Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the pr...Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.展开更多
Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases,yet its association with progressive periodontitis remains unexplored.To investigate the involvement and significance of ferropto...Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases,yet its association with progressive periodontitis remains unexplored.To investigate the involvement and significance of ferroptosis in periodontitis progression,we assessed sixteen periodontitis-diagnosed patients.Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid(GCF)collection was performed for further analyses.Clinical metrics,proteomic data,in silico methods,and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis.Subsequent western blot analyses validated key findings.Finally,a single-cell RNA sequencing(scRNA-seq)dataset(GSE164241)for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression.Periodontitis progression was identified as occurring at a faster rate than traditionally thought.GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles.In addition,specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins,including SNCA,CA1,HBB,SLC4A1,and ANK1 was strongly associated with the clinical progression status of periodontitis.Moreover,we found specific proteins-drivers or suppressors-associated with ferroptosis(SNCA,FTH1,HSPB1,CD44,and GCLC),revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis.Additionally,the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis.Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients,which offer new insights into the molecular mechanisms of progressive periodontal disease.These findings may lead to novel diagnostic and therapeutic strategies.展开更多
Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas ma...Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas made it an important target for the development ofantiviral and anticancer drugs. Taking account of the re-cent developments in this field of research, this reviewfocuses on the role of thioredoxin and glutaredoxin sys-tems in the redox reactions of the RNR catalysis.展开更多
Coronavirus disease 2019(COVID-19)has been a pandemic for more than a year.With the expanding second wave of the pandemic in winter,the continuous evolution of SARS-CoV-2 has brought new issues,including the significa...Coronavirus disease 2019(COVID-19)has been a pandemic for more than a year.With the expanding second wave of the pandemic in winter,the continuous evolution of SARS-CoV-2 has brought new issues,including the significance of virus mutations in infection and the detection of asymptomatic infection.In this review,we first introduced several major SARS-CoV-2 mutations since the COVID-19 outbreak and then mentioned the widely used molecular detection techniques to diagnose COVID-19,primarily focusing on their strengths and limitations.We further discussed the effects of viral genetic variation and asymptomatic infection on the molecular detection of SARS-CoV-2 infection.The review finally summarized useful insights into the molecular diagnosis of COVID-19 under the special situation being challenged by virus mutation and asymptomatic infection.展开更多
Dear Editor,We present the reported case of a 37-year-old male atypical Cogan’s syndrome(CS)patient who was precisely diagnosed and clinically cured under our systematic therapeutic regime.CS is a rare autoimmune dis...Dear Editor,We present the reported case of a 37-year-old male atypical Cogan’s syndrome(CS)patient who was precisely diagnosed and clinically cured under our systematic therapeutic regime.CS is a rare autoimmune disorder involving the eye,characterised by interstitial keratitis(IK)and the auditory-vestibulo system with vestibular dysfunction.展开更多
Diabetic kidney disease(DKD)is one of the major chronic complications of diabetes mellitus(DM),as well as a main cause of end-stage renal disease.Over the last few years,substantial research studies have revealed a co...Diabetic kidney disease(DKD)is one of the major chronic complications of diabetes mellitus(DM),as well as a main cause of end-stage renal disease.Over the last few years,substantial research studies have revealed a contributory role of gut microbiota in the process of DM and DKD.Metabolites of gut microbiota like lipopolysaccharide,short-chain fatty acids,and trimethylamine N-oxide are key mediators of microbial–host crosstalk.However,the underlying mechanisms of how gut microbiota influences the onset and progression of DKD are relatively unknown.Besides,strategies to remodel the composition of gut microbiota or to reduce the metabolites of microbiota have been found recently,representing a new potential remedial target for DKD.In this minireview,we will address the possible contribution of the gut microbiota in the pathogenesis of DKD and its role as a therapeutic target.展开更多
Coronavirus disease 2019(COVID-19)has been associated with various liver injury cases worldwide.To date,the prevalence,mechanism,clinical manifestations,diagnosis,and outcomes of COVID-19-induced liver injury in vario...Coronavirus disease 2019(COVID-19)has been associated with various liver injury cases worldwide.To date,the prevalence,mechanism,clinical manifestations,diagnosis,and outcomes of COVID-19-induced liver injury in various at-risk groups are not well defined.Liver injury may arise in the prevention and treatment of COVID-19 from direct causes such as viral infection and indirect causes such as systemic inflammation,hypoxic changes,and drugs that exacerbate any pre-existing liver disease.Studies have found that patients with underlying liver disease are at higher risk of COVID-19-induced liver injury.Certain condition of cardiopulmonary and metabolic diseases and vulnerable stages in lifespan may also involve in the development of COVID-19-induced liver injury.This review summarized studies of COVID-19-induced liver injury in different at-risk groups regarding their clinical characteristics,parameters,and correlations of the severity with these indicators and signs as well as potential treatment suggestions,to increase attention to physiological and pathological conditions and continue liver function monitoring as they can help in strengthening early supportive treatment and reducing the incidence of adverse outcomes.展开更多
Plant 9-1ipoxygenases （9-LOX） and α-dioxygenases （α-DOX） initiate the synthesis of oxylipins after bacterial infection. Here, the role of these enzymes in plants＇ defense was investigated using individual Arabi...Plant 9-1ipoxygenases （9-LOX） and α-dioxygenases （α-DOX） initiate the synthesis of oxylipins after bacterial infection. Here, the role of these enzymes in plants＇ defense was investigated using individual Arabidopsis thaliana Ioxl and doxl mutants and a double Ioxl doxl mutant. Studies with Pseudomonas syringae pv. tomato （Pst） revealed the enhanced susceptibility of Ioxl to the virulent strain Pst DC3000 and the partial impairment of Ioxl and doxl mutants to activate systemic acquired resistance. Notably, both defects were enhanced in the Ioxl doxl plants as compared with individual mutants. We found that pre-treatment with 9-LOX- and α-DOX-generated oxylipins protected plant tissues against bacterial infection. The strongest effect in this respect was exerted by 9-ketooctadecatrienoic acid （9-KOT）, which is produced from linolenic acid by 9-LOX. Quantification of 9-KOT revealed its accumulation after bacterial infection. The levels were reduced in Ioxl and Ioxl doxl plants but strongly increased in the doxl mutant due to metabolic interaction of the two pathways. Transcriptional analyses indicated that 9-KOT pre-treatment modifies hormone homeostasis during bacterial infection. The nature of the changes detected suggested that 9-KOT interferes with the hormonal changes caused by bacterial effectors. This notion was substantiated by the finding that 9-KOT failed to reduce the growth of PstDC3OOOhrpA, a mutant compromised in effector secretion, and of the avirulent strain Pst DC3000 avrRpml. Further support for the action of the 9-LOX- and α-DOX-oxylipin pathways as modulators of hormone homeostasis was the ob- servation that Ioxl doxl seedlings are hypersensitive to the growth-inhibitory effect of ABA and showed enhanced ac- tivation of ABA-inducible marker genes as compared with wild-type plants.展开更多
Most of the mitochondrial and chloroplastic proteins are synthesized in the cytosol as precursor proteins carrying an N-terminal targeting peptide （TP） directing them specifically to a correct organelle. However, th...Most of the mitochondrial and chloroplastic proteins are synthesized in the cytosol as precursor proteins carrying an N-terminal targeting peptide （TP） directing them specifically to a correct organelle. However, there is a group of proteins that are dually targeted to mitochondria and chloroplasts using an ambiguous N-terminal dual targeting peptide （dTP）. Here, we have investigated pattern properties of import determinants of organelle-specific TPs and dTPs combining mathematical multivariate data analysis （MVDA） with in vitro organellar import studies. We have used large datasets of mitochondrial and chloroplastic proteins found in organellar proteomes as well as manually selected data sets of experimentally confirmed organelle-specific TPs and dTPs from Arabidopsis thaliana. Two classes of organelle-specific TPs could be distinguished by MVDA and potential patterns or periodicity in the amino acid sequence contributing to the separation were revealed, dTPs were found to have intermediate sequence features between the organelle-specific TPs. Interestingly, introducing positively charged residues to the dTPs showed clustering towards the mitochondrial TPs in silico and resulted in inhibition of chloroplast, but not mitochondrial import in in vitro organellar import studies. These findings suggest that positive charges in the N-terminal region of TPs may function as an ＇avoidance signal＇ for the chloroplast import.展开更多
Proteome-wide Amino aCid and Elemental composition （PACE） analysis is a novel and informative way of interrogating the proteome. The PACE approach consists of in silico decompo- sition of proteins detected and quant...Proteome-wide Amino aCid and Elemental composition （PACE） analysis is a novel and informative way of interrogating the proteome. The PACE approach consists of in silico decompo- sition of proteins detected and quantified in a proteomics experiment into 20 amino acids and five elements （C, H, N, O and S）, with protein abundances converted to relative abundances of amino acids and elements. The method is robust and very sensitive; it provides statistically reliable differ- entiation between very similar proteomes. In addition, PACE provides novel insights into prote- ome-wide metabolic processes, occurring, e.g., during cell starvation. For instance, both Escherichia coli and Synechocystis down-regulate sulfur-rich proteins upon sulfur deprivation, but E. coli preferentially down-regulates cysteine-rich proteins while Synechocystis mainly down- regulates methionine-rich proteins. Due to its relative simplicity, flexibility, generality and wide applicability, PACE analysis has the potential of becoming a standard analytical tool in proteomics.展开更多
Alport syndrome （AS） is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encod-ing the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane....Alport syndrome （AS） is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encod-ing the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identifed and the frst Al-port mouse model was developed using a knockout ap-proach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the patho-genesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharma-cological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refnement as research advances. In terms of the pharmacological drugs, angiotensin-con-verting enzyme inhibitors have been shown to be effec-tive in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.展开更多
In a recent publication in Nature,1 Zhang et al.have developed spatial ATAC-RNA-seq and spatial CUT&Tag-RNA-seq as innovative tools that enable the high-resolution mapping of epigenetic and transcriptomic features...In a recent publication in Nature,1 Zhang et al.have developed spatial ATAC-RNA-seq and spatial CUT&Tag-RNA-seq as innovative tools that enable the high-resolution mapping of epigenetic and transcriptomic features in cells from frozen tissue sections.By applying these techniques to mouse embryos and brains,the authors discovered unexpected interrelationships between epigenetic regulation and gene expression in various brain regions.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 Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone （ACTH） has been the major therapy for infantile spasms; however,...Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone （ACTH） has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms. Methods We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed. Results Four single nucleotide polymorphisms （SNPs） were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T〉C. Three SNPs （rs1893220, rs2186944 and -2T〉C） showed a significant difference between the cases and controls （P 〈0.05 for all）. The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases （39%） than in the controls （60%） （P=-0.00003）. The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers （RR=O.42, 95%C/ 0.26-0.70, P=-0.0001）. ACTH responsiveness was strongly associated with the TCCT haplotype （P=-0.000082）. Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy （P=0.0002; P=-0.0003, respectively）. Conclusions Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.展开更多
Wnts are a highly conserved family of Upid-modified glycoproteins that work as morphogens to activate several signaling pathways, leading to remodeling of the cytoskeleton and the regulation of gene transcription. Wnt...Wnts are a highly conserved family of Upid-modified glycoproteins that work as morphogens to activate several signaling pathways, leading to remodeling of the cytoskeleton and the regulation of gene transcription. Wnt signaling regulates multiple cellular functions and cell systems, including the development and maintenance of midbrain dopaminergic （m DA） neurons. These neurons are of consid- erable interest for regenerative medicine because their degeneration results in Parkinson＇s disease （PD）. This review focuses on new advances in understanding key functions of Wnts in mDA neuron development and using novel tools to regulate Wnt signaling in re- generative medicine for PD. Particularly, recent reports indicate that appropriate levels of Wnt signaling are essential to improve the quantity and quality of stem ceil- or reprogrammed ceU-derived mDA neurons to be used in drug discovery and cell replacement therapy for PD.展开更多
Backgrounds Common variable immunodeficiency(CVID),the most prevalent form of primary immunodeficiency(PID),is characterized by hypogammaglobulinemia and recurrent infections.Understanding protein-protein interaction(...Backgrounds Common variable immunodeficiency(CVID),the most prevalent form of primary immunodeficiency(PID),is characterized by hypogammaglobulinemia and recurrent infections.Understanding protein-protein interaction(PPI)networks of CVID genes and identifying candidate CVID genes are critical steps in facilitating the early diagnosis of CVID.Here,the aim was to investigate PPI networks of CVID genes and identify candidate CVID genes using computation techniques.Methods:Network density and biological distance were used to study PPI data for CVID and PID genes obtained from the STRING database.Gene expression data of patients with CVID were obtained from the Gene Expression Omnibus,and then Pearson's correlation coefficient,a PPI database,and Kyoto Encyclopedia of Genes and Genomes were used to identify candidate CVID genes.We then evaluated our predictions and identified differentially expressed CVID genes.Results:The majority of CVID genes are characterized by a high network density and small biological distance,whereas most PID genes are characterized by a low network density and large biological distance,indicating that CVID genes are more functionally similar to each other and closely interact with one other compared with PID genes.Subsequently,we identified 172 CVID candidate genes that have similar biological functions to known CVID genes,and eight genes were recently reported as CVID-related genes.MYC,a candidate gene,was down-regulated in CVID duodenal biopsies,but up-regulated in blood samples compared with levels in healthy controls.Conclusion:Our findings will aid in a better understanding of the complex of CVID genes,possibly further facilitating the early diagnosis of CVID.展开更多
Stable isotopes of most important biological elements, such as C, H, N and O, affect living organisms. In rapidly growing species, deuterium and to a lesser extent other heavy isotopes reduce the growth rate. At least...Stable isotopes of most important biological elements, such as C, H, N and O, affect living organisms. In rapidly growing species, deuterium and to a lesser extent other heavy isotopes reduce the growth rate. At least for deuterium it is known that its depletion also negatively impacts the speed of biological processes. As a rule, living organisms ＂resist＂ changes in their isotopic environment, preferring natural isotopic abundances. This preference could be due to evolutionary optimization; an additional effect could be due to the presence of the ＂isotopic resonance＂. The isotopic resonance phenomenon has been linked to the choice of earliest amino acids, and thus af- fected the evolution of genetic code. To test the isotopic resonance hypothesis, literature data were analyzed against quantitative and qualitative predictions of the hypothesis. Four studies provided five independent datasets, each in very good quantitative agreement with the predictions. Thus, the isotopic resonance hypothesis is no longer simply plausible; it can now be deemed likely. Additional testing is needed, however, before full acceptance of this hypothesis.展开更多
Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of th...Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of the required sample size and loss of statistical power.Conversely,when there is actually no apparent delay in treatment effects,alternative trial designs for addressing DTE may lead to an over-estimation of sample size and unnecessary prolongation of the trial duration.To mitigate this challenge,we propose the use of a DTE predicting(DTEP)model to better guide immuno-oncology trial designs.Methods:The DTEP model was developed and validated using data from 147 pub-lished randomized immuno-oncology trials.The eligible trials were divided into a training set(approximately 75%of the trials)and a test set(approximately 25%).We employed linear discriminant analysis(LDA)to develop the DTEP model for pre-dicting the DTE status using baseline characteristics available at the trial design stage.The receiver operating characteristic(ROC)curve was utilized to assess the ability of the model to distinguish between trials with and without DTE.We further re-conducted the JUPITER-02 trial in a simulation setting,employing three design approaches to assess the potential benefits of utilizing the DTEP model.Results:Baseline characteristics available during the trial design stage,including cancer type,line of treatment,and experimental and control arm regimens were incorporated,and high accuracy in predicting the DTE status in both the training set(area under the operating characteristic curve(AUC),0.79;95%confidence interval(CI),0.71-0.88)and test set(AUC,0.78;95%CI,0.66-0.90)was achieved.Notably,the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team(ESCORT-1st(absence of DTE)and JUPITER-02(presence of DTE)).In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model.Conclusions:The DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs,thereby facilitating the discovery of effective im-munotherapeutics in a more streamlined and expedited manner.展开更多
基金supported by the GRF RGC&CRF,Hong Kong(Grant Nos.:475012 and C5045-20 EF)HMRF,Hong Kong(Grant No.:03141386)+3 种基金ITF,Hong Kong(Grant No.:ITS/209/12)UGC Direct Grant 2011,2012,2021.032HKOG Trust Fund 2011,2014,2019the National Natural Science Foundation of China(Grant Nos.:81974225 and 82201823)。
文摘Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.
基金supported by the Faculty of Dentistry,University of Chile(Grant FIOUCH 23-02 to FEG)supported by a scholarship from the Chilean National Agency for Research and Development(ANID BECAS/DOCTORADO NACIONAL 21211505).
文摘Ferroptosis is implicated in the pathogenesis of numerous chronic-inflammatory diseases,yet its association with progressive periodontitis remains unexplored.To investigate the involvement and significance of ferroptosis in periodontitis progression,we assessed sixteen periodontitis-diagnosed patients.Disease progression was clinically monitored over twelve weeks via weekly clinical evaluations and gingival crevicular fluid(GCF)collection was performed for further analyses.Clinical metrics,proteomic data,in silico methods,and bioinformatics tools were combined to identify protein profiles linked to periodontitis progression and to explore their potential connection with ferroptosis.Subsequent western blot analyses validated key findings.Finally,a single-cell RNA sequencing(scRNA-seq)dataset(GSE164241)for gingival tissues was analyzed to elucidate cellular dynamics during periodontitis progression.Periodontitis progression was identified as occurring at a faster rate than traditionally thought.GCF samples from progressing and non-progressing periodontal sites showed quantitative and qualitatively distinct proteomic profiles.In addition,specific biological processes and molecular functions during progressive periodontitis were revealed and a set of hub proteins,including SNCA,CA1,HBB,SLC4A1,and ANK1 was strongly associated with the clinical progression status of periodontitis.Moreover,we found specific proteins-drivers or suppressors-associated with ferroptosis(SNCA,FTH1,HSPB1,CD44,and GCLC),revealing the co-occurrence of this specific type of regulated cell death during the clinical progression of periodontitis.Additionally,the integration of quantitative proteomic data with scRNA-seq analysis suggested the susceptibility of fibroblasts to ferroptosis.Our analyses reveal proteins and processes linked to ferroptosis for the first time in periodontal patients,which offer new insights into the molecular mechanisms of progressive periodontal disease.These findings may lead to novel diagnostic and therapeutic strategies.
基金Supported by The Swedish Research Council Medicine,No.3529The Swedish Cancer Society,No.961The Wallenberg Foundation
文摘Ribonucleotide reductase(RNR), the rate-limitingenzyme in DNA synthesis, catalyzes reduction of thedifferent ribonucleotides to their corresponding deoxyri-bonucleotides. The crucial role of RNR in DNA synthesishas made it an important target for the development ofantiviral and anticancer drugs. Taking account of the re-cent developments in this field of research, this reviewfocuses on the role of thioredoxin and glutaredoxin sys-tems in the redox reactions of the RNR catalysis.
基金supported by the National Natural Science Foundation of China(project No.81970029)Fundamental Research Funds for the Central Universities of China(The Emergency Projects on COVID-19,xzy032020042)Qinnong Bank-XJTU special project for COVID-19(qnxjtu-12)。
文摘Coronavirus disease 2019(COVID-19)has been a pandemic for more than a year.With the expanding second wave of the pandemic in winter,the continuous evolution of SARS-CoV-2 has brought new issues,including the significance of virus mutations in infection and the detection of asymptomatic infection.In this review,we first introduced several major SARS-CoV-2 mutations since the COVID-19 outbreak and then mentioned the widely used molecular detection techniques to diagnose COVID-19,primarily focusing on their strengths and limitations.We further discussed the effects of viral genetic variation and asymptomatic infection on the molecular detection of SARS-CoV-2 infection.The review finally summarized useful insights into the molecular diagnosis of COVID-19 under the special situation being challenged by virus mutation and asymptomatic infection.
文摘Dear Editor,We present the reported case of a 37-year-old male atypical Cogan’s syndrome(CS)patient who was precisely diagnosed and clinically cured under our systematic therapeutic regime.CS is a rare autoimmune disorder involving the eye,characterised by interstitial keratitis(IK)and the auditory-vestibulo system with vestibular dysfunction.
文摘Diabetic kidney disease(DKD)is one of the major chronic complications of diabetes mellitus(DM),as well as a main cause of end-stage renal disease.Over the last few years,substantial research studies have revealed a contributory role of gut microbiota in the process of DM and DKD.Metabolites of gut microbiota like lipopolysaccharide,short-chain fatty acids,and trimethylamine N-oxide are key mediators of microbial–host crosstalk.However,the underlying mechanisms of how gut microbiota influences the onset and progression of DKD are relatively unknown.Besides,strategies to remodel the composition of gut microbiota or to reduce the metabolites of microbiota have been found recently,representing a new potential remedial target for DKD.In this minireview,we will address the possible contribution of the gut microbiota in the pathogenesis of DKD and its role as a therapeutic target.
文摘Coronavirus disease 2019(COVID-19)has been associated with various liver injury cases worldwide.To date,the prevalence,mechanism,clinical manifestations,diagnosis,and outcomes of COVID-19-induced liver injury in various at-risk groups are not well defined.Liver injury may arise in the prevention and treatment of COVID-19 from direct causes such as viral infection and indirect causes such as systemic inflammation,hypoxic changes,and drugs that exacerbate any pre-existing liver disease.Studies have found that patients with underlying liver disease are at higher risk of COVID-19-induced liver injury.Certain condition of cardiopulmonary and metabolic diseases and vulnerable stages in lifespan may also involve in the development of COVID-19-induced liver injury.This review summarized studies of COVID-19-induced liver injury in different at-risk groups regarding their clinical characteristics,parameters,and correlations of the severity with these indicators and signs as well as potential treatment suggestions,to increase attention to physiological and pathological conditions and continue liver function monitoring as they can help in strengthening early supportive treatment and reducing the incidence of adverse outcomes.
文摘Plant 9-1ipoxygenases （9-LOX） and α-dioxygenases （α-DOX） initiate the synthesis of oxylipins after bacterial infection. Here, the role of these enzymes in plants＇ defense was investigated using individual Arabidopsis thaliana Ioxl and doxl mutants and a double Ioxl doxl mutant. Studies with Pseudomonas syringae pv. tomato （Pst） revealed the enhanced susceptibility of Ioxl to the virulent strain Pst DC3000 and the partial impairment of Ioxl and doxl mutants to activate systemic acquired resistance. Notably, both defects were enhanced in the Ioxl doxl plants as compared with individual mutants. We found that pre-treatment with 9-LOX- and α-DOX-generated oxylipins protected plant tissues against bacterial infection. The strongest effect in this respect was exerted by 9-ketooctadecatrienoic acid （9-KOT）, which is produced from linolenic acid by 9-LOX. Quantification of 9-KOT revealed its accumulation after bacterial infection. The levels were reduced in Ioxl and Ioxl doxl plants but strongly increased in the doxl mutant due to metabolic interaction of the two pathways. Transcriptional analyses indicated that 9-KOT pre-treatment modifies hormone homeostasis during bacterial infection. The nature of the changes detected suggested that 9-KOT interferes with the hormonal changes caused by bacterial effectors. This notion was substantiated by the finding that 9-KOT failed to reduce the growth of PstDC3OOOhrpA, a mutant compromised in effector secretion, and of the avirulent strain Pst DC3000 avrRpml. Further support for the action of the 9-LOX- and α-DOX-oxylipin pathways as modulators of hormone homeostasis was the ob- servation that Ioxl doxl seedlings are hypersensitive to the growth-inhibitory effect of ABA and showed enhanced ac- tivation of ABA-inducible marker genes as compared with wild-type plants.
文摘Most of the mitochondrial and chloroplastic proteins are synthesized in the cytosol as precursor proteins carrying an N-terminal targeting peptide （TP） directing them specifically to a correct organelle. However, there is a group of proteins that are dually targeted to mitochondria and chloroplasts using an ambiguous N-terminal dual targeting peptide （dTP）. Here, we have investigated pattern properties of import determinants of organelle-specific TPs and dTPs combining mathematical multivariate data analysis （MVDA） with in vitro organellar import studies. We have used large datasets of mitochondrial and chloroplastic proteins found in organellar proteomes as well as manually selected data sets of experimentally confirmed organelle-specific TPs and dTPs from Arabidopsis thaliana. Two classes of organelle-specific TPs could be distinguished by MVDA and potential patterns or periodicity in the amino acid sequence contributing to the separation were revealed, dTPs were found to have intermediate sequence features between the organelle-specific TPs. Interestingly, introducing positively charged residues to the dTPs showed clustering towards the mitochondrial TPs in silico and resulted in inhibition of chloroplast, but not mitochondrial import in in vitro organellar import studies. These findings suggest that positive charges in the N-terminal region of TPs may function as an ＇avoidance signal＇ for the chloroplast import.
基金the Swedish Research Council(Grant No.2009-4103)
文摘Proteome-wide Amino aCid and Elemental composition （PACE） analysis is a novel and informative way of interrogating the proteome. The PACE approach consists of in silico decompo- sition of proteins detected and quantified in a proteomics experiment into 20 amino acids and five elements （C, H, N, O and S）, with protein abundances converted to relative abundances of amino acids and elements. The method is robust and very sensitive; it provides statistically reliable differ- entiation between very similar proteomes. In addition, PACE provides novel insights into prote- ome-wide metabolic processes, occurring, e.g., during cell starvation. For instance, both Escherichia coli and Synechocystis down-regulate sulfur-rich proteins upon sulfur deprivation, but E. coli preferentially down-regulates cysteine-rich proteins while Synechocystis mainly down- regulates methionine-rich proteins. Due to its relative simplicity, flexibility, generality and wide applicability, PACE analysis has the potential of becoming a standard analytical tool in proteomics.
文摘Alport syndrome （AS） is a hereditary nephritis caused by mutations in COL4A3, COL4A4 or COL4A5 encod-ing the type IV collagen α3, α4, and α5 chains, which are major components of the glomerular basement membrane. About 20 years have passed since COL4A3, COL4A4, and COL4A5 were identifed and the frst Al-port mouse model was developed using a knockout ap-proach. The phenotype of Alport mice is similar to that of Alport patients, including characteristic thickening and splitting of the glomerular basement membrane. Alport mice have been widely used to study the patho-genesis of AS and to develop effective therapies. In this review, the newer therapies for AS, such as pharma-cological interventions, genetic approaches and stem cell therapies, are discussed. Although some stem cell therapies have been demonstrated to slow the renal disease progression in Alport mice, these therapies demand continual refnement as research advances. In terms of the pharmacological drugs, angiotensin-con-verting enzyme inhibitors have been shown to be effec-tive in Alport mice. Novel therapies that can provide a better outcome or lead to a cure are still awaited.
文摘In a recent publication in Nature,1 Zhang et al.have developed spatial ATAC-RNA-seq and spatial CUT&Tag-RNA-seq as innovative tools that enable the high-resolution mapping of epigenetic and transcriptomic features in cells from frozen tissue sections.By applying these techniques to mouse embryos and brains,the authors discovered unexpected interrelationships between epigenetic regulation and gene expression in various brain regions.
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This study was supported by the grants from the National Natural Science Foundation of China （No. 30770747）, the Beijing Municipal Natural Science Foundation （No. 7081002, No. 7042024） and the Capital Development Foundation of Beijing （No. 2003-2007）.
文摘Background Infantile spasms is a severe epileptic encephalopathy, which is refractory to conventional antiepileptic drugs. Adrenocorticotropic hormone （ACTH） has been the major therapy for infantile spasms; however, ACTH therapy is ineffective for some patients. The variations in the receptor genes can contribute to antiepileptic drug resistance. This study was to elucidate the possible associations between the variations of the MC2R gene and ACTH responsiveness in patients with infantile spasms. Methods We screened for variations in the promoter and coding region of the MC2R gene in 91 Chinese patients with infantile spasms and 94 controls, using PCR and a direct sequencing method. The frequencies of the genotypes, alleles and reconstructed haplotypes were analyzed in the cases and controls. The association between ACTH responsiveness and genetic variations of the MC2R gene was also assessed. Results Four single nucleotide polymorphisms （SNPs） were identified in the MC2R promoter, one of which was a novel specimen at position-2 from the transcription start site ATT, -2T〉C. Three SNPs （rs1893220, rs2186944 and -2T〉C） showed a significant difference between the cases and controls （P 〈0.05 for all）. The frequency of the common TCCT haplotype carrying four-SNP major alleles was significantly lower in the cases （39%） than in the controls （60%） （P=-0.00003）. The homozygous carriers of the TCCT haplotype had a much lower relative risk than the non-carriers （RR=O.42, 95%C/ 0.26-0.70, P=-0.0001）. ACTH responsiveness was strongly associated with the TCCT haplotype （P=-0.000082）. Compared with non-carriers of the TCCT haplotype, the homozygous and heterozygous carriers were more responsive to ACTH therapy （P=0.0002; P=-0.0003, respectively）. Conclusions Our results indicated that the TCCT haplotype in the MC2R promoter is strongly associated with the responsiveness of the ACTH therapy performed on patients with infantile spasms. The polymorphisms of the MC2R promoter might be one important factor that influences the efficacy of ACTH therapy on infantile spasms.
文摘Wnts are a highly conserved family of Upid-modified glycoproteins that work as morphogens to activate several signaling pathways, leading to remodeling of the cytoskeleton and the regulation of gene transcription. Wnt signaling regulates multiple cellular functions and cell systems, including the development and maintenance of midbrain dopaminergic （m DA） neurons. These neurons are of consid- erable interest for regenerative medicine because their degeneration results in Parkinson＇s disease （PD）. This review focuses on new advances in understanding key functions of Wnts in mDA neuron development and using novel tools to regulate Wnt signaling in re- generative medicine for PD. Particularly, recent reports indicate that appropriate levels of Wnt signaling are essential to improve the quantity and quality of stem ceil- or reprogrammed ceU-derived mDA neurons to be used in drug discovery and cell replacement therapy for PD.
文摘Backgrounds Common variable immunodeficiency(CVID),the most prevalent form of primary immunodeficiency(PID),is characterized by hypogammaglobulinemia and recurrent infections.Understanding protein-protein interaction(PPI)networks of CVID genes and identifying candidate CVID genes are critical steps in facilitating the early diagnosis of CVID.Here,the aim was to investigate PPI networks of CVID genes and identify candidate CVID genes using computation techniques.Methods:Network density and biological distance were used to study PPI data for CVID and PID genes obtained from the STRING database.Gene expression data of patients with CVID were obtained from the Gene Expression Omnibus,and then Pearson's correlation coefficient,a PPI database,and Kyoto Encyclopedia of Genes and Genomes were used to identify candidate CVID genes.We then evaluated our predictions and identified differentially expressed CVID genes.Results:The majority of CVID genes are characterized by a high network density and small biological distance,whereas most PID genes are characterized by a low network density and large biological distance,indicating that CVID genes are more functionally similar to each other and closely interact with one other compared with PID genes.Subsequently,we identified 172 CVID candidate genes that have similar biological functions to known CVID genes,and eight genes were recently reported as CVID-related genes.MYC,a candidate gene,was down-regulated in CVID duodenal biopsies,but up-regulated in blood samples compared with levels in healthy controls.Conclusion:Our findings will aid in a better understanding of the complex of CVID genes,possibly further facilitating the early diagnosis of CVID.
基金supported by the Swedish Research Council (Grant 2007-4410)
文摘Stable isotopes of most important biological elements, such as C, H, N and O, affect living organisms. In rapidly growing species, deuterium and to a lesser extent other heavy isotopes reduce the growth rate. At least for deuterium it is known that its depletion also negatively impacts the speed of biological processes. As a rule, living organisms ＂resist＂ changes in their isotopic environment, preferring natural isotopic abundances. This preference could be due to evolutionary optimization; an additional effect could be due to the presence of the ＂isotopic resonance＂. The isotopic resonance phenomenon has been linked to the choice of earliest amino acids, and thus af- fected the evolution of genetic code. To test the isotopic resonance hypothesis, literature data were analyzed against quantitative and qualitative predictions of the hypothesis. Four studies provided five independent datasets, each in very good quantitative agreement with the predictions. Thus, the isotopic resonance hypothesis is no longer simply plausible; it can now be deemed likely. Additional testing is needed, however, before full acceptance of this hypothesis.
基金supported by the National Natural Science Foundation of China(82003269,82173128,81803327,81930065,and 81903406)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-036)the Young Faculty Development Project of Sun Yat-sen University(84000-31660002).
文摘Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of the required sample size and loss of statistical power.Conversely,when there is actually no apparent delay in treatment effects,alternative trial designs for addressing DTE may lead to an over-estimation of sample size and unnecessary prolongation of the trial duration.To mitigate this challenge,we propose the use of a DTE predicting(DTEP)model to better guide immuno-oncology trial designs.Methods:The DTEP model was developed and validated using data from 147 pub-lished randomized immuno-oncology trials.The eligible trials were divided into a training set(approximately 75%of the trials)and a test set(approximately 25%).We employed linear discriminant analysis(LDA)to develop the DTEP model for pre-dicting the DTE status using baseline characteristics available at the trial design stage.The receiver operating characteristic(ROC)curve was utilized to assess the ability of the model to distinguish between trials with and without DTE.We further re-conducted the JUPITER-02 trial in a simulation setting,employing three design approaches to assess the potential benefits of utilizing the DTEP model.Results:Baseline characteristics available during the trial design stage,including cancer type,line of treatment,and experimental and control arm regimens were incorporated,and high accuracy in predicting the DTE status in both the training set(area under the operating characteristic curve(AUC),0.79;95%confidence interval(CI),0.71-0.88)and test set(AUC,0.78;95%CI,0.66-0.90)was achieved.Notably,the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team(ESCORT-1st(absence of DTE)and JUPITER-02(presence of DTE)).In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model.Conclusions:The DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs,thereby facilitating the discovery of effective im-munotherapeutics in a more streamlined and expedited manner.
