Spinal cord injury(SCI) is a devastating traumatic injury that causes persistent, severe motor and sensory dysfunction. Immune responses are involved in functional recovery after SCI. Mucosa-associated lymphoid tissue...Spinal cord injury(SCI) is a devastating traumatic injury that causes persistent, severe motor and sensory dysfunction. Immune responses are involved in functional recovery after SCI. Mucosa-associated lymphoid tissue lymphoma translocation 1(MALT1) has been shown to regulate the survival and differentiation of immune cells and to play a critical role in many diseases, but its function in lesion recovery after SCI remains unclear. In this paper, we generated KI(knock in) mice with a point mutation(C472 G) in the active center of MALT1 and found that the KI mice exhibited improved functional recovery after SCI.Fewer macrophages were recruited to the injury site in KI mice and these macrophages differentiated into anti-inflammatory macrophages. Moreover, macrophages from KI mice exhibited reduced phosphorylation of p65, which in turn resulted in decreased SOCS3 expression and increased pSTAT6 levels.Similar results were obtained upon inhibition of MALT1 paracaspase with the small molecule inhibitor‘‘MI-2' or the more specific inhibitor ‘‘MLT-827'. In patients with SCI, peripheral blood mononuclear cells(PBMC) displayed increased MALT1 paracaspase. Human macrophages showed reduced proinflammatory and increased anti-inflammatory characteristics following the inhibition of MALT1 paracaspase. These findings suggest that inhibition of MALT1 paracaspase activity in the clinic may improve lesion recovery in subjects with SCI.展开更多
To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1(dominant variant identified in the current India outbreak)on the infectivity and ...To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1(dominant variant identified in the current India outbreak)on the infectivity and neutralization activities of the immune sera,L452R and E484Q(L452R-E484Q variant),pseudotyped virus was constructed(with the D614G background).The impact on binding with the neutralizing antibodies was also assessed with an ELISA assay.Pseudotyped virus carrying a L452R-E484Q variant showed a comparable infectivity compared with D614G.However,there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant receptor binding domain(RBD)protein,convalescent patients,and healthy vaccinees vaccinated with anmRNA vaccine.In addition,there was a reduction in binding of L452R-E484Q-D614G protein to the antibodies of theimmune sera fromvaccinated nonhuman primates.These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2.Reduced neutralization activities against the L452R-E484Q variant will have an impact on health authority planning and implications for the vaccination strategy/newvaccine development.展开更多
The high risk of postoperative mortality in lung adenocarcinoma(LUAD)patients is principally driven by cancer recurrence and low response rates to adjuvant treatment.Here,A combined cohort containing 1,026 stageⅠ-Ⅲp...The high risk of postoperative mortality in lung adenocarcinoma(LUAD)patients is principally driven by cancer recurrence and low response rates to adjuvant treatment.Here,A combined cohort containing 1,026 stageⅠ-Ⅲpatients was divided into the learning(n Z 678)and validation datasets(n Z 348).The former was used to establish a 16-mRNA risk signature for recurrence prediction with multiple statistical algorithms,which was verified in the valida-tion set.Univariate and multivariate analyses confirmed it as an independent indicator for both recurrence-free survival(RFS)and overall survival(OS).Distinct molecular characteristics between the two groups including genomic alterations,and hallmark pathways were compre-hensively analyzed.Remarkably,the classifier was tightly linked to immune infiltrations,high-lighting the critical role of immune surveillance in prolonging survival for LUAD.Moreover,the classifier was a valuable predictor for therapeutic responses in patients,and the low-risk group was more likely to yield clinical benefits from immunotherapy.A transcription factor regulato-ry proteineprotein interaction network(TF-PPI-network)was constructed via weighted gene co-expression network analysis(WGCNA)concerning the hub genes of the signature.The con-structed multidimensional nomogram dramatically increased the predictive accuracy.There-fore,our signature provides a forceful basis for individualized LUAD management with promising potential implications.展开更多
The high recurrence and low responsiveness to immunotherapy make ovarian cancer(OC)the most lethal gynecological malignancy.Tumor microenvironment is critical in risk stratification and the discovery of molecular targ...The high recurrence and low responsiveness to immunotherapy make ovarian cancer(OC)the most lethal gynecological malignancy.Tumor microenvironment is critical in risk stratification and the discovery of molecular targets.We developed a prognostic classification for OC,which could also predict the prognosis of other gynecological cancers including breast cancer,endometrial cancer,and cervical cancer.Somatic mutation,hallmark pathways,and immune landscapes were characterized.Integrative analysis of immune checkpoints and multiple immune signatures revealed the low-risk group responds better to immune checkpoint inhibitors,which was validated by an external immunotherapeutic cohort(IMvigor210).Singlecell RNA sequencing(scRNA-seq)confirmed the high expression of SERPINB1 and SERPINB9 in dendritic cells,and AlphaFold2 was used to infer their 3D protein structures.Putative molecular compounds binding to SERPINB1/SERPINB9 were predicted by virtual screening.展开更多
基金supported by the National Natural Science Foundation of China (31470872 to YG and 31400770 to ZY)the ‘‘111” project (B16021 to YG and ZY)+5 种基金the Science and Technology Program of Guangzhou (201604020162 to YG)Science & Technology Planning and Key Technology Innovation Projects of Guangdong (201803010001 to ZL)the National Natural Science Foundation of Guangdong (2018A030313576 to GS)Traditional Chinese Medicine Bureau of Guangdong (20181071 to JH)the National Natural Science Foundation of China (31800721 to QW)Medical and Health Development Plan of Shandong Province (2017WS446 to LZ)
文摘Spinal cord injury(SCI) is a devastating traumatic injury that causes persistent, severe motor and sensory dysfunction. Immune responses are involved in functional recovery after SCI. Mucosa-associated lymphoid tissue lymphoma translocation 1(MALT1) has been shown to regulate the survival and differentiation of immune cells and to play a critical role in many diseases, but its function in lesion recovery after SCI remains unclear. In this paper, we generated KI(knock in) mice with a point mutation(C472 G) in the active center of MALT1 and found that the KI mice exhibited improved functional recovery after SCI.Fewer macrophages were recruited to the injury site in KI mice and these macrophages differentiated into anti-inflammatory macrophages. Moreover, macrophages from KI mice exhibited reduced phosphorylation of p65, which in turn resulted in decreased SOCS3 expression and increased pSTAT6 levels.Similar results were obtained upon inhibition of MALT1 paracaspase with the small molecule inhibitor‘‘MI-2' or the more specific inhibitor ‘‘MLT-827'. In patients with SCI, peripheral blood mononuclear cells(PBMC) displayed increased MALT1 paracaspase. Human macrophages showed reduced proinflammatory and increased anti-inflammatory characteristics following the inhibition of MALT1 paracaspase. These findings suggest that inhibition of MALT1 paracaspase activity in the clinic may improve lesion recovery in subjects with SCI.
文摘To assess the impact of the key non-synonymous amino acid substitutions in the RBD of the spike protein of SARS-CoV-2 variant B.1.617.1(dominant variant identified in the current India outbreak)on the infectivity and neutralization activities of the immune sera,L452R and E484Q(L452R-E484Q variant),pseudotyped virus was constructed(with the D614G background).The impact on binding with the neutralizing antibodies was also assessed with an ELISA assay.Pseudotyped virus carrying a L452R-E484Q variant showed a comparable infectivity compared with D614G.However,there was a significant reduction in the neutralization activity of the immune sera from non-human primates vaccinated with a recombinant receptor binding domain(RBD)protein,convalescent patients,and healthy vaccinees vaccinated with anmRNA vaccine.In addition,there was a reduction in binding of L452R-E484Q-D614G protein to the antibodies of theimmune sera fromvaccinated nonhuman primates.These results highlight the interplay between infectivity and other biologic factors involved in the natural evolution of SARS-CoV-2.Reduced neutralization activities against the L452R-E484Q variant will have an impact on health authority planning and implications for the vaccination strategy/newvaccine development.
文摘The high risk of postoperative mortality in lung adenocarcinoma(LUAD)patients is principally driven by cancer recurrence and low response rates to adjuvant treatment.Here,A combined cohort containing 1,026 stageⅠ-Ⅲpatients was divided into the learning(n Z 678)and validation datasets(n Z 348).The former was used to establish a 16-mRNA risk signature for recurrence prediction with multiple statistical algorithms,which was verified in the valida-tion set.Univariate and multivariate analyses confirmed it as an independent indicator for both recurrence-free survival(RFS)and overall survival(OS).Distinct molecular characteristics between the two groups including genomic alterations,and hallmark pathways were compre-hensively analyzed.Remarkably,the classifier was tightly linked to immune infiltrations,high-lighting the critical role of immune surveillance in prolonging survival for LUAD.Moreover,the classifier was a valuable predictor for therapeutic responses in patients,and the low-risk group was more likely to yield clinical benefits from immunotherapy.A transcription factor regulato-ry proteineprotein interaction network(TF-PPI-network)was constructed via weighted gene co-expression network analysis(WGCNA)concerning the hub genes of the signature.The con-structed multidimensional nomogram dramatically increased the predictive accuracy.There-fore,our signature provides a forceful basis for individualized LUAD management with promising potential implications.
基金the China Postdoctoral Science Foundation(No.2022M720896).
文摘The high recurrence and low responsiveness to immunotherapy make ovarian cancer(OC)the most lethal gynecological malignancy.Tumor microenvironment is critical in risk stratification and the discovery of molecular targets.We developed a prognostic classification for OC,which could also predict the prognosis of other gynecological cancers including breast cancer,endometrial cancer,and cervical cancer.Somatic mutation,hallmark pathways,and immune landscapes were characterized.Integrative analysis of immune checkpoints and multiple immune signatures revealed the low-risk group responds better to immune checkpoint inhibitors,which was validated by an external immunotherapeutic cohort(IMvigor210).Singlecell RNA sequencing(scRNA-seq)confirmed the high expression of SERPINB1 and SERPINB9 in dendritic cells,and AlphaFold2 was used to infer their 3D protein structures.Putative molecular compounds binding to SERPINB1/SERPINB9 were predicted by virtual screening.
