplifying(TA)and then progenitor cells.Eukaryotic translation initiation ...Intestinal homeostasis is sustained by self-renewal of intestinal stem cells(ISCs),which continuously divide and produce proliferative transit-amplifying(TA)and then progenitor cells.Eukaryotic translation initiation factor 5A(eIF5A),a conserved translation factor,involves in a variety of cellular processes,yet its role in intestinal homeostasis remains unclear.Here,we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis.Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss,suppressed cell proliferation,and increased apoptosis within the crypts,concurrent with shortened gut length,reduced mouse body weight and rapid animal mortality.Consistently,Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes.Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins,particularly those involved in mitochondrial translation,upon eIF5A depletion.Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes,including Dars2,are highly expressed in ISC,TA and progenitor cells.Furthermore,eIF5A-deficient organoids exhibit impaired mitochondrial function,characterized by reduced ATP levels and increased reactive oxygen species(ROS).These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation,providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.展开更多
Recent studies published in Cell have elucidated the collaborative roles of LAG-3 and PD-1 in driving T cell exhaustion,revealing how targeting both immune checkpoints could enhance immune responses[1],[2],[3].Among t...Recent studies published in Cell have elucidated the collaborative roles of LAG-3 and PD-1 in driving T cell exhaustion,revealing how targeting both immune checkpoints could enhance immune responses[1],[2],[3].Among these,two studies were led by Dario A.A.Vignali's team at the University of Pittsburgh School of Medicine,while the third was conducted by E.John Wherry's team at the University of Pennsylvania.展开更多
The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad ofmicrobial and dietary antigens. It is crucial in preventing pathogen invasion and establis...The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad ofmicrobial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensiveunderstanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points,thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remainsincomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hasunderscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on thedynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures andfunctions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanismsinvolved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-relateddiseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immuneresponses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines andinhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention andtreatment.展开更多
Left ventricular non-compaction(LVNC),is a hereditary cardiomyopathy with limited treatments.Our previous study linked phosphodiesterase 4D interacting protein(PDE4DIP)to LVNC development.To explore the functional rol...Left ventricular non-compaction(LVNC),is a hereditary cardiomyopathy with limited treatments.Our previous study linked phosphodiesterase 4D interacting protein(PDE4DIP)to LVNC development.To explore the functional role of PDE4DIP activation in regulating cell polarity,skeleton,and energy metabolism,and to elucidate its mechanisms driving LVNC development,bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects.Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes,respectively.Electron microscopy,MitoTracker-Green staining,and an ATP kit were employed to assess mitochondria's morphology and functional status.Real-time quantitative PCR,western blotting,and immunofluorescence assays were employed to detect the expression of cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins.Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2,respectively.We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects.Furthermore,overexpression of PDE4DIP induced cytoskeletal disorganization,decreased ATP content and cell migration,and increased cell proliferation and mitochondrial vacuolation.Moreover,the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration.Mechanically,overexpression of PDE4DIP inhibited cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins,which could be increased by knockdown of PDE4DIP,suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway.This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity,skeleton,and energy metabolism through the Rho-ROCK pathway.展开更多
Organoid technology provides a transformative approach to understand human physiology and pathology,offering valuable insights for scientific research and therapeutic development.Human gastric organoids,in particular,...Organoid technology provides a transformative approach to understand human physiology and pathology,offering valuable insights for scientific research and therapeutic development.Human gastric organoids,in particular,have gained significant interest for applications in disease modeling,drug discovery,and studies of tissue regeneration and homeostasis.However,the lack of standardized quality control has limited their extensive clinical applications.The"Human Gastric Organoids"is part of a series of guidelines for human gastric organoids in China,which establishes comprehensive standards on terminology,technical specifications,testing methods,inspection rules,usage instruc-tions,labeling,transportation,and storage,developed by experts from the Chinese Society for Cell Biology and its branch societies.Released on October 29,2024,this guideline aims to establish standardized protocols,enhance insti-tutional practices,and promote international standardization for clinical and research applications of human gastric organoids.展开更多
Gastric cancer is one of the most common malignancies with poor prognosis.The use of organoids to simulate gastric cancer has rapidly developed over the past several years.Patient-derived gastric cancer organoids serv...Gastric cancer is one of the most common malignancies with poor prognosis.The use of organoids to simulate gastric cancer has rapidly developed over the past several years.Patient-derived gastric cancer organoids serve as in vitro models that closely mimics donor characteristics,ofering new opportunities for both basic and applied research.The“Human Gastric Cancer Organoid”is part of a series of guidelines for human gastric cancer organoids in China,jointly drafted by experts from the Chinese Society for Cell Biology and its branches,and initially released on October 29,2024.This standard outlines terminology,technical requirements,assessment protocols,and applies to production,evaluation procedures,and quality control for human gastric cancer organoids.The publication of this guideline aims to assist institutions in endorsing,establishing,and applying best practices,advancing the international standardiza-tion of human gastric cancer organoids for clinical development and therapeutic application.展开更多
The family of secreted dimeric proteins known as the Transforming Growth Factor-β(TGF-β)family plays a critical role in facilitating intercellular communication within multicellular animals.A recent symposium on TGF...The family of secreted dimeric proteins known as the Transforming Growth Factor-β(TGF-β)family plays a critical role in facilitating intercellular communication within multicellular animals.A recent symposium on TGF-βBiology-Signaling,Development,and Diseases,held on December 19–21,2023,in Hangzhou,China,showcased some latest advances in our understanding TGF-βbiology and also served as an important forum for scientific collaboration and exchange of ideas.More than twenty presentations and discussions at the symposium delved into the intri-cate mechanisms of TGF-βsuperfamily signaling pathways,their roles in normal development and immunity,and the pathological conditions associated with pathway dysregulation.展开更多
In a recent study published in Cell,Litsios et al.revealed a highresolution spatiotemporal map of the eukaryotic cell cycle proteome.1 They identified proteome-level changes in both abundance and spatial distribution ...In a recent study published in Cell,Litsios et al.revealed a highresolution spatiotemporal map of the eukaryotic cell cycle proteome.1 They identified proteome-level changes in both abundance and spatial distribution throughout the cell cycle and provided a valuable resource for future exploration into the global proteome dynamics that drive cell cycle progression(https://thecellvision.org/cellcycle).展开更多
In a recent Cell publication,Cheong et al.uncover how COVID-19 causes IL-6 induced epigenetic reprogramming of human immune stem cells,which causes lasting alterations in the composition and response characteristics o...In a recent Cell publication,Cheong et al.uncover how COVID-19 causes IL-6 induced epigenetic reprogramming of human immune stem cells,which causes lasting alterations in the composition and response characteristics of circulating immune cells.1 The study provides important insights into the mechanisms by which SARSCoV-2 infections impact the human immune system and is an important hook into unraveling the mechanisms of post-acute sequelae of COVID-19(PASC)commonly referred to as longCOVID.展开更多
基金supported by the National Key Research and Development Program of China(No.2022YFC2804800 to W.J.)the National Natural Science Foundation of China(No.22494704.,22137002 to Y.D.,92253305 to W.J.and 31971111 to C.L.)+6 种基金the Science and Technology Commission of Shanghai Municipality(Grant 20JC1410900 to Y.D.)the University Innovation Research Group in Chongqing(No.CXQT21016 to Y.D.)the Chongqing Talent Program Project(No.CQYC20200302119 to Y.D.)High-Level Innovation Platform Cultivation Plan of Chongqing(to Y.D.)Joint Fund of the Natural Science Innovation and Development Foundation of Chongqing(to Y.D.)Program for Professor of Special Appointment(Eastern Scholar)at Shanghai Institutions of Higher Learning(to W.J.)Chongqing Doctoral Express Entry Project(No.CSTB2022BSXM-JCX0044 to J.H.).
文摘Natural products play a crucial role in new drug development,but their druggability is often limited by uncertain molecular targets and insufficient research on mechanisms of action.In this study,we developed a new RPL19-TRAP^(KI)-seq method,combining CRISPR/Cas9 and TRAP technologies,to investigate these mechanisms.We identified and validated seven ribosomal large subunit surface proteins suitable for TRAP,selecting RPL19 for its high enrichment.We successfully established a stable cell line expressing EGFP-RPL19 using CRISPR knock-in and verified its efficiency and specificity in enriching ribosomes and translating mRNA.Integrated with next-generation sequencing,this method allows precise detection of translating mRNA.We validated RPL19-TRAP^(KI)-seq by investigating rapamycin,an mTOR inhibitor,yielding results consistent with previous reports.This optimized TRAP technology provides an accurate representation of translating mRNA,closely reflecting protein expression levels.Furthermore,we investigated SBF-1,a 23-oxa-analog of natural saponin OSW-1 with significant anti-tumor activity but an unclear mechanism.Using RPL19-TRAP^(KI)-seq,we found that SBF-1 exerts its cytotoxic effects on tumor cells by disturbing cellular oxidative phosphorylation.In conclusion,our method has been proven to be a promising tool that can reveal the mechanisms of small molecules with greater accuracy,setting the stage for future exploration of small molecules and advancing the fields of pharmacology and therapeutic development.
基金Supported by National Science Foundation of China,No.82160546the Science Foundation of Jiangxi Province,No.20202BBG73027+1 种基金the Foundation of Jiangxi Province for Distinguished Scholars,No.jxsq2023201020the Science and Technology Project of Jiangxi Administration of Traditional Chinese Medicine,No.2022B789.
文摘BACKGROUND Colorectal polyps,which are characterized by a high recurrence rate,represent preneoplastic conditions of the intestine.Due to unclear mechanisms of pathogenesis,first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection.Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps,the exact compositions and roles of bacteria in the mucosa around the lesions,rather than feces,remain unsettled.AIM To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps.METHODS Mucosal samples were collected from four patients consistently with adenomatous polyps(Ade),seven consistently with non-Ade(Pol),ten with current Pol but previous Ade,and six healthy individuals,and bacterial patterns were evaluated by 16S rDNA sequencing.Linear discriminant analysis and Student’s t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes.Pearson’s correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators.RESULTS The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals.These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps,but also existed in histologically normal tissue 10 cm distal from the lesions.Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions,Pol,and Ade.Increased abundance of Gram-negative bacteria,including Klebsiella,Plesiomonas,and Cronobacter,was observed in Pol group and Ade group,suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment.Meanwhile,age and gender were linked to bacteria changes,indicating the potential involvement of sex hormones.CONCLUSION These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps,especially adenoma.Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.
基金supported by the National Natural Science Foundation of China(22078211)the China Postdoctoral Science Foundation(2022M721115).
文摘The interactions between lignin oligomers and solvents determine the behaviors of lignin oligomers self-assembling into uniform lignin nanoparticles(LNPs).Herein,several alcohol solvents,which readily interact with the lignin oligomers,were adopted to study their effects during solvent shifting process for LNPs’production.The lignin oligomers with widely distributed molecular weight and abundant guaiacyl units were extracted from wood waste(mainly consists of pine wood),exerting outstanding self-assembly capability.Uniform and spherical LNPs were generated in H_(2)O-n-propanol cosolvent,whereas irregular LNPs were obtained in H_(2)O-methanol cosolvent.The unsatisfactory self-assembly performance of the lignin oligomers in H_(2)O-methanol cosolvent could be attributed to two aspects.On one hand,for the initial dissolution state,the distinguishing Hansen solubility parameter and polarity between methanol solvent and lignin oligomers resulted in the poor dispersion of the lignin oligomers.On the other hand,strong hydrogen bonds between methanol solvent and lignin oligomers during solvent shifting process,hindered the interactions among the lignin oligomers for self-assembly.
基金supported by the National Natural Science Foundation of China(No.32171401)the Natural Science Foundation of Chongqing(Nos.CSTB2022NSCQ-MSX0808 and cstc2021jcyj-bsh0239)the Innovation Platform for Academicians of Hainan Province(No.YSPTZX202126),China。
文摘Multilayer paper-based cell culture,as an in vitro three-dimensional(3D)cell culture method,has been frequently used to research drug bioavailability,therapeutic efficacy,and dose-limiting toxicity in malignant tumors.This paper proposes a heterogenous multilayer paper stacking co-culture system to establish a model of natural killer(NK)cells moving through the endothelium layer and attacking tumor spheroids.This system consists of three layers:a bottom tumor-spheroid layer,a middle invasion layer,and a top endothelium layer.NK-92 cells were placed in the supernatant on top of the three layers.After two days of co-culture,the attack of tumor spheroids by NK cells was observed.We additionally examined the infiltration of NK-92 cells within the tumor spheroids at different Z-axis depths using a confocal microscope,and the results suggested that the system successfully realizes NK cells traveling cross the endothelium layer to form tumor-infiltrating NK cells(TINKs).The potential application of multilayer paper for co-culture models involving cancer cells and immune cells holds great promise for exploring the interaction dynamics of these two cell types.
文摘Since the start of the Precision Medicine Initiative by the United States of America in 2015,interest in personalized medicine has grown extensively.In short,personalized medicine is a term that describes medical treatment that is tuned to the individual.One possible way to realize personalized medicine is 3D printing.When using materials that can be tuned upon stimulation,4D printing is established.In recent years,many studies have been exploring a new field that combines 3D and 4D printing with therapeutics.This has resulted in many concepts of pharmaceutical devices and formulations that can be printed and,possibly,tailored to an individual.Moreover,the first 3D printed drug,Spritam®,has already found its way to the clinic.This review gives an overview of various 3D and 4D printing techniques and their applications in the pharmaceutical field as drug delivery systems and personalized medicine.
基金supported by grants from the National Natural Science Foundation of China(Grant No.:82270281)Chongqing Medical University Program for Youth Innovation in Future Medicine(Grant No.:W0133)+2 种基金Senior Medical Talents Program of Chongqing for Young and Middle-aged,China(Program No.:JianlinDu[2022])Postdoctoral Research Funding of the Second Affiliated Hospital of Chongqing Medical University,China(Grant No.:rsc-postdoctor114)and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University,China(Program No.:kryc-gg-2102).
文摘Tbx18,Wt1,and Tcf21 have been identified as epicardial markers during the early embryonic stage.However,the gene markers of mature epicardial cells remain unclear.Single-cell transcriptomic analysis was performed with the Seurat,Monocle,and CellphoneDB packages in R software with standard procedures.Spatial transcriptomics was performed on chilled Visium Tissue Optimization Slides(10x Genomics)and Visium Spatial Gene Expression Slides(10x Genomics).Spatial transcriptomics analysis was performed with Space Ranger software and R software.Immunofluorescence,whole-mount RNA in situ hybridization and X-gal staining were performed to validate the analysis results.Spatial transcriptomics analysis revealed distinct transcriptional profiles and functions between epicardial tissue and non-epicardial tissue.Several gene markers specific to postnatal epicardial tissue were identified,including Msln,C3,Efemp1,and Upk3b.Single-cell transcriptomic analysis revealed that cardiac cells from wildtype mouse hearts(from embryonic day 9.5 to postnatal day 9)could be categorized into six major cell types,which included epicardial cells.Throughout epicardial development,Wt1,Tbx18,and Upk3b were consistently expressed,whereas genes including Msln,C3,and Efemp1 exhibited increased expression during the mature stages of development.Pseudotime analysis further revealed two epicardial cell fates during maturation.Moreover,Upk3b,Msln,Efemp1,and C3 positive epicardial cells were enriched in extracellular matrix signaling.Our results suggested Upk3b,Efemp1,Msln,C3,and other genes were mature epicardium markers.Extracellular matrix signaling was found to play a critical role in the mature epicardium,thus suggesting potential therapeutic targets for heart regeneration in future clinical practice.
文摘After publication of the PACIFIC trial results,immune checkpoint inhibitor-based immunotherapy was included in the treatment algorithm of locally advanced non-small cell lung cancer(NSCLC).The PACIFIC trial demonstrated that 12 mo of durvalumab consolidation therapy after radical-intent platinum doublet chemotherapy with concomitant radiotherapy improved both progression-free survival and overall survival in patients with unresectable stage III NSCLC.This is the first treatment in decades to successfully improve survival in this clinical setting,with manageable toxicity and without deterioration in quality of life.The integration of durvalumab in the management of locally advanced NSCLC accentuates the need for multidisciplinary,coordinated decision-making among lung cancer specialists,bringing new challenges and controversies as well as important changes in clinical work routines.The aim of the present article is to review—from a practical,multidisciplinary perspective—the findings and implications of the PACIFIC trial.We evaluate the immunobiological basis of durvalumab as well as practical aspects related to programmed cell death ligand 1 determination.In addition,we comprehensively assess the efficacy and toxicity data from the PACIFIC trial and discuss the controversies and practical aspects of incorporating durvalumab into routine clinical practice.Finally,we discuss unresolved questions and future challenges.In short,the present document aims to provide clinicians with a practical guide for the application of the PACIFIC regimen in routine clinical practice.
基金supported by grants from the Beijing Science and Technology Plan(Z231100007223006)the Natural Science Foundation of China(92354306,31988101)+2 种基金the National Key Research and Development Program of China(2023YFA1800603)the Shenzhen Medical Research Fund(B2302022)the Natural Science Foundation of Jiangxi Province(20224 ACB209001).
文摘The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis.Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation,the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood.In this study,by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways,we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids.These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues.Specifically,BMP4 signaling stimulates pit cell and parietal cell differentiation.Furthermore,BMP4 and EGF signaling cooperate to enhance pit cell differentiation,whereas inhibition of TGF-βand BMP4 signaling promotes chief cell differentiation.We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation.In addition,BMP4,together with the small molecule Isoxazole 9,promotes parietal and enteroendocrine cell differentiation.Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human.Together,our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human,laying a foundation for future investigation and potential clinical use of gastric organoids.
基金supported by the National Natural Science Foundation of China(No.31970536,32370891)the Fundamental Research Funds from Tongji University(No.2023-3-YB-06).
文摘Tumor metastasis is the primary cause of mortality in cancer patients,yet its mechanism remains poorly understood.Among the known cancer-related factors,lifestyle and environmental influences such as tobacco use,diet,and viral infections have been considered“stressors”.Prolonged exposure to these stresses significantly increases the risk of tumor formation.Yet,the impact of these environmental factors on tumor metastasis remains an intriguing and open question.
基金supported by a special program from the National Key Research and Development Program of China(2021YFA1101000,2022YFA1105200)the National Natural Science Fundation of China(92169122,82473119,32125016,T2321005,U20A201376,U20A20393,31925013)+3 种基金Excellent Youth Fund of Jiangsu Province(BK2024014)Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022442,ZXL2022505)Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2302017,YXY2303027)the Priority Acadamic Program Development of Jiangsu Higher Education Institutions。
文摘The ketogenic diet(KD)has attracted attention in recent years for its potential anticancer effects.KD is a dietary structure of high fat,moderate protein,and extremely low carbohydrate content.Originally introduced as a treatment for epilepsy,KD has been widely applied in weight loss programs and the management of metabolic diseases.Previous studies have shown that KD can potentially inhibit the growth and spread of cancer by limiting energy supply to tumor cells,thereby inhibiting tumor angiogenesis,reducing oxidative stress in normal cells,and affecting cancer cell signaling and other processes.Moreover,KD has been shown to influence T-cell-mediated immune responses and inflammation by modulating the gut microbiota,enhance the efficacy of standard cancer treatments,and mitigate the complications of chemotherapy.However,controversies and uncertainties remain regarding the specific mechanisms and clinical effects of KD as an adjunctive therapy for cancer.Therefore,this review summarizes the existing research and explores the intricate relationships between KD and cancer treatment.
基金supported by the National Key R&D Program of China(2022YFA1303600)National Natural Science Foundation of China[No.22137002 to Y.D.,No.92353303,22277010 and 22477013 to Z.G.,No.U23A20472 and 82273423 to J.C.,No.82302507 to H.Y.]+5 种基金Ministry of Human Resources and Social Security Funding Scheme for High-Level Overseas Chinese Students’Return of China[to Z.G.]China Postdoctoral Science Foundation[No.2021T140784 and 2020M683638XB to J.H.]Natural Science Foundation of Chongqing[No.CSTB2022NSCQ-MSX1061 to Z.G.]Chongqing Postdoctoral Science Foundation[No.CSTB2022NSCQ-BHX0616 to J.H.]CQMU Program for Youth Innovation in Future Medicine[No.W0074 to Z.G.]Joint Project of Pinnacle Disciplinary Group of the Second Affiliated Hospital of Chongqing Medical University.
文摘Dear Editor,Chronic hepatitis B virus(HBV)is a global health problem closely associated with a spectrum of liver diseases.Current clinical treatment options for HBV infection are generally not curative,highlighting the need for the development of novel therapeutics.Sodium taurocholate cotransporting polypeptide(NTCP)was identified as a functional receptor for HBV entry,making it a promising therapeutic target for developing novel anti-HBV agents.
基金supported by grants from the National Key Research and Development Program of China(2023YFA1800600)the Natural Science Foundation of China(31988101,92354306)+2 种基金the Beijing Science and Technology Plan(Z231100007223006)the Shenzhen Medical Research Fund(B2302022)the Natural Science Foundation of Jiangxi Province(20224 ACB209001).
文摘Intestinal homeostasis is sustained by self-renewal of intestinal stem cells(ISCs),which continuously divide and produce proliferative transit-amplifying(TA)and then progenitor cells.Eukaryotic translation initiation factor 5A(eIF5A),a conserved translation factor,involves in a variety of cellular processes,yet its role in intestinal homeostasis remains unclear.Here,we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis.Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss,suppressed cell proliferation,and increased apoptosis within the crypts,concurrent with shortened gut length,reduced mouse body weight and rapid animal mortality.Consistently,Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes.Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins,particularly those involved in mitochondrial translation,upon eIF5A depletion.Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes,including Dars2,are highly expressed in ISC,TA and progenitor cells.Furthermore,eIF5A-deficient organoids exhibit impaired mitochondrial function,characterized by reduced ATP levels and increased reactive oxygen species(ROS).These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation,providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.
基金National Natural Science Foundation of China(31925013,32125016,T2321005 and W2411011)National Key Research and Development Program of China(2021YFA1101000,2022YFA1105200 and 2023YFA1800200)+5 种基金Key R&D Program of Zhejiang Province(2024C03142)Joint Project of Pinnacle Disciplinary Group,the Second Affiliated Hospital of Chongqing Medical,the Science Foundation of Jiangsu Province(19KJA550003)Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022505)Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2303027)Key Cross-research Projects of the School of Medicine,Soochow University(YXY2303027)support of Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases.
文摘Recent studies published in Cell have elucidated the collaborative roles of LAG-3 and PD-1 in driving T cell exhaustion,revealing how targeting both immune checkpoints could enhance immune responses[1],[2],[3].Among these,two studies were led by Dario A.A.Vignali's team at the University of Pittsburgh School of Medicine,while the third was conducted by E.John Wherry's team at the University of Pennsylvania.
基金supported by Chinese National Natural Science Funds(32125016,31925013,92169122,82473119,U20A20393 and T2321005)the National Key R&D Program of China(2021YFA1101000,2022YFA1105200,2023YFA1800200)+5 种基金“Leading Goose”R&D Program of Zhejiang Province(2024C03142)Excellent Youth Fund of Jiangsu Province(BK20240148)Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022505,ZXL2022442)Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2303027,YXY2302017)Bo Xi Clinical Research Project of the First Affiliated Hospital of Soochow University(BXLC007)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).
文摘The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad ofmicrobial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensiveunderstanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points,thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remainsincomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hasunderscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on thedynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures andfunctions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanismsinvolved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-relateddiseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immuneresponses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines andinhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention andtreatment.
基金supported by the National Natural Science Foundation of China(No.81570218,82170244)the Program for Youth Innovation in Future Medicine of Chongqing Medical University(No.W0176)the National Clinical Key Specialty Construction Project(China)(No.010140).
文摘Left ventricular non-compaction(LVNC),is a hereditary cardiomyopathy with limited treatments.Our previous study linked phosphodiesterase 4D interacting protein(PDE4DIP)to LVNC development.To explore the functional role of PDE4DIP activation in regulating cell polarity,skeleton,and energy metabolism,and to elucidate its mechanisms driving LVNC development,bioinformatics analysis was performed to compare its expression in LVNC patients and normal subjects.Overexpression and knockdown of PDE4DIP were constructed in H9C2 cells and neonatal Sprague–Dawley rat primary cardiomyocytes,respectively.Electron microscopy,MitoTracker-Green staining,and an ATP kit were employed to assess mitochondria's morphology and functional status.Real-time quantitative PCR,western blotting,and immunofluorescence assays were employed to detect the expression of cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins.Cell scratching and CCK-8 assays were employed to detect cell migration and proliferation abilities of H9C2,respectively.We found that PDE4DIP expression was increased in the LVNC-derived human-induced pluripotent stem cell-derived cardiomyocytes compared with normal subjects.Furthermore,overexpression of PDE4DIP induced cytoskeletal disorganization,decreased ATP content and cell migration,and increased cell proliferation and mitochondrial vacuolation.Moreover,the knockdown of PDE4DIP promoted cytoskeleton formation and contributed to increased ATP content and elevated cell migration.Mechanically,overexpression of PDE4DIP inhibited cell polarity-,skeleton-,and Rho-ROCK signaling-related genes and proteins,which could be increased by knockdown of PDE4DIP,suggesting that a critical regulation of PDE4DIP to Rho-ROCK pathway.This discovery suggests that PDE4DIP contributes to the development of LVNC by regulating cell polarity,skeleton,and energy metabolism through the Rho-ROCK pathway.
基金supported by grants from the National Natural Science Foun‑dation of China(31988101 to Y.‑G.C.,32300586 to Y.L.W.)the National Key Research and Development Program of China(2023YFA1800603 to Y.‑G.C)+1 种基金Major Project of Guangzhou National Laboratory(GZNL2023A02008 to Y.L.W.)Young Talent Support Project of Guangzhou Association for Science and Technology(QT2024‑019 to Y.L.W.)。
文摘Organoid technology provides a transformative approach to understand human physiology and pathology,offering valuable insights for scientific research and therapeutic development.Human gastric organoids,in particular,have gained significant interest for applications in disease modeling,drug discovery,and studies of tissue regeneration and homeostasis.However,the lack of standardized quality control has limited their extensive clinical applications.The"Human Gastric Organoids"is part of a series of guidelines for human gastric organoids in China,which establishes comprehensive standards on terminology,technical specifications,testing methods,inspection rules,usage instruc-tions,labeling,transportation,and storage,developed by experts from the Chinese Society for Cell Biology and its branch societies.Released on October 29,2024,this guideline aims to establish standardized protocols,enhance insti-tutional practices,and promote international standardization for clinical and research applications of human gastric organoids.
基金supported by grants from the National Natural Science Foun-dation of China(31988101 to Y.-G.C.,32300586 to Y.L.W.)the National Key Research and Development Program of China(2023YFA1800603 to Y.-G.C)+1 种基金Major Project of Guangzhou National Laboratory(GZNL2023A02008 to Y.L.W.)Young Talent Support Project of Guangzhou Association for Science and Technology(QT2024-019 to Y.L.W.)。
文摘Gastric cancer is one of the most common malignancies with poor prognosis.The use of organoids to simulate gastric cancer has rapidly developed over the past several years.Patient-derived gastric cancer organoids serve as in vitro models that closely mimics donor characteristics,ofering new opportunities for both basic and applied research.The“Human Gastric Cancer Organoid”is part of a series of guidelines for human gastric cancer organoids in China,jointly drafted by experts from the Chinese Society for Cell Biology and its branches,and initially released on October 29,2024.This standard outlines terminology,technical requirements,assessment protocols,and applies to production,evaluation procedures,and quality control for human gastric cancer organoids.The publication of this guideline aims to assist institutions in endorsing,establishing,and applying best practices,advancing the international standardiza-tion of human gastric cancer organoids for clinical development and therapeutic application.
基金National Key Research and Development Program of China(2022YFC3401502 to X-H.F.,2023YFA1800603 to Y-G.C.)National Natural Science Foundation of China(U21A20356 and 32321002 to X-H.F.,31988101 to Y-G.C.)+1 种基金Zhejiang Provincial Natural Science Foundation(LD21C070001 to X-H.F.,LZ22C070001 to S.G.)Fundamental Research Funds for the Central Universities。
文摘The family of secreted dimeric proteins known as the Transforming Growth Factor-β(TGF-β)family plays a critical role in facilitating intercellular communication within multicellular animals.A recent symposium on TGF-βBiology-Signaling,Development,and Diseases,held on December 19–21,2023,in Hangzhou,China,showcased some latest advances in our understanding TGF-βbiology and also served as an important forum for scientific collaboration and exchange of ideas.More than twenty presentations and discussions at the symposium delved into the intri-cate mechanisms of TGF-βsuperfamily signaling pathways,their roles in normal development and immunity,and the pathological conditions associated with pathway dysregulation.
基金supported by Chinese National Natural Science Funds(31925013,U20A20393)a special programs from the Ministry of Science and Technology of China(2021YFA1101000).
文摘In a recent study published in Cell,Litsios et al.revealed a highresolution spatiotemporal map of the eukaryotic cell cycle proteome.1 They identified proteome-level changes in both abundance and spatial distribution throughout the cell cycle and provided a valuable resource for future exploration into the global proteome dynamics that drive cell cycle progression(https://thecellvision.org/cellcycle).
文摘In a recent Cell publication,Cheong et al.uncover how COVID-19 causes IL-6 induced epigenetic reprogramming of human immune stem cells,which causes lasting alterations in the composition and response characteristics of circulating immune cells.1 The study provides important insights into the mechanisms by which SARSCoV-2 infections impact the human immune system and is an important hook into unraveling the mechanisms of post-acute sequelae of COVID-19(PASC)commonly referred to as longCOVID.
