The fluorescence properties of reduced nicotinamide adenine dinucleotide(NADH)and oxidizedflavoproteins(Fp)including flavin adenine dinucleotide(FAD)in the respiratory chain are sensitive indicators of intracellular m...The fluorescence properties of reduced nicotinamide adenine dinucleotide(NADH)and oxidizedflavoproteins(Fp)including flavin adenine dinucleotide(FAD)in the respiratory chain are sensitive indicators of intracellular metabolic states and have been applied to the studies of mitochondrial function with energy-linked processes.The redox scanner,a three-dimensional(3D)low temperature imager previously developed by Chance et al.,measures the in vivo metabolicproperties of tissue samples by acquiring fluorescence images of NADH and Fp.The redox ratios,i.e.Fp/(Fp+NADH)and NADH/(Fp+NADH),provided a sensitive index of the mitochondrialredox state and were determined based on relative signal intensity ratios.Here we report thefurther development of the redox scanning technique by using a calibration method to quantifythe nominal concentration of the fluorophores in tissues.The redox scanner exhibited very goodlinear response in the range of NADH concentration between 165–1318µM and Fp between90–720µM using snap-frozen solution standards.Tissue samples such as human tumor mousexenografts and various mouse organs were redox-scanned together with adjacent NADH and Fpstandards of known concentration at liquid nitrogen temperature.The nominal NADH and Fpconcentrations as well as the redox ratios in the tissue samples were quantified by normalizing the tissue NADH and Fp fluorescence signal to that of the snap-frozen solution standards.This calibration procedure allows comparing redox images obtained at different time,independent of instrument settings.The quantitative multi-slice redox images revealed heterogeneity inmitochondrial redox state in the tissues.展开更多
NAD+/NADH redox state has been implicated in many diseases such as cancer and diabetes aswell as in the regulation of embryonic development and aging,To fluorimetrically sssthemitochondrial redox state,Dr.Chance and c...NAD+/NADH redox state has been implicated in many diseases such as cancer and diabetes aswell as in the regulation of embryonic development and aging,To fluorimetrically sssthemitochondrial redox state,Dr.Chance and co-workers measured the fluorescence of NADH andoxidized flavoproteins(Fp)including favin-adenine-dinucleotide(FAD)and demonstrated theirratio(i.e.the redox ratio)is a sensitive indicator of the mitochondrial redox states.,The Chanceredox sca mer was built to simult aneously measure NADH and Fp in tisue at submilimeter scalein 3D using the freeze-trap protocol.This paper summarizes our recent research experience,development and new applications of the redox scanning technique in collaboration with Dr.Chance beginning in 2005.Dr.Chance initiated or actively involved in many of the projectsduring the last several years of his life.We advanced the redox scanning technigue by measuringthe nominal concentrations(in reference to the frozen solution standards)of the endogenousfuorescent analy tes,i.e.,[NADH]and[rp]to quantify the redox ratios in various biologicaltissues.The advancement has enabled us to identify an array of the redox indices as quantitativeimaging,biomarkers(including[NADH],[Fp],[Fp]/[NADH]+[Fp],[NADH]/[Fp],and theirstandard deviations)for studying some important biological questions on cancer and normaltsue metabolism.We found that the redox indices were asociated or changed with(NADH)tumorigenesis(cancer versus non-cancer of human breast tisue biopsies);(2)tumor metastaticpotential;(3)tumor glucose uptake;(4)tumor p53 stat us;(5)PI3K pathway activation in pre-malignant tissue;(6)therapeutic ffects on tumors;(7)embryonic stem cell diferentiation;(8)the heart under fasting,Together,our work demonstrated that the tisue redox indices obtainedfrom the redox scanning technique may provide usefil information about tisue met abolism and physiology status in normal and diseased tissues.The Chance redox scanner and other redoximaging techniques may have wide-ranging potential applications in many fields,such as cancer,diabetes,developmental process,mitochondrial diseases,neurodegenerative diseases,and aging.展开更多
Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer.The redox scanning method developed at ...Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer.The redox scanning method developed at the Chance laboratory about 30 years ago has allowed 3D highresolution(∼50×50×10µm^(3))imaging of mitochondrial redox state in tissue on the basis of the fluorescence of NADH(reduced nicotinamide adenine dinucleotide)and Fp(oxidized flavoproteins including flavin adenine dinucleotide,i.e.,FAD).In this review,we illustrate its basic principles,recent technical developments,and biomedical applications to cancer diagnostic and therapeutic studies in small animal models.Recently developed calibration procedures for the redox imaging using reference standards allow quantification of nominal NADH and Fp concentrations,and the concentration-based redox ratios,e.g.,Fp/(Fp+NADH)and NADH/(Fp+NADH)in tissues.This calibration facilitates the comparison of redox imaging results acquired for different metabolic states at different times and/or with different instrumental settings.A redox imager using a CCD detector has been developed to acquire 3D images faster and with a higher in-plane resolution down to 10µm.Ex vivo imaging and in vivo imaging of tissue mitochondrial redox status have been demonstrated with the CCD imager.Applications of tissue redox imaging in small animal cancer models include metabolic imaging of glioma and myc-induced mouse mammary tumors,predicting the metastatic potentials of human melanoma and breast cancer mouse xenografts,differentiating precancerous and normal tissues,and monitoring the tumor treatment response to photodynamic therapy.Possible future directions for the development of redox imaging are also discussed.展开更多
The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported.Nor has how p53 regulates mitochondial respi ration been measured at(deep)tissue level,presumably d...The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported.Nor has how p53 regulates mitochondial respi ration been measured at(deep)tissue level,presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration depth.Our prior work demonstrated that the mito-chondrial redox state and its intnatumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models,with the more metastatic tumons exhi-bit ing localized negions of more oxidized redox state.Using the Chance redox scanner with an in-plane spatial resolution of 200 pm,we imaged the mitochondrial redox state of the wild-type p53 colon tumors(HCT116 p53 ut)and the p5-deleted colon tumors(HCT116 p53-/-)by cllcting the fuorescence si gnals of nicotinamide adenine dimucleotide(NA DH)and oxidized flavoproteins [Fp,including favin adenine dinucleotide(FAD)]from the mouse xenogmafts snap frozen at low temperature.Our results show that:(1)both tumor lines have significant degree of intratumor heterogeneity of the redox state,typically exhibiting a distinct bi modal distribution that either correlates with the spatial core-rim pattern or the“hot/oold”oxida tion-roduction patches;.(2)the p531-group is significantly more beterogencous in the mitochondrial redox state and has a more oxidized turmor core compared to the p53 wt group when the tunor sizes of the two groups are matched;(3)the tumor size dependence of the redox indices(such as Fp and Fp redox ratio)is significant in the p531-group with the larger ones being more oxidized and more hetero-geneous in their redox state,particularly more oxidized in the tumor central regions;(4)the H&E staining images of tumor soctions grossly correlate with the redox images.The present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattem of the mitochon-drial redox state in colon cancer and the first to indicate that at tissue level the mitochondial redox state is p53 dependent.The findings should assist in our understanding on colon cancer pa thology and developing new imaging biomarkers for dlinical applications.展开更多
Britton Chance:One of the Most Outstanding Scientists in the World On June 3rd and 4th,2011,over 300 scientists and professionals from all over the world gathered at the Translational Research Center of the University...Britton Chance:One of the Most Outstanding Scientists in the World On June 3rd and 4th,2011,over 300 scientists and professionals from all over the world gathered at the Translational Research Center of the University of Pennsylvania to attend a memorial symposium on\Britton Chance:His Life,Times and Legacy"and a\Molecular Spectroscopy/Imaging Workshop:from bench top to bedside"dedicated to Britton Chance as well.展开更多
I had been closely working with Dr.Britton Chance from 2005-2010 on imaging mitochondrial redox state in cancer and stem cells.I had also learned much from him in daily work and personal life.Here I would like to shar...I had been closely working with Dr.Britton Chance from 2005-2010 on imaging mitochondrial redox state in cancer and stem cells.I had also learned much from him in daily work and personal life.Here I would like to share some of my memories and experiences including(1)Great science is not necessarily done with top-grade expensive instruments;(2)Brit was genuinely interested in and dedicated to science;(3)Brit's attention to detail and timely action;(4)Brit's open-mindedness;and(5)Brit being modest,appreciative,and caring for others.展开更多
The heart requires continuous ATP availability that is generated in the mitochondria.Althoughstudies using the cell culture and perfiused organ models have been carried out to investigate thebiochemistry in the mitoch...The heart requires continuous ATP availability that is generated in the mitochondria.Althoughstudies using the cell culture and perfiused organ models have been carried out to investigate thebiochemistry in the mitochondria in response to a change in substrate supply,mitochondrialbioenergetics of heart under normal feed or fasting conditions has not been studied at the tissuelevel with a sub-millimeter spatial resolution either in vivo or er vivo.Oxidation of many food-derived metabolites to generate ATP in the mitochondria is realized through the NADH/NAD+couple acting as a central electron carrier.We employed the Chance redox scanner thelow-temperat ure fluorescence scanner to image the three-dimensional(3D)spatial distribution of themitochondrial redox states in heart tissues of rats under normai feeding or an overnight star-vation for 14.5 h.Multiple consecutive sections of each heart were imaged to map three redoxindices,i.e,NADH,oxidized favoproteins Fp,including flavin adenine dinucleotide(FAD)andthe redox ratio NADH/Fp.The imaging results revealed the micro-heterogeneity and the spatial distribution of these redox indices.The quantitative analysis showed that in the fasted hearts thestandard deviation of both NADH and Fp,ie.,SD NADH and SDFp,significantly decreasedwith a p value of 0.032 and 0.045,respectively,indicating that the hearts become relatively morehomogeneous after fasting.The fasted hearts contained 28.6%less NADH(p=0.038).No sig.nificant change in Fp was foumnd(p=0.4).The NADH/Fp ratio decreased with a marginalP value(0.076).The decreased NADH im the fasted hearts is consistent with the cardiac celsreliance of fatty acids consumption for energy metabolism when glucose becomes scarce.Theexperimental o bservation of N ADH decrease induced by dietary restriction in the heart at tissuelevel has not been reported to our best knowledge.The Chance redox scanner demonstrated thefeasibility of 3D imaging of the mitochondrial redox st ate in the heart and provides a usefil toolto study heart metabolism and fiunction under normal,dietary-change and pathological con-ditions at tisue level. We would like to thank Dr.Joseph Baur for thehelpful discussion and Dr.Hui Qiao for animalpreparation and organ harvesting.展开更多
Redox state mediates embryonic stem cell(ESC)differentiation and thus offers an important complementary approach to understanding the pluripotency of stem cells.NADH redox ratio(NADH/(Fp t NADH)),where NADH is the red...Redox state mediates embryonic stem cell(ESC)differentiation and thus offers an important complementary approach to understanding the pluripotency of stem cells.NADH redox ratio(NADH/(Fp t NADH)),where NADH is the reduced form of nicotinamide adenine dinucleotide and Fp is the oxidizedflavoproteins,has been established as a sensitive indicator of mitochondrial redox state.In this paper,we report our redox imaging data on the mitochondrial redox state of mouse ESC(mESC)colonies and the implications thereof.The low-temperature NADH/Fp redox scanner was employed to image mESC colonies grown on a feeder layer of gamma-irradiated mouse embryonicfibroblasts(MEFs)on glass cover slips.The result showed significant heterogeneity in the mitochondrial redox state within individual mESC colonies(size:~200-440μm),exhibiting a core with a more reduced state than the periphery.This more reduced state positively correlates with the expression pattern of Oct4,a well-established marker of pluripotency.Our observation is thefirst to show the heterogeneity in the mitochondrial redox state within a mESC colony,suggesting that mitochondrial redox state should be further investigated as a potential new biomarker for the stemness of embryonic stem cells.展开更多
We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival.The redox state can be imaged by the redox scanner that collects t...We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival.The redox state can be imaged by the redox scanner that collects the fuorescence signals from both the oxidized-fAavoproteins(Fp)and the reduced form of nicotinamide adenine dinucleotide(NADH)in snap frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses.Here,with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B.cell lymphoma cell line(DLCL2).The mice were treated with CHOP therapy,i.e,cyclophosphamide(C)+hydroxydoxorubicin(H)+Oncovin(O)+prednisone(P)with CHO administration on day 1 and prednisone administration on days 1-5.The Fp content of the treated group was significantly decreased(p=0.033)on day 5,and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group(p=0.048).The decrease of the Fp heterogeneity(measured by the mean st andard deviation)had a border-line statistical significance(p=0.071).The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.展开更多
Britton Chance was a pioneer in many scientifc fields such as enzymatic reaction kinetis,bioenergetics,metabolism,in vivo NMr,and biophotonics.As an engineer,physical chemist,physicist,physiologist,biophysicist,bioche...Britton Chance was a pioneer in many scientifc fields such as enzymatic reaction kinetis,bioenergetics,metabolism,in vivo NMr,and biophotonics.As an engineer,physical chemist,physicist,physiologist,biophysicist,biochemist,innovator and educator,he had worked indiversifed fields over extended periods bet ween 1926 until his death in 2010,at the age of 97.Inorder to illustrate his scientific career and great impact on research from a new perspective,weemploy scientometric analysis tools to analyze the publications of Britton Chance with datadownloaded from the ISI Citation Indexes in April 2013.We included articles,reviews andproceding papers but excluded meeting abstracts.In total,we obtained 1023 publication recordswith 1236 authors in 266 joumals with 17,114 citations from 1945 to 2013.We show the annualpublications and citations that Britton Chance received from 1945 to 2013,and generate HistCitemaps on the basis of the global citations(GCS)and local(sel)citations(LCS)to show thecitation relationships among the top-30 publications of Britton Chance.Metabolism and the development of physical methods to probe it appear to be the commecting thread of the lifelongresearch of Britton Chance.Furthermore,we generate the joumal map and co-authorship maptoshow the broad scope of research topics and collaborators and the high impacts of the scientificoeuvre of Britton Chance ranging from physics,engineering,chemistry and biology to medicine.展开更多
Background： Despite the rapid growth in the incidence of acute myocardial infarction （AMI） in China, there is limited information about patients＇ experiences after AMI hospitalization, especially on long-tern1 adv...Background： Despite the rapid growth in the incidence of acute myocardial infarction （AMI） in China, there is limited information about patients＇ experiences after AMI hospitalization, especially on long-tern1 adverse events and patient-reported outcomes （PROs）. Methods： The China Patient-centered Evaluative Assessment of Cardiac Events （PEACE）-Prospective AMI Study will enroll 4000 consecutive AM I patients from 53 diverse hospitals across China and follow them longitudinally for 12 months to docunlent their treatment, recovery, and outcomes. Details of patients＇ medical history, treatment, and in-hospital outcomes are abstracted from medical charts. Comprehensive baseline interviews are being conducted to characterize patient demographics, risk factors, presentation, and healthcare utilization. As part of these interviews, validated instruments are administered to measure PROs, including quality of life, symptoms, mood, cognition, and sexual activity. Follow-up interviews, measuring PROs, medication adherence, risk factor control, and collecting hospitalization events are conducted at 1, 6, and 12 months after discharge. Supporting documents for potential outcomes are collected for adjudication by clinicians at the National Coordinating Center. Blood and urine samples are also obtained at baseline, 1 - and 12-month follow-up. In addition, we are conducting a survey of participating hospitals to characterize their organizational characteristics. Conclusion： The China PEACE-Prospective AMI study will be uniquely positioned to generate new information regarding patient＇s experiences and outcomes alter AMI in China and seiwe as a foundation for quality improveinent activities.展开更多
基金the Susan G.Komen Foundation Grant KG081069(PI:L.Z.Li)an NIH supported research resource(P41-RR02305,PI:R.Reddy)+1 种基金the Network of Translational Research in Optical Imaging(NTROI)at the University of Pennsylvania(U54 CA105008,PI:W.S.El-Deiry)an NIH Grant UO1-CA105490(PI:L.A.Chodosh).
文摘The fluorescence properties of reduced nicotinamide adenine dinucleotide(NADH)and oxidizedflavoproteins(Fp)including flavin adenine dinucleotide(FAD)in the respiratory chain are sensitive indicators of intracellular metabolic states and have been applied to the studies of mitochondrial function with energy-linked processes.The redox scanner,a three-dimensional(3D)low temperature imager previously developed by Chance et al.,measures the in vivo metabolicproperties of tissue samples by acquiring fluorescence images of NADH and Fp.The redox ratios,i.e.Fp/(Fp+NADH)and NADH/(Fp+NADH),provided a sensitive index of the mitochondrialredox state and were determined based on relative signal intensity ratios.Here we report thefurther development of the redox scanning technique by using a calibration method to quantifythe nominal concentration of the fluorophores in tissues.The redox scanner exhibited very goodlinear response in the range of NADH concentration between 165–1318µM and Fp between90–720µM using snap-frozen solution standards.Tissue samples such as human tumor mousexenografts and various mouse organs were redox-scanned together with adjacent NADH and Fpstandards of known concentration at liquid nitrogen temperature.The nominal NADH and Fpconcentrations as well as the redox ratios in the tissue samples were quantified by normalizing the tissue NADH and Fp fluorescence signal to that of the snap-frozen solution standards.This calibration procedure allows comparing redox images obtained at different time,independent of instrument settings.The quantitative multi-slice redox images revealed heterogeneity inmitochondrial redox state in the tissues.
基金made possible by the financial support of National Institute of Health(R01 CA155348(L.Z.Li))。
文摘NAD+/NADH redox state has been implicated in many diseases such as cancer and diabetes aswell as in the regulation of embryonic development and aging,To fluorimetrically sssthemitochondrial redox state,Dr.Chance and co-workers measured the fluorescence of NADH andoxidized flavoproteins(Fp)including favin-adenine-dinucleotide(FAD)and demonstrated theirratio(i.e.the redox ratio)is a sensitive indicator of the mitochondrial redox states.,The Chanceredox sca mer was built to simult aneously measure NADH and Fp in tisue at submilimeter scalein 3D using the freeze-trap protocol.This paper summarizes our recent research experience,development and new applications of the redox scanning technique in collaboration with Dr.Chance beginning in 2005.Dr.Chance initiated or actively involved in many of the projectsduring the last several years of his life.We advanced the redox scanning technigue by measuringthe nominal concentrations(in reference to the frozen solution standards)of the endogenousfuorescent analy tes,i.e.,[NADH]and[rp]to quantify the redox ratios in various biologicaltissues.The advancement has enabled us to identify an array of the redox indices as quantitativeimaging,biomarkers(including[NADH],[Fp],[Fp]/[NADH]+[Fp],[NADH]/[Fp],and theirstandard deviations)for studying some important biological questions on cancer and normaltsue metabolism.We found that the redox indices were asociated or changed with(NADH)tumorigenesis(cancer versus non-cancer of human breast tisue biopsies);(2)tumor metastaticpotential;(3)tumor glucose uptake;(4)tumor p53 stat us;(5)PI3K pathway activation in pre-malignant tissue;(6)therapeutic ffects on tumors;(7)embryonic stem cell diferentiation;(8)the heart under fasting,Together,our work demonstrated that the tisue redox indices obtainedfrom the redox scanning technique may provide usefil information about tisue met abolism and physiology status in normal and diseased tissues.The Chance redox scanner and other redoximaging techniques may have wide-ranging potential applications in many fields,such as cancer,diabetes,developmental process,mitochondrial diseases,neurodegenerative diseases,and aging.
基金the Susan G.Komen Foundation Grant KG081069(PI:L.Z.Li)The Center for Magnietic Resonance and Optical Imaging,and an NIH supported research resource(P41-RR02305,PI:R.Reddy).
文摘Mitochondrial redox states provide important information about energy-linked biological processes and signaling events in tissues for various disease phenotypes including cancer.The redox scanning method developed at the Chance laboratory about 30 years ago has allowed 3D highresolution(∼50×50×10µm^(3))imaging of mitochondrial redox state in tissue on the basis of the fluorescence of NADH(reduced nicotinamide adenine dinucleotide)and Fp(oxidized flavoproteins including flavin adenine dinucleotide,i.e.,FAD).In this review,we illustrate its basic principles,recent technical developments,and biomedical applications to cancer diagnostic and therapeutic studies in small animal models.Recently developed calibration procedures for the redox imaging using reference standards allow quantification of nominal NADH and Fp concentrations,and the concentration-based redox ratios,e.g.,Fp/(Fp+NADH)and NADH/(Fp+NADH)in tissues.This calibration facilitates the comparison of redox imaging results acquired for different metabolic states at different times and/or with different instrumental settings.A redox imager using a CCD detector has been developed to acquire 3D images faster and with a higher in-plane resolution down to 10µm.Ex vivo imaging and in vivo imaging of tissue mitochondrial redox status have been demonstrated with the CCD imager.Applications of tissue redox imaging in small animal cancer models include metabolic imaging of glioma and myc-induced mouse mammary tumors,predicting the metastatic potentials of human melanoma and breast cancer mouse xenografts,differentiating precancerous and normal tissues,and monitoring the tumor treatment response to photodynamic therapy.Possible future directions for the development of redox imaging are also discussed.
基金supported by the Center of Magnetic Resonance and Optical Imaging(CMROI)-an NIH supported research resource P41 RR02305(R.Reddy)the Small Animal Imaging Resources Program 2U24-CA083105(J.D.Glickson and L.Chodosh).
文摘The mitochondrial redox state and its heterogeneity of colon cancer at tissue level have not been previously reported.Nor has how p53 regulates mitochondial respi ration been measured at(deep)tissue level,presumably due to the unavailability of the technology that has sufficient spatial resolution and tissue penetration depth.Our prior work demonstrated that the mito-chondrial redox state and its intnatumor heterogeneity is associated with cancer aggressiveness in human melanoma and breast cancer in mouse models,with the more metastatic tumons exhi-bit ing localized negions of more oxidized redox state.Using the Chance redox scanner with an in-plane spatial resolution of 200 pm,we imaged the mitochondrial redox state of the wild-type p53 colon tumors(HCT116 p53 ut)and the p5-deleted colon tumors(HCT116 p53-/-)by cllcting the fuorescence si gnals of nicotinamide adenine dimucleotide(NA DH)and oxidized flavoproteins [Fp,including favin adenine dinucleotide(FAD)]from the mouse xenogmafts snap frozen at low temperature.Our results show that:(1)both tumor lines have significant degree of intratumor heterogeneity of the redox state,typically exhibiting a distinct bi modal distribution that either correlates with the spatial core-rim pattern or the“hot/oold”oxida tion-roduction patches;.(2)the p531-group is significantly more beterogencous in the mitochondrial redox state and has a more oxidized turmor core compared to the p53 wt group when the tunor sizes of the two groups are matched;(3)the tumor size dependence of the redox indices(such as Fp and Fp redox ratio)is significant in the p531-group with the larger ones being more oxidized and more hetero-geneous in their redox state,particularly more oxidized in the tumor central regions;(4)the H&E staining images of tumor soctions grossly correlate with the redox images.The present work is the first to reveal at the submillimeter scale the intratumor heterogeneity pattem of the mitochon-drial redox state in colon cancer and the first to indicate that at tissue level the mitochondial redox state is p53 dependent.The findings should assist in our understanding on colon cancer pa thology and developing new imaging biomarkers for dlinical applications.
文摘Britton Chance:One of the Most Outstanding Scientists in the World On June 3rd and 4th,2011,over 300 scientists and professionals from all over the world gathered at the Translational Research Center of the University of Pennsylvania to attend a memorial symposium on\Britton Chance:His Life,Times and Legacy"and a\Molecular Spectroscopy/Imaging Workshop:from bench top to bedside"dedicated to Britton Chance as well.
文摘I had been closely working with Dr.Britton Chance from 2005-2010 on imaging mitochondrial redox state in cancer and stem cells.I had also learned much from him in daily work and personal life.Here I would like to share some of my memories and experiences including(1)Great science is not necessarily done with top-grade expensive instruments;(2)Brit was genuinely interested in and dedicated to science;(3)Brit's attention to detail and timely action;(4)Brit's open-mindedness;and(5)Brit being modest,appreciative,and caring for others.
基金supported by the Center of Magnetic Resonance and Optical Imaging(CMROn)--an NIH supported research resource P41RR02305(R.Reddy)。
文摘The heart requires continuous ATP availability that is generated in the mitochondria.Althoughstudies using the cell culture and perfiused organ models have been carried out to investigate thebiochemistry in the mitochondria in response to a change in substrate supply,mitochondrialbioenergetics of heart under normal feed or fasting conditions has not been studied at the tissuelevel with a sub-millimeter spatial resolution either in vivo or er vivo.Oxidation of many food-derived metabolites to generate ATP in the mitochondria is realized through the NADH/NAD+couple acting as a central electron carrier.We employed the Chance redox scanner thelow-temperat ure fluorescence scanner to image the three-dimensional(3D)spatial distribution of themitochondrial redox states in heart tissues of rats under normai feeding or an overnight star-vation for 14.5 h.Multiple consecutive sections of each heart were imaged to map three redoxindices,i.e,NADH,oxidized favoproteins Fp,including flavin adenine dinucleotide(FAD)andthe redox ratio NADH/Fp.The imaging results revealed the micro-heterogeneity and the spatial distribution of these redox indices.The quantitative analysis showed that in the fasted hearts thestandard deviation of both NADH and Fp,ie.,SD NADH and SDFp,significantly decreasedwith a p value of 0.032 and 0.045,respectively,indicating that the hearts become relatively morehomogeneous after fasting.The fasted hearts contained 28.6%less NADH(p=0.038).No sig.nificant change in Fp was foumnd(p=0.4).The NADH/Fp ratio decreased with a marginalP value(0.076).The decreased NADH im the fasted hearts is consistent with the cardiac celsreliance of fatty acids consumption for energy metabolism when glucose becomes scarce.Theexperimental o bservation of N ADH decrease induced by dietary restriction in the heart at tissuelevel has not been reported to our best knowledge.The Chance redox scanner demonstrated thefeasibility of 3D imaging of the mitochondrial redox st ate in the heart and provides a usefil toolto study heart metabolism and fiunction under normal,dietary-change and pathological con-ditions at tisue level. We would like to thank Dr.Joseph Baur for thehelpful discussion and Dr.Hui Qiao for animalpreparation and organ harvesting.
基金provided by the Institute for Regenerative Medicine at University of Pennsylvania with an IRM pilot grant(L.Z.Li).
文摘Redox state mediates embryonic stem cell(ESC)differentiation and thus offers an important complementary approach to understanding the pluripotency of stem cells.NADH redox ratio(NADH/(Fp t NADH)),where NADH is the reduced form of nicotinamide adenine dinucleotide and Fp is the oxidizedflavoproteins,has been established as a sensitive indicator of mitochondrial redox state.In this paper,we report our redox imaging data on the mitochondrial redox state of mouse ESC(mESC)colonies and the implications thereof.The low-temperature NADH/Fp redox scanner was employed to image mESC colonies grown on a feeder layer of gamma-irradiated mouse embryonicfibroblasts(MEFs)on glass cover slips.The result showed significant heterogeneity in the mitochondrial redox state within individual mESC colonies(size:~200-440μm),exhibiting a core with a more reduced state than the periphery.This more reduced state positively correlates with the expression pattern of Oct4,a well-established marker of pluripotency.Our observation is thefirst to show the heterogeneity in the mitochondrial redox state within a mESC colony,suggesting that mitochondrial redox state should be further investigated as a potential new biomarker for the stemness of embryonic stem cells.
基金The grant support to this work incude the Center of Magnetic Resonance and Optical Imaging(CMROI)-an NIH-supported research resource P41RR02305(R.Reddy)the Small A nimal Imaging Resources Program(SAIR)2U24-CA083105(J.D.Glickson and L.Chodosh)+1 种基金2R01-CA101700(J.D.Glickson)NIH K99/R00-CA 126187(R.Choe)。
文摘We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival.The redox state can be imaged by the redox scanner that collects the fuorescence signals from both the oxidized-fAavoproteins(Fp)and the reduced form of nicotinamide adenine dinucleotide(NADH)in snap frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses.Here,with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B.cell lymphoma cell line(DLCL2).The mice were treated with CHOP therapy,i.e,cyclophosphamide(C)+hydroxydoxorubicin(H)+Oncovin(O)+prednisone(P)with CHO administration on day 1 and prednisone administration on days 1-5.The Fp content of the treated group was significantly decreased(p=0.033)on day 5,and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group(p=0.048).The decrease of the Fp heterogeneity(measured by the mean st andard deviation)had a border-line statistical significance(p=0.071).The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy.
文摘Britton Chance was a pioneer in many scientifc fields such as enzymatic reaction kinetis,bioenergetics,metabolism,in vivo NMr,and biophotonics.As an engineer,physical chemist,physicist,physiologist,biophysicist,biochemist,innovator and educator,he had worked indiversifed fields over extended periods bet ween 1926 until his death in 2010,at the age of 97.Inorder to illustrate his scientific career and great impact on research from a new perspective,weemploy scientometric analysis tools to analyze the publications of Britton Chance with datadownloaded from the ISI Citation Indexes in April 2013.We included articles,reviews andproceding papers but excluded meeting abstracts.In total,we obtained 1023 publication recordswith 1236 authors in 266 joumals with 17,114 citations from 1945 to 2013.We show the annualpublications and citations that Britton Chance received from 1945 to 2013,and generate HistCitemaps on the basis of the global citations(GCS)and local(sel)citations(LCS)to show thecitation relationships among the top-30 publications of Britton Chance.Metabolism and the development of physical methods to probe it appear to be the commecting thread of the lifelongresearch of Britton Chance.Furthermore,we generate the joumal map and co-authorship maptoshow the broad scope of research topics and collaborators and the high impacts of the scientificoeuvre of Britton Chance ranging from physics,engineering,chemistry and biology to medicine.
文摘Background： Despite the rapid growth in the incidence of acute myocardial infarction （AMI） in China, there is limited information about patients＇ experiences after AMI hospitalization, especially on long-tern1 adverse events and patient-reported outcomes （PROs）. Methods： The China Patient-centered Evaluative Assessment of Cardiac Events （PEACE）-Prospective AMI Study will enroll 4000 consecutive AM I patients from 53 diverse hospitals across China and follow them longitudinally for 12 months to docunlent their treatment, recovery, and outcomes. Details of patients＇ medical history, treatment, and in-hospital outcomes are abstracted from medical charts. Comprehensive baseline interviews are being conducted to characterize patient demographics, risk factors, presentation, and healthcare utilization. As part of these interviews, validated instruments are administered to measure PROs, including quality of life, symptoms, mood, cognition, and sexual activity. Follow-up interviews, measuring PROs, medication adherence, risk factor control, and collecting hospitalization events are conducted at 1, 6, and 12 months after discharge. Supporting documents for potential outcomes are collected for adjudication by clinicians at the National Coordinating Center. Blood and urine samples are also obtained at baseline, 1 - and 12-month follow-up. In addition, we are conducting a survey of participating hospitals to characterize their organizational characteristics. Conclusion： The China PEACE-Prospective AMI study will be uniquely positioned to generate new information regarding patient＇s experiences and outcomes alter AMI in China and seiwe as a foundation for quality improveinent activities.
