The gut microbiota is composed of approximately 10^(10)-10^(14) cells, including fungi,bacteria, archaea, protozoa, viruses, and bacteriophages; their genes and their various metabolites were found throughout the gast...The gut microbiota is composed of approximately 10^(10)-10^(14) cells, including fungi,bacteria, archaea, protozoa, viruses, and bacteriophages; their genes and their various metabolites were found throughout the gastrointestinal tract. It has co-evolved with each species to assist with day to day bodily functions, such as digestion,metabolism of xenobiotics, development of mucosal immunity and immunomodulation, and protection against invading pathogens. Because of the significant beneficial impact that gut microbiota may have, there is interest in learning more about it and translating these findings into clinical therapies. Results from recent studies characterizing the gut microbiota of various species have demonstrated the range of influences that may affect gut microbiota diversity, including animal strain, obesity, types of enrichment used, bedding and housing methods, treatment with antimicrobials,vendor source, specific animal housing, diet, and intercurrent disease. Relatively little is known about the functional consequences of alterations of the gut microbiota and exactly how changes in richness and diversity of the microbiota translate into changes in health and susceptibility to disease. Furthermore, questions have been raised as to whether germ-free or even ultraclean, barrier-raised mice are relevant models of human disease, given their significantly reduced gut microbiota diversity and complexity compared with conventionally housed mice. In addition, evidence suggests that the specific anatomical location selected for assessing the gut microbiota has a highly significant effect on study outcomes, in that bacterial phyla change significantly along the gastrointestinal tract. This paper will explore animal model reproducibility in light of this information about the gut microbiota.展开更多
Late-onset Alzheimer 's disease(LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older.LOAD is a neurodegenerative disorder characterized by progressive loss in synapti...Late-onset Alzheimer 's disease(LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older.LOAD is a neurodegenerative disorder characterized by progressive loss in synaptic function, notable bioenergetic decline, increased neuronal death and brain atrophy, and significant cognitive impairment.Because the etiology of LOAD remains unknown, a treatment for LOAD has not yet been formulated, a fact that is clearly demonstrated by the more than 200 failed clinical trials.展开更多
Background:The aim of the study was to demonstrate the efficacy of human muscle stem cells(MuSCs)isolated using innovative technology in restoring internal urinary sphincter function in a preclinical animal model.Meth...Background:The aim of the study was to demonstrate the efficacy of human muscle stem cells(MuSCs)isolated using innovative technology in restoring internal urinary sphincter function in a preclinical animal model.Methods:Colonies of pure human MuSCs were obtained from muscle biopsy speci-mens.Athymic rats were subjected to internal urethral sphincter damage by electro-cauterization.Five days after injury,2×105 muscle stem cells or medium as control were injected into the area of sphincter damage(n=5 in each group).Peak bladder pressure and rise in pressure were chosen as outcome measures.To repeatedly obtain the necessary pressure values,telemetry sensors had been implanted into the rat bladders 10 days prior to injury.Results:There was a highly significant improvement in the ability to build up peak pressure as well as a pressure rise in animals that had received muscle stem cells as compared to control(p=0.007)3 weeks after the cells had been injected.Only mini-mal histologic evidence of scarring was observed in treated rats.Conclusion:Primary human muscle stem cells obtained using innovative technology functionally restore internal urethral sphincter function after injury.Translation into use in clinical settings is foreseeable.展开更多
Background-Characteristics of individual calcified plaques, especially calcium concentration(CC), may provide incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events a...Background-Characteristics of individual calcified plaques, especially calcium concentration(CC), may provide incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and evaluation of therapeutic intervention. In this study, therefore, we assessed the characteristics of individual calcified plaques and their relationship to other parameters derived from CT analysis of coronary calcium in a community-based cross-sectional cohort. Methods and Results-Coronary artery calcium(CAC) was analyzed in 612 participants of the Framingham Heart Study(third-generation and offspring cohorts) using prospectively ECG-triggered multidetector CT.We determined the CC, Agatston score, calcified volume, and mineral mass of individual calcified plaques in each subject. Heterogeneity of CC was defined as the standard deviation of CC of all individual calcified plaques in a subject. CAC was detected in 274 of 605 subjects. After excluding 57 subjects(21%) because of motion artifacts, we identified a total of 956 calcified coronary plaques in 217 subjects(74 women, 143 men; mean age, 57.1±10.8 years) with detectable CAC and no image artifacts. CC of individual calcified plaques was independent of subject age(P=0.76) and sex(197.8±74.8 versus 183.6±52.8 mg/cm3 for men versus women; P=0.21). Among a subgroup of 125 subjects with multiple(≥3) individual calcified plaques, CC was heterogeneous within individual subjects(mean SD of CC, 43.6±23.1mg/cm3). The degree of heterogeneity of CC in these subjects was independent of age(P=0.60), sex(P=0.99), and number of plaques(P=0.06). Conclusions-The CC of individual calcified plaques is independent of age and sex but heterogeneous within a subject, which may reflect that the pathological process of calcified plaque formation and progression is the same in men and women regardless of age. CC may have incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and the evaluation of therapeutic intervention. Further studies are warranted to confirm that individual plaque analysis is preferable to global CAC scores to evaluate progression of atherosclerosis and to assess whether individual plaque analysis may be complementary to global CAC measures to assess coronary event risk.展开更多
A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse.Therapeutic options are currently being ex...A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse.Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease,including synthesis,chaperone-assisted folding and trafficking,and degradation via the proteasome and autophagy pathways.Other therapies,like mTOR inhibitors and activators of the heat shock response,can rebalance the entire proteostatic network.However,there are major challenges that impact the development of novel therapies,including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response.A notable development is the creation of collaborative ecosystems that include patients,clinicians,basic and translational researchers,foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent,reverse or delay the progression of neurodegenerative proteinopathies.展开更多
Magnesium metal(Mg)is a promising material for stent applications due to its biocompatibility and ability to be resorbed by the body.Manufacturing of stents by laser cutting has become an industry standard.Our alterna...Magnesium metal(Mg)is a promising material for stent applications due to its biocompatibility and ability to be resorbed by the body.Manufacturing of stents by laser cutting has become an industry standard.Our alternative approach uses photo-chemical etching to transfer a pattern of the stent onto a Mg sheet.In this study,we present three stages of creating and validating a stent prototype,which includes design and simulation using finite element analysis(FEA),followed by fabrication based on AZ31 alloy and,finally,in vivo testing in peripheral arteries of domestic pigs.Due to the preliminary character of this study,only six stents were implanted in two domestic farm pigs weighing 25-28 kg and they were evaluated after 28 days,with an interim follow-up on day 14.The left and right superficial femoral,the left iliac,and the right renal artery were selected for this study.The diameters of the stented artery segments were evaluated at the time of implantation,on day 14 and then,finally,on day 28,by quantitative vessel analysis(QVA)using fluoroscopic imaging.Optical Coherence Tomography(OCT)imaging displayed some malposition,breaks,stacking,and protrusion into the lumen at the proximal,distal,and mid-sections of the stented arteries.The stents degraded with time,but simultaneously became embedded in the intima.After 28 days,the animals were euthanized,and explanted vessels were fixed for micro-CT imaging and histology studies.Micro-CT imaging revealed stent morphological and volumetric changes due to the in-body degradation.An in vivo corrosion rate of 0.75 mm/year was obtained by the CT evaluation.The histology suggested no-life threatening effects,although moderate injury,inflammation,and endothelialization scores were observed.展开更多
文摘The gut microbiota is composed of approximately 10^(10)-10^(14) cells, including fungi,bacteria, archaea, protozoa, viruses, and bacteriophages; their genes and their various metabolites were found throughout the gastrointestinal tract. It has co-evolved with each species to assist with day to day bodily functions, such as digestion,metabolism of xenobiotics, development of mucosal immunity and immunomodulation, and protection against invading pathogens. Because of the significant beneficial impact that gut microbiota may have, there is interest in learning more about it and translating these findings into clinical therapies. Results from recent studies characterizing the gut microbiota of various species have demonstrated the range of influences that may affect gut microbiota diversity, including animal strain, obesity, types of enrichment used, bedding and housing methods, treatment with antimicrobials,vendor source, specific animal housing, diet, and intercurrent disease. Relatively little is known about the functional consequences of alterations of the gut microbiota and exactly how changes in richness and diversity of the microbiota translate into changes in health and susceptibility to disease. Furthermore, questions have been raised as to whether germ-free or even ultraclean, barrier-raised mice are relevant models of human disease, given their significantly reduced gut microbiota diversity and complexity compared with conventionally housed mice. In addition, evidence suggests that the specific anatomical location selected for assessing the gut microbiota has a highly significant effect on study outcomes, in that bacterial phyla change significantly along the gastrointestinal tract. This paper will explore animal model reproducibility in light of this information about the gut microbiota.
基金supported by the National Institutes of Health(NIHR21 AG055964, R21 AG059177, R01 AG061038 to LZ)。
文摘Late-onset Alzheimer 's disease(LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older.LOAD is a neurodegenerative disorder characterized by progressive loss in synaptic function, notable bioenergetic decline, increased neuronal death and brain atrophy, and significant cognitive impairment.Because the etiology of LOAD remains unknown, a treatment for LOAD has not yet been formulated, a fact that is clearly demonstrated by the more than 200 failed clinical trials.
基金SPARK-BIH Program,Berlin Institute of Health at Charité-Universitätsmedizin Berlin。
文摘Background:The aim of the study was to demonstrate the efficacy of human muscle stem cells(MuSCs)isolated using innovative technology in restoring internal urinary sphincter function in a preclinical animal model.Methods:Colonies of pure human MuSCs were obtained from muscle biopsy speci-mens.Athymic rats were subjected to internal urethral sphincter damage by electro-cauterization.Five days after injury,2×105 muscle stem cells or medium as control were injected into the area of sphincter damage(n=5 in each group).Peak bladder pressure and rise in pressure were chosen as outcome measures.To repeatedly obtain the necessary pressure values,telemetry sensors had been implanted into the rat bladders 10 days prior to injury.Results:There was a highly significant improvement in the ability to build up peak pressure as well as a pressure rise in animals that had received muscle stem cells as compared to control(p=0.007)3 weeks after the cells had been injected.Only mini-mal histologic evidence of scarring was observed in treated rats.Conclusion:Primary human muscle stem cells obtained using innovative technology functionally restore internal urethral sphincter function after injury.Translation into use in clinical settings is foreseeable.
文摘Background-Characteristics of individual calcified plaques, especially calcium concentration(CC), may provide incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and evaluation of therapeutic intervention. In this study, therefore, we assessed the characteristics of individual calcified plaques and their relationship to other parameters derived from CT analysis of coronary calcium in a community-based cross-sectional cohort. Methods and Results-Coronary artery calcium(CAC) was analyzed in 612 participants of the Framingham Heart Study(third-generation and offspring cohorts) using prospectively ECG-triggered multidetector CT.We determined the CC, Agatston score, calcified volume, and mineral mass of individual calcified plaques in each subject. Heterogeneity of CC was defined as the standard deviation of CC of all individual calcified plaques in a subject. CAC was detected in 274 of 605 subjects. After excluding 57 subjects(21%) because of motion artifacts, we identified a total of 956 calcified coronary plaques in 217 subjects(74 women, 143 men; mean age, 57.1±10.8 years) with detectable CAC and no image artifacts. CC of individual calcified plaques was independent of subject age(P=0.76) and sex(197.8±74.8 versus 183.6±52.8 mg/cm3 for men versus women; P=0.21). Among a subgroup of 125 subjects with multiple(≥3) individual calcified plaques, CC was heterogeneous within individual subjects(mean SD of CC, 43.6±23.1mg/cm3). The degree of heterogeneity of CC in these subjects was independent of age(P=0.60), sex(P=0.99), and number of plaques(P=0.06). Conclusions-The CC of individual calcified plaques is independent of age and sex but heterogeneous within a subject, which may reflect that the pathological process of calcified plaque formation and progression is the same in men and women regardless of age. CC may have incremental value to global calcium scores in the assessment of plaque burden and risk of coronary events and the evaluation of therapeutic intervention. Further studies are warranted to confirm that individual plaque analysis is preferable to global CAC scores to evaluate progression of atherosclerosis and to assess whether individual plaque analysis may be complementary to global CAC measures to assess coronary event risk.
文摘A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse.Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease,including synthesis,chaperone-assisted folding and trafficking,and degradation via the proteasome and autophagy pathways.Other therapies,like mTOR inhibitors and activators of the heat shock response,can rebalance the entire proteostatic network.However,there are major challenges that impact the development of novel therapies,including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response.A notable development is the creation of collaborative ecosystems that include patients,clinicians,basic and translational researchers,foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent,reverse or delay the progression of neurodegenerative proteinopathies.
基金The authors would like to acknowledge the financial support provided by the NSF ERC for Revolutionizing Biomaterials through grant EEC-EEC-0812348We would like to thank Dr.Sarah Pixley for helping us with the sample fixation for the micro-CT analysis and for proofreading the manuscriptThe help of Dr.Melodie Fickenscher with the SEM imaging and EDS analysis of the corroded stents is appreciated.
文摘Magnesium metal(Mg)is a promising material for stent applications due to its biocompatibility and ability to be resorbed by the body.Manufacturing of stents by laser cutting has become an industry standard.Our alternative approach uses photo-chemical etching to transfer a pattern of the stent onto a Mg sheet.In this study,we present three stages of creating and validating a stent prototype,which includes design and simulation using finite element analysis(FEA),followed by fabrication based on AZ31 alloy and,finally,in vivo testing in peripheral arteries of domestic pigs.Due to the preliminary character of this study,only six stents were implanted in two domestic farm pigs weighing 25-28 kg and they were evaluated after 28 days,with an interim follow-up on day 14.The left and right superficial femoral,the left iliac,and the right renal artery were selected for this study.The diameters of the stented artery segments were evaluated at the time of implantation,on day 14 and then,finally,on day 28,by quantitative vessel analysis(QVA)using fluoroscopic imaging.Optical Coherence Tomography(OCT)imaging displayed some malposition,breaks,stacking,and protrusion into the lumen at the proximal,distal,and mid-sections of the stented arteries.The stents degraded with time,but simultaneously became embedded in the intima.After 28 days,the animals were euthanized,and explanted vessels were fixed for micro-CT imaging and histology studies.Micro-CT imaging revealed stent morphological and volumetric changes due to the in-body degradation.An in vivo corrosion rate of 0.75 mm/year was obtained by the CT evaluation.The histology suggested no-life threatening effects,although moderate injury,inflammation,and endothelialization scores were observed.
