BACKGROUND Septic arthritis is an orthopedic emergency requiring immediate surgical intervention.Current diagnostic standard of care is an invasive joint aspiration.Aspirations provide information about the inflammato...BACKGROUND Septic arthritis is an orthopedic emergency requiring immediate surgical intervention.Current diagnostic standard of care is an invasive joint aspiration.Aspirations provide information about the inflammatory cells in the sample within a few hours,but there is often ambiguity about whether the source is infectious(e.g.bacterial)or non-infectious(e.g.gout).Cultures can take days to result,so decisions about surgery are often made with incomplete data.Novel diagnostics are thus needed.The“Sepsis MetaScore”(SMS)is an 11-mRNA host immune blood signature that can distinguish between infectious and noninfectious acute inflammation.It has been validated in multiple cohorts across heterogeneous clinical settings.AIM To study whether the SMS holds diagnostic validity in determining the etiology of acute arthritis.METHODS We conducted a blinded,prospective,non-interventional clinical study of the SMS.All patients undergoing work-up for a septic primary joint were enrolled.Patients proceeded through the normal standard-of-care pathway,including joint aspiration and inflammatory labs[white blood cell(WBC),erythrocyte sedimentation rate(ESR),C-reactive protein(CRP)].Venous blood was also drawn into PAX gene RNA-stabilizing tubes and mRNAs were measured using Nano String nCounter?.SMS was calculated blinded to clinical results.RESULTS A total of 20 samples were included,of which 11 were infected based on aspiration or intra-operative cultures.The SMS had an area under the ROC curve(AUROC)of 0.87 for separating infectious from non-infectious conditions.For comparison,the AUROCs for ESR=0.58,CRP=0.6,and WBC=0.59.At 100%sensitivity for infection,the specificity of the SMS was 40%,meaning nearly half of non-septic patients could have been ruled out for further intervention.CONCLUSION In this pilot study,SMS showed a high level of diagnostic accuracy in predicting septic joints compared to other diagnostic biomarkers.This quick blood test could be an important tool for early,accurate identification of acute septic joints and need for emergent surgery,improving clinical care and healthcare spending.展开更多
BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that protect cells against cellular stresses or injury.However,it has been increasingly recognized that they also play crucial roles in regulating fundament...BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that protect cells against cellular stresses or injury.However,it has been increasingly recognized that they also play crucial roles in regulating fundamental cellular processes.HSP20 has been implicated in cell proliferation,but conflicting studies have shown that it can either promote or suppress proliferation.The underlying mechanisms by which HSP20 regulates cell proliferation and pluripotency remain unexplored.While the effect of HSP20 on cell proliferation has been recognized,its role in inducing pluripotency in human-induced pluripotent stem cells(iPSCs)has not been addressed.AIM To evaluate the efficacy of HSP20 overexpression in human iPSCs and evaluate the ability to promote cell proliferation.The purpose of this study was to investigate whether overexpression of HSP20 in iPSCs can increase pluripotency and regeneration.METHODS We used iPSCs,which retain their potential for cell proliferation.HSP20 overexpression effectively enhanced cell proliferation and pluripotency.Overexpression of HSP20 in iPSCs was characterized by immunocytochemistry staining and realtime polymerase chain reaction.We also used cell culture,cell counting,western blotting,and flow cytometry analyses to validate HSP20 overexpression and its mechanism.RESULTS This study demonstrated that overexpression of HSP20 can increase the pluripotency in iPSCs.Furthermore,by overexpressing HSP20 in iPSCs,we showed that HSP20 upregulated proliferation markers,induced pluripotent genes,and drove cell proliferation in a sirtuin 1(SIRT1)-dependent manner.These data have practical applications in the field of stem cell-based therapies where the mass expansion of cells is needed to generate large quantities of stem cell-derived cells for transplantation purposes.CONCLUSION We found that the overexpression of HSP20 enhanced the proliferation of iPSCs in a SIRT1-dependent manner.Herein,we established the distinct crosstalk between HSP20 and SIRT1 in regulating cell proliferation and pluripotency.Our study provides novel insights into the mechanisms controlling cell proliferation that can potentially be exploited to improve the expansion and pluripotency of human iPSCs for cell transplantation therapies.These results suggest that iPSCs overexpressing HSP20 exert regenerative and proliferative effects and may have the potential to improve clinical outcomes.展开更多
Artificial intelligence(AI)refers to the simulation of human intelligence in machines programmed to convert raw input data into decision-making actions,like humans.AI programs are designed to make decisions,often usin...Artificial intelligence(AI)refers to the simulation of human intelligence in machines programmed to convert raw input data into decision-making actions,like humans.AI programs are designed to make decisions,often using deep learning and computer-guided programs that analyze and process raw data into clinical decision making for effective treatment.New techniques for predicting cancer at an early stage are needed as conventional methods have poor accuracy and are not applicable to personalized medicine.AI has the potential to use smart,intelligent computer systems for image interpretation and early diagnosis of cancer.AI has been changing almost all the areas of the medical field by integrating with new emerging technologies.AI has revolutionized the entire health care system through innovative digital diagnostics with greater precision and accuracy.AI is capable of detecting cancer at an early stage with accurate diagnosis and improved survival outcomes.AI is an innovative technology of the future that can be used for early prediction,diagnosis and treatment of cancer.展开更多
Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,effective vaccines are essential to control the current coronavirus disease 2019(COVID-19)pandemi...Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,effective vaccines are essential to control the current coronavirus disease 2019(COVID-19)pandemic.Plant-derived virus-like particle(VLP)vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza.Here,we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein(CoVLP)vaccine candidate formulated with or without Adjuvant System 03(AS03)or cytidine-phospho-guanosine(CpG)1018.Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses,booster immunization(at 28 days after priming)and adjuvant administration significantly improved both responses,with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP.Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2(IL-2)-driven response and IL-4 expression in CD4 T cells.Animals were challenged by multiple routes(i.e.,intratracheal,intranasal,and ocular)with a total viral dose of 106 plaque-forming units of SARS-CoV-2.Lower viral replication in nasal swabs and bronchoalveolar lavage fluid(BALF)as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03.No clinical,pathologic,or virologic evidence of vaccineassociated enhanced disease was observed in vaccinated animals.The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.展开更多
Introduction The human genome,comprising approximately 20,000 protein-encoding genes,appears surprisingly modest in complexity when juxtaposed with the genomic repertoire of maize,which boasts around 40,000 such genes...Introduction The human genome,comprising approximately 20,000 protein-encoding genes,appears surprisingly modest in complexity when juxtaposed with the genomic repertoire of maize,which boasts around 40,000 such genes(Ezkurdia et al.2014;Jiao et al.2017).While this comparison highlights the seemingly limited gene count in humans,it is crucial to recognize that a significant portion of our biological functionality extends beyond our own genome.展开更多
Protein microarrays based on fluorescence detection have been widely utilized for high-throughput functional proteomic analysis. However, a drawback of such assays has been low sensitivity and narrow dynamic range, li...Protein microarrays based on fluorescence detection have been widely utilized for high-throughput functional proteomic analysis. However, a drawback of such assays has been low sensitivity and narrow dynamic range, limiting their capabilities, especially for detecting low abundance biological molecules such as cytokines in human samples. Here, we present fluorescence-enhancing microarrays on plasmonic gold films for multiplexed cytokine detection with up to three orders of magnitude higher sensitivity than on conventional nitrocellulose and glass substrates. Cytokine detection on the gold plasmonic substrate is about one to two orders of magnitude more sensitive than enzyme-linked immunosorbent assay （ELISA） and can be multiplexed. A panel of six cytokines （Vascular endothelial growth factor （VEGF）, Interleukin 1β （IL-1β）, Interleukin 4 （IL-4）, Interleukin 6 （IL-6）, Interferon γ （IFN-γ）, and Tumor necrosis factor （TNF）） were detected in the culture media of cancer cells. This work establishes a new method of high throughput multiplexed cytokine detection with higher sensitivity and dynamic range than ELISA.展开更多
A recent outbreak of coronavirus disease 2019(COVID-19)caused by the single-stranded enveloped RNA virus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has developed into a global pandemic,after it was fir...A recent outbreak of coronavirus disease 2019(COVID-19)caused by the single-stranded enveloped RNA virus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has developed into a global pandemic,after it was first reported in Wuhan in December 2019.SARS-CoV-2 is an emerging virus,and little is known about the basic characteristics of this pathogen,the underlying mechanism of infection,and the potential treatments.The immune system has been known to be actively involved in viral infections.To facilitate the development of COVID-19 treatments,the understanding of immune regulation by this viral infection is urgently needed.This review describes the mechanisms of immune system involvement in viral infections and provides an overview of the dysregulation of immune responses in COVID-19 patients in recent studies.Furthermore,we emphasize the role of gut microbiota in regulating immunity and summarized the impact of SARS-CoV-2 infection on the composition of the microbiome.Overall,this review provides insights for understanding and developing preventive and therapeutic strategies by regulating the immune system and microbiota.展开更多
文摘BACKGROUND Septic arthritis is an orthopedic emergency requiring immediate surgical intervention.Current diagnostic standard of care is an invasive joint aspiration.Aspirations provide information about the inflammatory cells in the sample within a few hours,but there is often ambiguity about whether the source is infectious(e.g.bacterial)or non-infectious(e.g.gout).Cultures can take days to result,so decisions about surgery are often made with incomplete data.Novel diagnostics are thus needed.The“Sepsis MetaScore”(SMS)is an 11-mRNA host immune blood signature that can distinguish between infectious and noninfectious acute inflammation.It has been validated in multiple cohorts across heterogeneous clinical settings.AIM To study whether the SMS holds diagnostic validity in determining the etiology of acute arthritis.METHODS We conducted a blinded,prospective,non-interventional clinical study of the SMS.All patients undergoing work-up for a septic primary joint were enrolled.Patients proceeded through the normal standard-of-care pathway,including joint aspiration and inflammatory labs[white blood cell(WBC),erythrocyte sedimentation rate(ESR),C-reactive protein(CRP)].Venous blood was also drawn into PAX gene RNA-stabilizing tubes and mRNAs were measured using Nano String nCounter?.SMS was calculated blinded to clinical results.RESULTS A total of 20 samples were included,of which 11 were infected based on aspiration or intra-operative cultures.The SMS had an area under the ROC curve(AUROC)of 0.87 for separating infectious from non-infectious conditions.For comparison,the AUROCs for ESR=0.58,CRP=0.6,and WBC=0.59.At 100%sensitivity for infection,the specificity of the SMS was 40%,meaning nearly half of non-septic patients could have been ruled out for further intervention.CONCLUSION In this pilot study,SMS showed a high level of diagnostic accuracy in predicting septic joints compared to other diagnostic biomarkers.This quick blood test could be an important tool for early,accurate identification of acute septic joints and need for emergent surgery,improving clinical care and healthcare spending.
文摘BACKGROUND Heat shock proteins(HSPs)are molecular chaperones that protect cells against cellular stresses or injury.However,it has been increasingly recognized that they also play crucial roles in regulating fundamental cellular processes.HSP20 has been implicated in cell proliferation,but conflicting studies have shown that it can either promote or suppress proliferation.The underlying mechanisms by which HSP20 regulates cell proliferation and pluripotency remain unexplored.While the effect of HSP20 on cell proliferation has been recognized,its role in inducing pluripotency in human-induced pluripotent stem cells(iPSCs)has not been addressed.AIM To evaluate the efficacy of HSP20 overexpression in human iPSCs and evaluate the ability to promote cell proliferation.The purpose of this study was to investigate whether overexpression of HSP20 in iPSCs can increase pluripotency and regeneration.METHODS We used iPSCs,which retain their potential for cell proliferation.HSP20 overexpression effectively enhanced cell proliferation and pluripotency.Overexpression of HSP20 in iPSCs was characterized by immunocytochemistry staining and realtime polymerase chain reaction.We also used cell culture,cell counting,western blotting,and flow cytometry analyses to validate HSP20 overexpression and its mechanism.RESULTS This study demonstrated that overexpression of HSP20 can increase the pluripotency in iPSCs.Furthermore,by overexpressing HSP20 in iPSCs,we showed that HSP20 upregulated proliferation markers,induced pluripotent genes,and drove cell proliferation in a sirtuin 1(SIRT1)-dependent manner.These data have practical applications in the field of stem cell-based therapies where the mass expansion of cells is needed to generate large quantities of stem cell-derived cells for transplantation purposes.CONCLUSION We found that the overexpression of HSP20 enhanced the proliferation of iPSCs in a SIRT1-dependent manner.Herein,we established the distinct crosstalk between HSP20 and SIRT1 in regulating cell proliferation and pluripotency.Our study provides novel insights into the mechanisms controlling cell proliferation that can potentially be exploited to improve the expansion and pluripotency of human iPSCs for cell transplantation therapies.These results suggest that iPSCs overexpressing HSP20 exert regenerative and proliferative effects and may have the potential to improve clinical outcomes.
文摘Artificial intelligence(AI)refers to the simulation of human intelligence in machines programmed to convert raw input data into decision-making actions,like humans.AI programs are designed to make decisions,often using deep learning and computer-guided programs that analyze and process raw data into clinical decision making for effective treatment.New techniques for predicting cancer at an early stage are needed as conventional methods have poor accuracy and are not applicable to personalized medicine.AI has the potential to use smart,intelligent computer systems for image interpretation and early diagnosis of cancer.AI has been changing almost all the areas of the medical field by integrating with new emerging technologies.AI has revolutionized the entire health care system through innovative digital diagnostics with greater precision and accuracy.AI is capable of detecting cancer at an early stage with accurate diagnosis and improved survival outcomes.AI is an innovative technology of the future that can be used for early prediction,diagnosis and treatment of cancer.
基金sponsored by Medicago.Medicago Inc.received support for the CoVLP development program from the Federal Government on behalf of Her Majesty the Queen in right of Canada.
文摘Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,effective vaccines are essential to control the current coronavirus disease 2019(COVID-19)pandemic.Plant-derived virus-like particle(VLP)vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza.Here,we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein(CoVLP)vaccine candidate formulated with or without Adjuvant System 03(AS03)or cytidine-phospho-guanosine(CpG)1018.Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses,booster immunization(at 28 days after priming)and adjuvant administration significantly improved both responses,with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP.Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2(IL-2)-driven response and IL-4 expression in CD4 T cells.Animals were challenged by multiple routes(i.e.,intratracheal,intranasal,and ocular)with a total viral dose of 106 plaque-forming units of SARS-CoV-2.Lower viral replication in nasal swabs and bronchoalveolar lavage fluid(BALF)as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03.No clinical,pathologic,or virologic evidence of vaccineassociated enhanced disease was observed in vaccinated animals.The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.
基金funded by Innovative Medicines Accelerator(grant no.IMA-1051)Grant and Leona MHarry B.Helmsley Charitable Trust(grant no.G-2004-03820)+2 种基金M.M.D.is supported by the Howard Hughes Medical Institute,the Bill and Melinda Gates Foundation(51731)and grants from the US National Institutes of Health(NIHU19AI057229)X.Z.received fellowship support from NIH/NIA Resource Centers for Minority Aging Research grant P30AG059307.
文摘Introduction The human genome,comprising approximately 20,000 protein-encoding genes,appears surprisingly modest in complexity when juxtaposed with the genomic repertoire of maize,which boasts around 40,000 such genes(Ezkurdia et al.2014;Jiao et al.2017).While this comparison highlights the seemingly limited gene count in humans,it is crucial to recognize that a significant portion of our biological functionality extends beyond our own genome.
文摘Protein microarrays based on fluorescence detection have been widely utilized for high-throughput functional proteomic analysis. However, a drawback of such assays has been low sensitivity and narrow dynamic range, limiting their capabilities, especially for detecting low abundance biological molecules such as cytokines in human samples. Here, we present fluorescence-enhancing microarrays on plasmonic gold films for multiplexed cytokine detection with up to three orders of magnitude higher sensitivity than on conventional nitrocellulose and glass substrates. Cytokine detection on the gold plasmonic substrate is about one to two orders of magnitude more sensitive than enzyme-linked immunosorbent assay （ELISA） and can be multiplexed. A panel of six cytokines （Vascular endothelial growth factor （VEGF）, Interleukin 1β （IL-1β）, Interleukin 4 （IL-4）, Interleukin 6 （IL-6）, Interferon γ （IFN-γ）, and Tumor necrosis factor （TNF）） were detected in the culture media of cancer cells. This work establishes a new method of high throughput multiplexed cytokine detection with higher sensitivity and dynamic range than ELISA.
文摘A recent outbreak of coronavirus disease 2019(COVID-19)caused by the single-stranded enveloped RNA virus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has developed into a global pandemic,after it was first reported in Wuhan in December 2019.SARS-CoV-2 is an emerging virus,and little is known about the basic characteristics of this pathogen,the underlying mechanism of infection,and the potential treatments.The immune system has been known to be actively involved in viral infections.To facilitate the development of COVID-19 treatments,the understanding of immune regulation by this viral infection is urgently needed.This review describes the mechanisms of immune system involvement in viral infections and provides an overview of the dysregulation of immune responses in COVID-19 patients in recent studies.Furthermore,we emphasize the role of gut microbiota in regulating immunity and summarized the impact of SARS-CoV-2 infection on the composition of the microbiome.Overall,this review provides insights for understanding and developing preventive and therapeutic strategies by regulating the immune system and microbiota.
