The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we colle...The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we collected three types of tissue including cartilage,subchondral bone,and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients.By applying unsupervised clustering analysis to the cartilage transcriptome,OA patients were classified into four subtypes with distinct molecular signatures:a glycosaminoglycan metabolic disorder subtype(C1),a collagen metabolic disorder subtype(C2),an activated sensory neuron subtype(C3),and an inflammation subtype(C4).Through ligand-receptor crosstalk analysis of the three knee tissue types,we linked molecular functions with the clinical symptoms of different OA subtypes.For example,the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4,which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients.Based on the marker genes of the four OA subtypes identified in this study,we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification.The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients,which may allow for precise diagnosis and treatment of OA.展开更多
Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due t...Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.展开更多
Articular cartilage damage is a universal health problem.Despite recent progress,chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration.Loss-of-function chang...Articular cartilage damage is a universal health problem.Despite recent progress,chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration.Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions,but the characteristics and intermediate molecular mechanisms remain unclear.In this study,we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation.We performed various assays,such as single-cell RNA sequencing(scRNA-seq),live-cell metabolic assays,and assays for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq),to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages.Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation,whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling.Using the chemical inhibitor BTB06584,we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss.Notably,this two-stage transition was also validated in human chondrocytes.An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers.Overall,this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.展开更多
Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are ...Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are lacking. Here, we developed a novel ring-shaped cardiac microtissue comprised of chamber-specific tissues to achieve a geometrically non-orientable ventricular myocardial band, similar to a M?bius loop. The ring-shaped cardiac tissue was constructed of hi PSC-CMs and human cardiac fibroblasts(h CFs) through a facile cellular self-assembly approach. It exhibited basic anatomical structure,positive cardiac troponin T(c Tn T) immunostaining, regular calcium transients, and cardiac-like mechanical strength. The cardiac rings can be self-assembled and scaled up into various sizes with outstanding stability, suggesting their potential for precise therapy, pathophysiological investigation, and large-scale drug screening.展开更多
Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune checkpoint inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltration of CD8^(+)...Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune checkpoint inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltration of CD8^(+)T cells.Using bulk ribonucleic acid sequencing(RNA-seq)data from 9311 tumor samples across 30 cancer types,we developed a novel tool called the modulator of TMB-associated immune infiltration(MOTIF),which comprises genes that can determine the extent of CD8^(+)T cell infiltration prompted by a certain TMB level.We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle.By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors,we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8^(+)T cell infiltration.Using pretreatment RNA-seq data from 13 ICI-treated cohorts,we validated the use of MOTIF in predicting CD8^(+)T cell infiltration and ICI efficacy.Among the components of MOTIF,we identified EMC3 as a negative regulator of CD8^(+)T cell infiltration,which was validated via in vivo studies.Additionally,MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8^(+)T cell infiltration and improve ICI efficacy.展开更多
Background Rabies continues to be a serious threat to global public health endangering people’s health and public health safety.In the People’s Republic of China,multi-sectoral and comprehensive prevention and contr...Background Rabies continues to be a serious threat to global public health endangering people’s health and public health safety.In the People’s Republic of China,multi-sectoral and comprehensive prevention and control strategies have aimed to extensively curb human rabies transmission.Here,we examine the current state of rabies infection in China,explore strategic interventions put in place in response to WHO’s ambition of“Zero rabies deaths by 2030”and critically assess the constraints and feasibility of dog-mediated rabies elimination in China.Methods This study analyzed and evaluated the process towards dog-mediated rabies elimination in China from five perspectives:namely,human,dog,policy,challenge,and prospects.Evidence-based data on progress of dog-mediated rabies elimination in China was derived from a number of sources;a literature search was undertaken using PubMed,Web of Science and CNKI databases,distribution data for human rabies cases as derived from the Data-center of the China Public Health Science and policy and document data were obtained from official websites of the relevant China ministries and commissions.Results The incidence of human rabies cases in China have shown a downward trend year-on-year since 2007.Implementation of a government-led,multi-sectoral“One Health”approach to combating rabies has driven down the total number of rabies deaths nationwide to around 200 in 2020.The number of provincial-level administrative divisions(PLADs)reporting human cases of rabies has also decreased to 21 in 2020,13 of which reported less than 10 cases.Furthermore,the number of outpatient visits seeking rabies post-exposure prophylaxis has risen dramatically over the past two decades,with demand being 15 times higher than it was initially.There remain however,significant gaps in rabies elimination outcomes across the different regions of China.To date the target of achieving a canine rabies vaccination rate of>75%has not been met.The challenges of rabies immunization of dogs and dog management in underdeveloped cities and rural areas need to be addressed together with more effective animal surveillance and rabies risk from and too wildlife and livestock.Conclusions The Chinese government-led,multi-sectoral“One Health”approach to combating rabies and has made significant progress over the past decade.Development and adoption of more cost-effective One Health strategies can achieve more nationally beneficial rabies elimination outcomes.The ambitious target of“Zero rabies deaths by 2030”can be met through establishment of long-lasting herd immunity in dogs by means of dog mass vaccination campaigns,dog population management,epidemiological surveillance and the application of large-scale oral rabies vaccine to eliminate rabies in wild animals coupled with deployment of cost-effective human post-exposure prophylaxis,and community education.展开更多
The pore architecture of porous scaffolds is a critical factor in osteogenesis,but it is a challenge to precisely configure strut-based scaffolds because of the inevitable filament corner and pore geometry deformation...The pore architecture of porous scaffolds is a critical factor in osteogenesis,but it is a challenge to precisely configure strut-based scaffolds because of the inevitable filament corner and pore geometry deformation.This study provides a pore architecture tailoring strategy in which a series of Mg-doped wollastonite scaffolds with fully interconnected pore networks and curved pore architectures called triply periodic minimal surfaces(TPMS),which are similar to cancellous bone,are fabricated by a digital light processing technique.The sheet-TPMS pore geometries(s-Diamond,s-Gyroid)contribute to a 3‒4-fold higher initial compressive strength and 20%-40%faster Mg-ion-release rate compared to the other-TPMS scaffolds,including Diamond,Gyroid,and the Schoen’s I-graph-Wrapped Package(IWP)in vitro.However,we found that Gyroid and Diamond pore scaffolds can significantly induce osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs).Analyses of rabbit experiments in vivo show that the regeneration of bone tissue in the sheet-TPMS pore geometry is delayed;on the other hand,Diamond and Gyroid pore scaffolds show notable neo-bone tissue in the center pore regions during the early stages(3-5 weeks)and the bone tissue uniformly fills the whole porous network after 7 weeks.Collectively,the design methods in this study provide an important perspective for optimizing the pore architecture design of bioceramic scaffolds to accelerate the rate of osteogenesis and promote the clinical translation of bioceramic scaffolds in the repair of bone defects.展开更多
Inflammatory bowel disease(IBD)is a chronic,immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier.Due to the poor remission effect and...Inflammatory bowel disease(IBD)is a chronic,immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier.Due to the poor remission effect and severe adverse events associated with current clinical medications,IBD remains an incurable disease.Here,we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating.The molecular coating is composed of o-nitrobenzaldehyde(NB)-modified Gelatin(GelNB),which can strongly bond with-NH_(2)on the intestinal surface of tissue to form a thin biophysical barrier.We found that this molecular coating was able to stay on the surface of the intestine for long periods of time,effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora.In addition,our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration,but also achieved a better outcome of IBD by reducing intestinal inflammation.Moreover,the in vivo experiments showed that the GelNB was better than the classic clinical medication-mesalazine.Therefore,our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.展开更多
Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice.Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regenera...Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice.Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regeneration without uneven surface,graft necrosis and sclerosis.However,poor gap integration is a serious concern,which eventually leads to deterioration of joint function.To deal with such complications,this study has developed a strategy to effectively enhance integration of the gap region following mosaicplasty by applying injectable bioactive supramolecular nanofiber-enabled gelatin methacryloyl(GelMA)hydrogel(BSN-GelMA).A rabbit osteochondral defect model demonstrated that BSN-GelMA achieved seamless osteochondral healing in the gap region between plugs of osteochondral defects following mosaicplasty,as early as six weeks.Moreover,the International Cartilage Repair Society score,histology score,glycosaminoglycan content,subchondral bone volume,and collagen II expression were observed to be the highest in the gap region of BSN-GelMA treated group.This improved outcome was due to bio-interactive materials,which acted as tissue fillers to bridge the gap,prevent cartilage degeneration,and promote graft survival and migration of bone marrow mesenchymal stem cells by releasing bioactive supramolecular nanofibers from the GelMA hydrogel.This study provides a powerful and applicable approach to improve gap integration after autologous mosaicplasty.It is also a promising off-the-shelf bioactive material for cell-free in situ tissue regeneration.展开更多
Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation(AST).However,it remains largely unknown how Lkb1 deficiency dynamically regulates...Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation(AST).However,it remains largely unknown how Lkb1 deficiency dynamically regulates AST.Using the classical AST mouse model(Kras LSL-G12D/+;Lkb1flox/flox,KL),we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker(DNB)and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species(ROS)through its downstream effector FOXO3A.Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST.Importantly,pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation,highlighting the irreversibility of AST after crossing the tipping point.Through comparative transcriptomic analyses of mouse and human tumors,we find that the lineage-specific transcription factors(TFs)of adenocarcinoma and squamous cell carcinoma form a“Yin-Yang”counteracting network.Interestingly,inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the“Yin-Yang”homeostasis to lean towards the squamous lineage,whereas ectopic expression of NKX2-1,an adenomatous lineage TF,significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation.The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma.Collectively,our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno-and squamous-specific TF networks at the AST tipping point.展开更多
Dear Editor,Age-dependent adipose tissue malfunction raises the risk of diseases like diabetes,cardiovascular disease,and even cancer by contributing to metabolic decline,heterotopic fat storage,and chronic systemic i...Dear Editor,Age-dependent adipose tissue malfunction raises the risk of diseases like diabetes,cardiovascular disease,and even cancer by contributing to metabolic decline,heterotopic fat storage,and chronic systemic inflammation.1 Understanding adipose tissue aging requires in-depth knowledge of the cellular and molecular properties of various adipose tissue cell types.Although the heterogeneity of the cell population during mouse aging has been studied,2 little is known about the cellular and molecular basis of human adipose tissues aging.展开更多
Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus(SLE),which makes B-cell depletion a potential strategy for SLE treatment.The clinical success of anti-CD19 CAR-T cells in treating B-c...Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus(SLE),which makes B-cell depletion a potential strategy for SLE treatment.The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers.In this study,we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model.We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice.Furthermore,anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention.According to our observations,compared with antibody treatment,the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice.The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression.We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif,CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment.Taken together,these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE,indicating its potential for clinical use in patients.展开更多
Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation.As an essential trace element,iron is vital for many biological processes.Evidence has revealed ...Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation.As an essential trace element,iron is vital for many biological processes.Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation.Ferroptosis,a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids(PUFAs),is a promising therapeutic target for therapyresistant cancers.Previous studies have reported that long noncoding RNA(lncRNA)is a group of critical regulators involved in modulating cell metabolism,proliferation,apoptosis,and ferroptosis.In this review,we summarize the associations among iron metabolism,ferroptosis,and ferroptosis-related lncRNA in tumorigenesis.This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.展开更多
Genome stability can be threatened by both endogenous and exogenous agents.Organisms have evolved numerous mechanisms to repair DNA damage,including homologous recombination(HR)and non-homologous end joining(NHEJ).Amo...Genome stability can be threatened by both endogenous and exogenous agents.Organisms have evolved numerous mechanisms to repair DNA damage,including homologous recombination(HR)and non-homologous end joining(NHEJ).Among the factors associated with DNA repair,the MRE11-RAD50-NBS1(MRN)complex(MRE11-RAD50-XRS2 in Saccharomyces cerevisiae)plays important roles not only in DNA damage recognition and signaling but also in subsequent HR or NHEJ repair.Upon detecting DNA damage,the MRN complex activates signaling molecules,such as the protein kinase ataxia-telangiectasia mutated(ATM),to trigger a broad DNA damage response,including cell cycle arrest.The nuclease activity of the MRN complex is responsible for DNA end resection,which guides DNA repair to HR in the presence of sister chromatids.The MRN complex is also involved in NHEJ,and has a species-specific role in hairpin repair.This review focuses on the structure of the MRN complex and its function in DNA damage repair.展开更多
Pancreaticβ-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes(T2D).Recent clinical and experimental studies have suggested that the functional capacity ofβ-cells,particularly in ...Pancreaticβ-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes(T2D).Recent clinical and experimental studies have suggested that the functional capacity ofβ-cells,particularly in the first phase of insulin secretion,is a primary contributor to the progression of T2D and its associated complications.Pancreaticβ-cells undergo dynamic compensation and decompensation processes during the development of T2D,in which metabolic stresses such as endoplasmic reticulum stress,oxidative stress,and inflammatory signals are key regulators ofβ-cell dynamics.Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D,especially in the early stages.Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague,accumulating evidence has implicated the improvement ofβ-cell functional capacity.In this review,we summarize recent advances in the understanding of the dynamic adaptations ofβ-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions onβ-cell dysfunction in T2D.This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D,and more importantly,it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.展开更多
In 2023,one hundred years will have passed since penicillin was discovered.My parents'generation was bor around the time penicillin was introduced(in 1942),raising their children when the last class of antibiotics...In 2023,one hundred years will have passed since penicillin was discovered.My parents'generation was bor around the time penicillin was introduced(in 1942),raising their children when the last class of antibiotics was introduced(Daptomycin in the late 1980s),and recently saw major players of the pharmaceutical industry abandon their research programs on novel antibiotics.1,2 In the span of one lifetime,mankind has experienced the tremendous success of antibiotics and the realization of the horrific consequences of their failure,with over 10 million deaths predicted by 2050 due to multidrug-resistant infections.3 With the rise of multidrug resistant pathogens,resistant to many if not all compounds,it scems the golden era of antibiotics has lasted less than one century.展开更多
Our trust in modern medicine is currently eroding as we come to realize the global health crisis that is caused by pathogens that are resistant to many,if not all,antibiotics.Soon,we will be exposed to a situation sim...Our trust in modern medicine is currently eroding as we come to realize the global health crisis that is caused by pathogens that are resistant to many,if not all,antibiotics.Soon,we will be exposed to a situation similar to the era before the discovery of Penicillin,where an ordinary injury,a simple cut-if infected-could result in our lives coming to an abrupt end.1 With the emergence of bacteria that are antibiotic resistant[antimicrobial resistance(AMR)],governments of many countries have recognized the criticality of this issue and have started programmes to understand the molecular and evolutionary basis of AMR,in order to avoid the spreading of resistance and to develop novel treatments against multi-drug resistant pathogens.展开更多
Exploring new polymerization strategy for current available monomers is a big challenge in polymer science. Here we re-investigate radical polymerization of monovinyl monomer(MVM) initiated by uniform branched polyfun...Exploring new polymerization strategy for current available monomers is a big challenge in polymer science. Here we re-investigate radical polymerization of monovinyl monomer(MVM) initiated by uniform branched polyfunctional initiator(PFI), which is termed non-linear radical additions-coupling polymerization(NLRAs CP). In NLRAs CP, both addition and coupling reactions of radical contribute to the construction of the polymer chains, which leads to continuous growth of branch topology. Theoretical analysis of NLRAs CP predicts that the gelation is determined by the functionality of PFI(a), the extent of initiation of the PFI(q) and the termination factor of radical(φ). NLRAs CPs of styrene and methyl methacrylate promoted by Cu(0)/MeTREN or Mn_(2)(CO)_(10)/visible light were conducted. After the cleavage of incorporated PFI fragment or junctions in the network, the network was transformed to linear chains having almost the same structure as segmental chains in the precursor network. This allows the reverse deducing the network structure from its cleaved products. It has been proven that NLRAs CP includes stepwise initiation of PFI, chain-growth of segmental chains and successive endlinking of macroradicals derived from PFI. The three parameters related to the gelation process, a, q and φ, were adjusted via binary PFI, the feed ratio of [Mn_(2)(CO)_(10)]/[PFI] and addition of non-homopolymerizable comonomer respectively. The minimum values of a and q, and the minimum amount of comonomer required for gelation were determined,which can be applied to estimate φ of various macroradicals. NLRAs CP opens a general and facile strategy for synthesis of a variety of polymer networks with heritable architecture by one-pot polymerization of various MVMs.展开更多
Mitochondria are organelles that serve numerous critical cellular functions,including energy production,Ca2+home-ostasis,redox signaling,and metabolism.These functions are intimately linked to mitochondrial morphology...Mitochondria are organelles that serve numerous critical cellular functions,including energy production,Ca2+home-ostasis,redox signaling,and metabolism.These functions are intimately linked to mitochondrial morphology,which is highly dynamic and capable of rapid and transient changes to alter cellular functions in response to environmental cues and cellular demands.Mitochondrial morphology and activity are critical for various physiological processes,including wound healing.In mammals,wound healing is a complex process that requires coordinated function of multiple cell types and progresses in partially overlapping but distinct stages:hemostasis and inflammation,cell pro-liferation and migration,and tissue remodeling.The repair process at the single-cell level forms the basis for wound healing and regeneration in tissues.Recent findings reveal that mitochondria fulfill the intensive energy demand for wound repair and aid wound closure by cytoskeleton remodeling via morphological changes and mitochondrial reactive oxygen species(mtROS)signaling.In this review,we will mainly elucidate how wounding induces changes in mitochondrial morphology and activity and how these changes,in turn,contribute to cellular wound response and repair.展开更多
In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in thi...In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in this case,indicating the potential of application of B cell-targeting CAR-T cell therapy in severe autoimmune diseases.展开更多
基金the National Key R&D Program of China(2017YFA0104900)the National Natural Science Foundation of China(81630065,31830029,and 81802195)the China Postdoctoral Science Foundation(2017M621913).
文摘The limited molecular classifications and disease signatures of osteoarthritis(OA)impede the development of prediagnosis and targeted therapeutics for OA patients.To classify and understand the subtypes of OA,we collected three types of tissue including cartilage,subchondral bone,and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients.By applying unsupervised clustering analysis to the cartilage transcriptome,OA patients were classified into four subtypes with distinct molecular signatures:a glycosaminoglycan metabolic disorder subtype(C1),a collagen metabolic disorder subtype(C2),an activated sensory neuron subtype(C3),and an inflammation subtype(C4).Through ligand-receptor crosstalk analysis of the three knee tissue types,we linked molecular functions with the clinical symptoms of different OA subtypes.For example,the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4,which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients.Based on the marker genes of the four OA subtypes identified in this study,we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification.The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients,which may allow for precise diagnosis and treatment of OA.
基金supported by the National Key R&D Program of China(2017YFA0104900)the National Natural Science Foundation of China(31830029,81501937 and 81522029)the Fundamental Research Funds for the Central Universities(K20200099).
文摘Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO.
基金supported by the National Key R&D Program of China(2017YFA0104900)National Natural Science Foundation of China(T2121004,31830029,82002319)。
文摘Articular cartilage damage is a universal health problem.Despite recent progress,chondrocyte dedifferentiation has severely compromised the clinical outcomes of cell-based cartilage regeneration.Loss-of-function changes are frequently observed in chondrocyte expansion and other pathological conditions,but the characteristics and intermediate molecular mechanisms remain unclear.In this study,we demonstrate a time-lapse atlas of chondrocyte dedifferentiation to provide molecular details and informative biomarkers associated with clinical chondrocyte evaluation.We performed various assays,such as single-cell RNA sequencing(scRNA-seq),live-cell metabolic assays,and assays for transposase-accessible chromatin with high-throughput sequencing(ATAC-seq),to develop a biphasic dedifferentiation model consisting of early and late dedifferentiation stages.Early-stage chondrocytes exhibited a glycolytic phenotype with increased expression of genes involved in metabolism and antioxidation,whereas late-stage chondrocytes exhibited ultrastructural changes involving mitochondrial damage and stress-associated chromatin remodeling.Using the chemical inhibitor BTB06584,we revealed that early and late dedifferentiated chondrocytes possessed distinct recovery potentials from functional phenotype loss.Notably,this two-stage transition was also validated in human chondrocytes.An image-based approach was established for clinical use to efficiently predict chondrocyte plasticity using stage-specific biomarkers.Overall,this study lays a foundation to improve the quality of chondrocytes in clinical use and provides deep insights into chondrocyte dedifferentiation.
基金supported by the Scientific and Technology Platform and Talents Project of Changsha (No.kh1801129) (to HW)Hunan Cancer Hospital Climb Plan (No.YF2020007) (to HW)+1 种基金the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China (No.LHDMZ22H020001) (To XY)the Science and Technology Program of Jinhua Science and Technology Bureau (No.2021-3-001) (To XY)。
文摘Although human-induced pluripotent stem cell-derived cardiomyocytes(hi PSC-CMs) have been used for disease modeling and drug discovery, clinically relevant three-dimensional(3D) functional myocardial microtissues are lacking. Here, we developed a novel ring-shaped cardiac microtissue comprised of chamber-specific tissues to achieve a geometrically non-orientable ventricular myocardial band, similar to a M?bius loop. The ring-shaped cardiac tissue was constructed of hi PSC-CMs and human cardiac fibroblasts(h CFs) through a facile cellular self-assembly approach. It exhibited basic anatomical structure,positive cardiac troponin T(c Tn T) immunostaining, regular calcium transients, and cardiac-like mechanical strength. The cardiac rings can be self-assembled and scaled up into various sizes with outstanding stability, suggesting their potential for precise therapy, pathophysiological investigation, and large-scale drug screening.
基金supported by the National Natural Science Foundation of China(81930065,82173128,82102921,and 82003269)the Cancer Innovation Research Program of Sun Yat-sen University Cancer Center(CIRP-SYSUCC-0004)+5 种基金the Swedish Research Council(VR-MH 2014-46602-117891-30)the CAMS Innovation Fund for Medical Sciences(CIFMS)(2019-I2M-5-036)the Youth Teacher Cultivation Program of Sun Yat-sen UniversityGuangdong Provincial Clinical Medical Research Center for Malignant Tumors(84000-31660002)the China Postdoctoral Science Foundation(2023M744049)the Chih Kuang Scholarship for Outstanding Young Physician-Scientists of Sun Yat-sen University Cancer Center(CKS-SYSUCC-2023001)。
文摘Patients with high tumor mutational burden(TMB)levels do not consistently respond to immune checkpoint inhibitors(ICIs),possibly because a high TMB level does not necessarily result in adequate infiltration of CD8^(+)T cells.Using bulk ribonucleic acid sequencing(RNA-seq)data from 9311 tumor samples across 30 cancer types,we developed a novel tool called the modulator of TMB-associated immune infiltration(MOTIF),which comprises genes that can determine the extent of CD8^(+)T cell infiltration prompted by a certain TMB level.We confirmed that MOTIF can accurately reflect the integrity and defects of the cancer-immunity cycle.By analyzing 84 human single-cell RNA-seq datasets from 32 types of solid tumors,we revealed that MOTIF can provide insights into the diverse roles of various cell types in the modulation of CD8^(+)T cell infiltration.Using pretreatment RNA-seq data from 13 ICI-treated cohorts,we validated the use of MOTIF in predicting CD8^(+)T cell infiltration and ICI efficacy.Among the components of MOTIF,we identified EMC3 as a negative regulator of CD8^(+)T cell infiltration,which was validated via in vivo studies.Additionally,MOTIF provided guidance for the potential combinations of programmed death 1 blockade with certain immunostimulatory drugs to facilitate CD8^(+)T cell infiltration and improve ICI efficacy.
基金GY is grateful to the National Natural Science Foundation(Grant no.82260655)Hainan Provincial Natural Science Foundation(Grant no.821CXTD440)+1 种基金the Open Foundation of Key Laboratory of Tropical Translational Medicine of Ministry of Education(ZDKJ202003)Hainan Medical University,as well as National Key Research and Development Program of China(No.2021YFC2300800,2021YFC2300804).
文摘Background Rabies continues to be a serious threat to global public health endangering people’s health and public health safety.In the People’s Republic of China,multi-sectoral and comprehensive prevention and control strategies have aimed to extensively curb human rabies transmission.Here,we examine the current state of rabies infection in China,explore strategic interventions put in place in response to WHO’s ambition of“Zero rabies deaths by 2030”and critically assess the constraints and feasibility of dog-mediated rabies elimination in China.Methods This study analyzed and evaluated the process towards dog-mediated rabies elimination in China from five perspectives:namely,human,dog,policy,challenge,and prospects.Evidence-based data on progress of dog-mediated rabies elimination in China was derived from a number of sources;a literature search was undertaken using PubMed,Web of Science and CNKI databases,distribution data for human rabies cases as derived from the Data-center of the China Public Health Science and policy and document data were obtained from official websites of the relevant China ministries and commissions.Results The incidence of human rabies cases in China have shown a downward trend year-on-year since 2007.Implementation of a government-led,multi-sectoral“One Health”approach to combating rabies has driven down the total number of rabies deaths nationwide to around 200 in 2020.The number of provincial-level administrative divisions(PLADs)reporting human cases of rabies has also decreased to 21 in 2020,13 of which reported less than 10 cases.Furthermore,the number of outpatient visits seeking rabies post-exposure prophylaxis has risen dramatically over the past two decades,with demand being 15 times higher than it was initially.There remain however,significant gaps in rabies elimination outcomes across the different regions of China.To date the target of achieving a canine rabies vaccination rate of>75%has not been met.The challenges of rabies immunization of dogs and dog management in underdeveloped cities and rural areas need to be addressed together with more effective animal surveillance and rabies risk from and too wildlife and livestock.Conclusions The Chinese government-led,multi-sectoral“One Health”approach to combating rabies and has made significant progress over the past decade.Development and adoption of more cost-effective One Health strategies can achieve more nationally beneficial rabies elimination outcomes.The ambitious target of“Zero rabies deaths by 2030”can be met through establishment of long-lasting herd immunity in dogs by means of dog mass vaccination campaigns,dog population management,epidemiological surveillance and the application of large-scale oral rabies vaccine to eliminate rabies in wild animals coupled with deployment of cost-effective human post-exposure prophylaxis,and community education.
基金The authors would like to acknowledge financial support from the National Key Research and Development Program of China(2017YFE0117700)National Natural Science Foundation of China(82172419,81902225,81871775)+1 种基金Natural Science Foundation of Zhejiang Province(LGF21H060006,LZ22E020002,LQ23H060005,LQ23H150004)Zhejiang Province Public Welfare Technology Application Research Project(LGF22E030002).
文摘The pore architecture of porous scaffolds is a critical factor in osteogenesis,but it is a challenge to precisely configure strut-based scaffolds because of the inevitable filament corner and pore geometry deformation.This study provides a pore architecture tailoring strategy in which a series of Mg-doped wollastonite scaffolds with fully interconnected pore networks and curved pore architectures called triply periodic minimal surfaces(TPMS),which are similar to cancellous bone,are fabricated by a digital light processing technique.The sheet-TPMS pore geometries(s-Diamond,s-Gyroid)contribute to a 3‒4-fold higher initial compressive strength and 20%-40%faster Mg-ion-release rate compared to the other-TPMS scaffolds,including Diamond,Gyroid,and the Schoen’s I-graph-Wrapped Package(IWP)in vitro.However,we found that Gyroid and Diamond pore scaffolds can significantly induce osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs).Analyses of rabbit experiments in vivo show that the regeneration of bone tissue in the sheet-TPMS pore geometry is delayed;on the other hand,Diamond and Gyroid pore scaffolds show notable neo-bone tissue in the center pore regions during the early stages(3-5 weeks)and the bone tissue uniformly fills the whole porous network after 7 weeks.Collectively,the design methods in this study provide an important perspective for optimizing the pore architecture design of bioceramic scaffolds to accelerate the rate of osteogenesis and promote the clinical translation of bioceramic scaffolds in the repair of bone defects.
文摘Inflammatory bowel disease(IBD)is a chronic,immune-mediated inflammatory disease characterized by the destruction of the structure and function of the intestinal epithelial barrier.Due to the poor remission effect and severe adverse events associated with current clinical medications,IBD remains an incurable disease.Here,we demonstrated a novel treatment strategy with high safety and effective inflammation remission via tissue-adhesive molecular coating.The molecular coating is composed of o-nitrobenzaldehyde(NB)-modified Gelatin(GelNB),which can strongly bond with-NH_(2)on the intestinal surface of tissue to form a thin biophysical barrier.We found that this molecular coating was able to stay on the surface of the intestine for long periods of time,effectively protecting the damaged intestinal epithelium from irritations of external intestinal metabolites and harmful flora.In addition,our results showed that this coating not only provided a beneficial environment for cell migration and proliferation to promote intestinal repair and regeneration,but also achieved a better outcome of IBD by reducing intestinal inflammation.Moreover,the in vivo experiments showed that the GelNB was better than the classic clinical medication-mesalazine.Therefore,our molecular coating showed potential as a promising strategy for the prevention and treatment of IBD.
基金supported by the National Key Research and Development Program of China(2016YFB0700804)National Natural Science Foundation of China(NO.T2121004,31830029).
文摘Autologous mosaicplasty is a common approach used to treat osteochondral defects in clinical practice.Gap integration between host and transplanted plugs requires bone tissue reservation and hyaline cartilage regeneration without uneven surface,graft necrosis and sclerosis.However,poor gap integration is a serious concern,which eventually leads to deterioration of joint function.To deal with such complications,this study has developed a strategy to effectively enhance integration of the gap region following mosaicplasty by applying injectable bioactive supramolecular nanofiber-enabled gelatin methacryloyl(GelMA)hydrogel(BSN-GelMA).A rabbit osteochondral defect model demonstrated that BSN-GelMA achieved seamless osteochondral healing in the gap region between plugs of osteochondral defects following mosaicplasty,as early as six weeks.Moreover,the International Cartilage Repair Society score,histology score,glycosaminoglycan content,subchondral bone volume,and collagen II expression were observed to be the highest in the gap region of BSN-GelMA treated group.This improved outcome was due to bio-interactive materials,which acted as tissue fillers to bridge the gap,prevent cartilage degeneration,and promote graft survival and migration of bone marrow mesenchymal stem cells by releasing bioactive supramolecular nanofibers from the GelMA hydrogel.This study provides a powerful and applicable approach to improve gap integration after autologous mosaicplasty.It is also a promising off-the-shelf bioactive material for cell-free in situ tissue regeneration.
基金We thank Drs.Tyler Jacks,Ronald A.DePinho,Kwok-kin Wong,and Lijian Hui for the generous gift of various mouse strains.We also thank Ruiqi Wang,Rui Liu,Pei Chen,Chao Zheng,and Jifan Shi for helpful discussion.This work was supported by the National Basic Research Program of China(Nos.2017YFA0505500 to H.J.and L.C.,2020YFA0803300 to H.J.)the National Natural Science Foundation of China(Nos.91731314,82030083,31621003,81872312,82011540007 to H.J.,12131020,31930022,12026608 to L.C.,82273093 to Z.F.,81871875,82173340 to L.H.,81802279 to H.H.,81902326 to X.W.,81402371 to Y.J.)+7 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDB19020201 to H.J.,XDB38040400 to L.C.)Basic Frontier Scientific Research Program of Chinese Academy of Science(No.ZDBS-LY-SM006 to H.J.)International Cooperation Project of Chinese Academy of Sciences(No.153D31KYSB20190035 to H.J.)the Science and Technology Commission of Shanghai Municipality(No.21ZR1470300 to L.H.)the Youth Innovation Promotion Association CAS(No.Y919S31371 to X.W.)Special Fund for Science and Technology Innovation Strategy of Guangdong Province(Nos.2021B0909050004,2021B0909060002 to L.C.)Major Key Project of PCL(No.PCL2021A12 to L.C.)JST Moonshot R&D Project(No.JPMJMS2021 to L.C.).
文摘Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation(AST).However,it remains largely unknown how Lkb1 deficiency dynamically regulates AST.Using the classical AST mouse model(Kras LSL-G12D/+;Lkb1flox/flox,KL),we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker(DNB)and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species(ROS)through its downstream effector FOXO3A.Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST.Importantly,pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation,highlighting the irreversibility of AST after crossing the tipping point.Through comparative transcriptomic analyses of mouse and human tumors,we find that the lineage-specific transcription factors(TFs)of adenocarcinoma and squamous cell carcinoma form a“Yin-Yang”counteracting network.Interestingly,inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the“Yin-Yang”homeostasis to lean towards the squamous lineage,whereas ectopic expression of NKX2-1,an adenomatous lineage TF,significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation.The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma.Collectively,our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno-and squamous-specific TF networks at the AST tipping point.
基金the National Natural Sciences Foundation of China(T2121004,31830029)。
文摘Dear Editor,Age-dependent adipose tissue malfunction raises the risk of diseases like diabetes,cardiovascular disease,and even cancer by contributing to metabolic decline,heterotopic fat storage,and chronic systemic inflammation.1 Understanding adipose tissue aging requires in-depth knowledge of the cellular and molecular properties of various adipose tissue cell types.Although the heterogeneity of the cell population during mouse aging has been studied,2 little is known about the cellular and molecular basis of human adipose tissues aging.
基金This work was supported by grants from the National Natural Science Foundation of China(31770954,31530019 to L.L.and 31900628 to Q.X.)the Fundamental Research Funds for the Central Universities(2018XZZX001-12 to L.L.).
文摘Dysregulated B-cell activation plays pivotal roles in systemic lupus erythematosus(SLE),which makes B-cell depletion a potential strategy for SLE treatment.The clinical success of anti-CD19 CAR-T cells in treating B-cell malignancies has attracted the attention of researchers.In this study,we aimed to investigate the feasibility of applying anti-CD19 CAR-T cell therapy to SLE treatment in a mouse disease model.We constructed murine anti-CD19 CARs with either CD28 or 4-1BB as the intracellular costimulatory motif and evaluated the therapeutic function of the corresponding CAR-T cells by infusing them into MRL-lpr mice.Furthermore,anti-CD19 CAR-T cells were transferred to MRL-lpr mice before the onset of disease to determine their role in SLE prevention.According to our observations,compared with antibody treatment,the adoptive transfer of our anti-CD19 CAR-T cells showed a more sustained B-cell-depletion effect in MRL-lpr mice.The transfer of syngeneic anti-CD19 CAR-T cells not only prevented disease pathogenesis before the onset of disease symptoms but also displayed therapeutic benefits at a later stage after disease progression.We also tried to optimize the treatment strategy and found that compared with CAR-T cells with the CD28 costimulatory motif,CAR-T cells with the 4-1BB costimulatory motif showed better therapeutic efficiency without cell enrichment.Taken together,these results show that anti-CD19 CAR-T cell therapy was effective in the prevention and treatment of a murine model of SLE,indicating its potential for clinical use in patients.
基金supported by the National Key Research and Development Program of China(No.2021YFC2700903)the National Basic Research Program of China(No.2017YFA0105201)+3 种基金the National Natural Science Foundation of China(Nos.81672791 and 81872300)the Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(No.LR18C060002)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMY22H160006)the ZJU-QILU Joint Research Institute QILU Group.
文摘Cancer cells undergo substantial metabolic alterations to sustain increased energy supply and uncontrolled proliferation.As an essential trace element,iron is vital for many biological processes.Evidence has revealed that cancer cells deploy various mechanisms to elevate the cellular iron concentration to accelerate proliferation.Ferroptosis,a form of cell death caused by iron-catalyzed excessive peroxidation of polyunsaturated fatty acids(PUFAs),is a promising therapeutic target for therapyresistant cancers.Previous studies have reported that long noncoding RNA(lncRNA)is a group of critical regulators involved in modulating cell metabolism,proliferation,apoptosis,and ferroptosis.In this review,we summarize the associations among iron metabolism,ferroptosis,and ferroptosis-related lncRNA in tumorigenesis.This information will help deepen understanding of the role of lncRNA in iron metabolism and raise the possibility of targeting lncRNA and ferroptosis in cancer combination therapy.
基金supported by the National Key Research and Development Program of China(No.2018YFC2000100)the National Natural Science Foundation of China(Nos.31730021,31971220,and 31961160725)+1 种基金the Fok Ying Tung Education Foundationthe China’s Fundamental Research Funds for the Central Universities。
文摘Genome stability can be threatened by both endogenous and exogenous agents.Organisms have evolved numerous mechanisms to repair DNA damage,including homologous recombination(HR)and non-homologous end joining(NHEJ).Among the factors associated with DNA repair,the MRE11-RAD50-NBS1(MRN)complex(MRE11-RAD50-XRS2 in Saccharomyces cerevisiae)plays important roles not only in DNA damage recognition and signaling but also in subsequent HR or NHEJ repair.Upon detecting DNA damage,the MRN complex activates signaling molecules,such as the protein kinase ataxia-telangiectasia mutated(ATM),to trigger a broad DNA damage response,including cell cycle arrest.The nuclease activity of the MRN complex is responsible for DNA end resection,which guides DNA repair to HR in the presence of sister chromatids.The MRN complex is also involved in NHEJ,and has a species-specific role in hairpin repair.This review focuses on the structure of the MRN complex and its function in DNA damage repair.
基金National Key Research and Development Programme of China(2018YFA0800403 and 2021YFC2701903)Training Program of the Major Research Plan of the National Natural Science Foundation of China(91857110)+6 种基金National Natural Science Fund for Excellent Young Scholars of China(81722012)National Natural Science Foundation of China(81670740)Zhejiang Provincial Natural Science Foundation of China(LZ21H070001)Innovative Institute of Basic Medical Sciences of Zhejiang University,the Fundamental Research Funds for the Central UniversitiesConstruction Fund of Medical Key Disciplines of Hangzhou(OO20200055)Hangzhou Science and Technology Bureau(20150733Q13 and ZD20200129)K.C.Wong Education Foundation.
文摘Pancreaticβ-cell dysfunction and insulin resistance are two of the major causes of type 2 diabetes(T2D).Recent clinical and experimental studies have suggested that the functional capacity ofβ-cells,particularly in the first phase of insulin secretion,is a primary contributor to the progression of T2D and its associated complications.Pancreaticβ-cells undergo dynamic compensation and decompensation processes during the development of T2D,in which metabolic stresses such as endoplasmic reticulum stress,oxidative stress,and inflammatory signals are key regulators ofβ-cell dynamics.Dietary and exercise interventions have been shown to be effective approaches for the treatment of obesity and T2D,especially in the early stages.Whilst the targeted tissues and underlying mechanisms of dietary and exercise interventions remain somewhat vague,accumulating evidence has implicated the improvement ofβ-cell functional capacity.In this review,we summarize recent advances in the understanding of the dynamic adaptations ofβ-cell function in T2D progression and clarify the effects and mechanisms of dietary and exercise interventions onβ-cell dysfunction in T2D.This review provides molecular insights into the therapeutic effects of dietary and exercise interventions on T2D,and more importantly,it paves the way for future research on the related underlying mechanisms for developing precision prevention and treatment of T2D.
文摘In 2023,one hundred years will have passed since penicillin was discovered.My parents'generation was bor around the time penicillin was introduced(in 1942),raising their children when the last class of antibiotics was introduced(Daptomycin in the late 1980s),and recently saw major players of the pharmaceutical industry abandon their research programs on novel antibiotics.1,2 In the span of one lifetime,mankind has experienced the tremendous success of antibiotics and the realization of the horrific consequences of their failure,with over 10 million deaths predicted by 2050 due to multidrug-resistant infections.3 With the rise of multidrug resistant pathogens,resistant to many if not all compounds,it scems the golden era of antibiotics has lasted less than one century.
文摘Our trust in modern medicine is currently eroding as we come to realize the global health crisis that is caused by pathogens that are resistant to many,if not all,antibiotics.Soon,we will be exposed to a situation similar to the era before the discovery of Penicillin,where an ordinary injury,a simple cut-if infected-could result in our lives coming to an abrupt end.1 With the emergence of bacteria that are antibiotic resistant[antimicrobial resistance(AMR)],governments of many countries have recognized the criticality of this issue and have started programmes to understand the molecular and evolutionary basis of AMR,in order to avoid the spreading of resistance and to develop novel treatments against multi-drug resistant pathogens.
文摘Exploring new polymerization strategy for current available monomers is a big challenge in polymer science. Here we re-investigate radical polymerization of monovinyl monomer(MVM) initiated by uniform branched polyfunctional initiator(PFI), which is termed non-linear radical additions-coupling polymerization(NLRAs CP). In NLRAs CP, both addition and coupling reactions of radical contribute to the construction of the polymer chains, which leads to continuous growth of branch topology. Theoretical analysis of NLRAs CP predicts that the gelation is determined by the functionality of PFI(a), the extent of initiation of the PFI(q) and the termination factor of radical(φ). NLRAs CPs of styrene and methyl methacrylate promoted by Cu(0)/MeTREN or Mn_(2)(CO)_(10)/visible light were conducted. After the cleavage of incorporated PFI fragment or junctions in the network, the network was transformed to linear chains having almost the same structure as segmental chains in the precursor network. This allows the reverse deducing the network structure from its cleaved products. It has been proven that NLRAs CP includes stepwise initiation of PFI, chain-growth of segmental chains and successive endlinking of macroradicals derived from PFI. The three parameters related to the gelation process, a, q and φ, were adjusted via binary PFI, the feed ratio of [Mn_(2)(CO)_(10)]/[PFI] and addition of non-homopolymerizable comonomer respectively. The minimum values of a and q, and the minimum amount of comonomer required for gelation were determined,which can be applied to estimate φ of various macroradicals. NLRAs CP opens a general and facile strategy for synthesis of a variety of polymer networks with heritable architecture by one-pot polymerization of various MVMs.
基金The work in the Xu lab is supported by the National Key R&D Program of China(2021YFA1300302,2021YFA1101002)the National Natural Science Foundation of China(91754111)the Zhejiang Province Natural Science Foundation(2-2060203-21-001)to S.X.
文摘Mitochondria are organelles that serve numerous critical cellular functions,including energy production,Ca2+home-ostasis,redox signaling,and metabolism.These functions are intimately linked to mitochondrial morphology,which is highly dynamic and capable of rapid and transient changes to alter cellular functions in response to environmental cues and cellular demands.Mitochondrial morphology and activity are critical for various physiological processes,including wound healing.In mammals,wound healing is a complex process that requires coordinated function of multiple cell types and progresses in partially overlapping but distinct stages:hemostasis and inflammation,cell pro-liferation and migration,and tissue remodeling.The repair process at the single-cell level forms the basis for wound healing and regeneration in tissues.Recent findings reveal that mitochondria fulfill the intensive energy demand for wound repair and aid wound closure by cytoskeleton remodeling via morphological changes and mitochondrial reactive oxygen species(mtROS)signaling.In this review,we will mainly elucidate how wounding induces changes in mitochondrial morphology and activity and how these changes,in turn,contribute to cellular wound response and repair.
基金Our work was supported by grants from the National Natural Science Foundation of China(31930038,31770954,and 31530019 to LL).
文摘In a recent study from NEJM,Mougiakakos et al.reported a case in which autologous anti-CD19 CAR-T cell therapy was used in the treatment of a refractory SLE patient[1].Rapid remission of severe SLE was observed in this case,indicating the potential of application of B cell-targeting CAR-T cell therapy in severe autoimmune diseases.
