Pub Date : 2025-07-28DOI: 10.1152/physrev.00057.2024
Lærke S. Gasbjerg, Casper K. Nielsen, Malte P. Suppli, Magnus F. G. Grøendahl, Jens J. Holst, Filip K. Knop, Palle B. Jeppesen, Asger B. Lund
Physiological Reviews, Ahead of Print.
《生理评论》，出版前。
{"title":"Proglucagon-derived Peptides: Human Physiology and Therapeutic Potential","authors":"Lærke S. Gasbjerg, Casper K. Nielsen, Malte P. Suppli, Magnus F. G. Grøendahl, Jens J. Holst, Filip K. Knop, Palle B. Jeppesen, Asger B. Lund","doi":"10.1152/physrev.00057.2024","DOIUrl":"https://doi.org/10.1152/physrev.00057.2024","url":null,"abstract":"Physiological Reviews, Ahead of Print. <br/>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"26 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144720202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-23DOI: 10.1152/physrev.00046.2024
Alexander M Jordan,Rebecca J G Drake,Kairbaan M Hodivala-Dilke
The emergence of treatment resistance and metastasis are significant challenges that need to be addressed to improve cancer patient outcomes. Greater insight into the mechanisms regulating these processes is needed to identify novel targets for the development of effective treatments. The importance of blood vessel interactions, including endothelial angiocrine and pericyte pericrine signals, with surrounding tissues, has been well established in regulating several normal physiological functions, including angiogenesis, metabolism, wound healing and development. They have also been implicated in the mechanisms of cancer growth, metastatic dissemination, regulation of the immune microenvironment and therapeutic resistance. This review provides an overview of the angiocrine and pericrine processes that regulate cancer, the tumor microenvironment and therapy responses. It highlights that endothelial cells and pericytes are not only important in maintaining blood vessel structure in cancer, but that their signaling roles are a pivotal regulatory element harnessed by tumors, some of which could be targeted for alternative cancer treatment strategies. Here, we summarize current research targeting angiocrine and pericrine signaling in cancer and propose new approaches for thorough exploration of these networks to further disentangle the intricate mechanisms at play.
{"title":"Angiocrine and Pericrine Signaling: How Endothelial Cells and Pericytes Drive Cancer Progression and Therapy Resistance.","authors":"Alexander M Jordan,Rebecca J G Drake,Kairbaan M Hodivala-Dilke","doi":"10.1152/physrev.00046.2024","DOIUrl":"https://doi.org/10.1152/physrev.00046.2024","url":null,"abstract":"The emergence of treatment resistance and metastasis are significant challenges that need to be addressed to improve cancer patient outcomes. Greater insight into the mechanisms regulating these processes is needed to identify novel targets for the development of effective treatments. The importance of blood vessel interactions, including endothelial angiocrine and pericyte pericrine signals, with surrounding tissues, has been well established in regulating several normal physiological functions, including angiogenesis, metabolism, wound healing and development. They have also been implicated in the mechanisms of cancer growth, metastatic dissemination, regulation of the immune microenvironment and therapeutic resistance. This review provides an overview of the angiocrine and pericrine processes that regulate cancer, the tumor microenvironment and therapy responses. It highlights that endothelial cells and pericytes are not only important in maintaining blood vessel structure in cancer, but that their signaling roles are a pivotal regulatory element harnessed by tumors, some of which could be targeted for alternative cancer treatment strategies. Here, we summarize current research targeting angiocrine and pericrine signaling in cancer and propose new approaches for thorough exploration of these networks to further disentangle the intricate mechanisms at play.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"14 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-16DOI: 10.1152/physrev.00022.2024
István Vadász, Eoin P Cummins, Deborah H. Brotherton, S Marina Casalino Matsuda, Laura A. Dada, Ori Green, Dustin T. King, Vitalii Kryvenko, Masahiko Shigemura, Peter H. S. Sporn, Moritz J. Strowitzki, Martin J. Cann, Jacob I. Sznajder
Physiological Reviews, Ahead of Print.
《生理评论》，出版前。
{"title":"Sensing molecular carbon dioxide - a translational focus for respiratory disease","authors":"István Vadász, Eoin P Cummins, Deborah H. Brotherton, S Marina Casalino Matsuda, Laura A. Dada, Ori Green, Dustin T. King, Vitalii Kryvenko, Masahiko Shigemura, Peter H. S. Sporn, Moritz J. Strowitzki, Martin J. Cann, Jacob I. Sznajder","doi":"10.1152/physrev.00022.2024","DOIUrl":"https://doi.org/10.1152/physrev.00022.2024","url":null,"abstract":"Physiological Reviews, Ahead of Print. <br/>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"267 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-11DOI: 10.1152/physrev.00043.2024
Gary C Sieck,Matthew J Fogarty
In mammals, breathing requires an inspiratory pump to generate a negative intrathoracic pressure and thus pull air into the lungs for gas exchange. Exclusively in mammals, the diaphragm muscle (DIAm) is the major inspiratory pump, which separates the thoracic and abdominal cavities. With DIAm contraction a negative intrathoracic and positive abdominal pressure are generated (i.e., transdiaphragmatic pressure (Pdi). During breathing,the DIAm is very active, with a duty cycle (time active vs inactive) similar to that of the heart. Like the heart, this is a pump that cannot fail! Thus, in controlling breathing, the nervous system must activate DIAm to accomplish pump function while avoiding fatigue. The timing of DIAm activations must also be coordinated with activation of the upper airway muscles (the pipes) to avoid airway occlusion and aspiration, the intercostal and abdominal muscles to appropriately stiffen the body cavities. Similarly, neural control and coordination of the DIAm in non-ventilatory behaviors (airway protection, swallowing, vocalization and voiding) is equally complex, with coordinated activation of the DIAm and abdominal muscles. It is becoming increasingly clear that impaired non-ventilatory functions underlie the pathophysiology of a variety of medical conditions. In this review, we will delve into the detailed mechanistic underpinnings of the neural control of the DIAm and the symphonic coordination of its activation during breathing and other behaviors. We will attempt to move the field from considering the DIAm only as an inspiratory pump, emphasising neural control of airway, intercostal and abdominal muscles that must be coordinated with DIAm activation.
{"title":"Diaphragm Muscle: A Pump That Can Not Fail.","authors":"Gary C Sieck,Matthew J Fogarty","doi":"10.1152/physrev.00043.2024","DOIUrl":"https://doi.org/10.1152/physrev.00043.2024","url":null,"abstract":"In mammals, breathing requires an inspiratory pump to generate a negative intrathoracic pressure and thus pull air into the lungs for gas exchange. Exclusively in mammals, the diaphragm muscle (DIAm) is the major inspiratory pump, which separates the thoracic and abdominal cavities. With DIAm contraction a negative intrathoracic and positive abdominal pressure are generated (i.e., transdiaphragmatic pressure (Pdi). During breathing,the DIAm is very active, with a duty cycle (time active vs inactive) similar to that of the heart. Like the heart, this is a pump that cannot fail! Thus, in controlling breathing, the nervous system must activate DIAm to accomplish pump function while avoiding fatigue. The timing of DIAm activations must also be coordinated with activation of the upper airway muscles (the pipes) to avoid airway occlusion and aspiration, the intercostal and abdominal muscles to appropriately stiffen the body cavities. Similarly, neural control and coordination of the DIAm in non-ventilatory behaviors (airway protection, swallowing, vocalization and voiding) is equally complex, with coordinated activation of the DIAm and abdominal muscles. It is becoming increasingly clear that impaired non-ventilatory functions underlie the pathophysiology of a variety of medical conditions. In this review, we will delve into the detailed mechanistic underpinnings of the neural control of the DIAm and the symphonic coordination of its activation during breathing and other behaviors. We will attempt to move the field from considering the DIAm only as an inspiratory pump, emphasising neural control of airway, intercostal and abdominal muscles that must be coordinated with DIAm activation.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"4 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144604050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1152/physrev.00053.2024
Modan R Goldman,Mariel Molina-Castro,Jumar C Etkins,Theodore L Koide,Vijay A Ramchandani,Martin H Plawecki,Julie A Mennella,Marta Yanina Pepino
Globally, alcohol is the most widely used psychoactive drug and a leading cause of premature death among individuals aged 15-49 years. Understanding the absorption, distribution, metabolism, and excretion of alcohol in the human body, otherwise known as alcohol pharmacokinetics, is essential for predicting its behavioral effects and toxic consequences. This review examines the evolutionary origins of alcohol consumption and metabolism, focusing on the activity of alcohol dehydrogenase enzymes across species, which serve as key catalysts in alcohol oxidation. It also highlights recent advances in understanding central alcohol metabolism and updates on the potential clinical significance of non-oxidative pathways of alcohol metabolism and endogenous alcohol production, particularly in the context of liver disease. In addition, the review inspects factors that modulate alcohol metabolism, including genetic polymorphisms, biological sex, food intake, women's reproductive status, and clinical interventions such as medications and metabolic surgeries. Understanding these sources of variability in alcohol metabolism is crucial for identifying individual risk factors and tailoring strategies to reduce alcohol-related harm. This comprehensive review offers a current perspective on alcohol pharmacokinetics, valuable insights into its implications for health, behavior, and potential innovative therapeutic targets.
{"title":"Recent advances in alcohol metabolism: from the gut to the brain.","authors":"Modan R Goldman,Mariel Molina-Castro,Jumar C Etkins,Theodore L Koide,Vijay A Ramchandani,Martin H Plawecki,Julie A Mennella,Marta Yanina Pepino","doi":"10.1152/physrev.00053.2024","DOIUrl":"https://doi.org/10.1152/physrev.00053.2024","url":null,"abstract":"Globally, alcohol is the most widely used psychoactive drug and a leading cause of premature death among individuals aged 15-49 years. Understanding the absorption, distribution, metabolism, and excretion of alcohol in the human body, otherwise known as alcohol pharmacokinetics, is essential for predicting its behavioral effects and toxic consequences. This review examines the evolutionary origins of alcohol consumption and metabolism, focusing on the activity of alcohol dehydrogenase enzymes across species, which serve as key catalysts in alcohol oxidation. It also highlights recent advances in understanding central alcohol metabolism and updates on the potential clinical significance of non-oxidative pathways of alcohol metabolism and endogenous alcohol production, particularly in the context of liver disease. In addition, the review inspects factors that modulate alcohol metabolism, including genetic polymorphisms, biological sex, food intake, women's reproductive status, and clinical interventions such as medications and metabolic surgeries. Understanding these sources of variability in alcohol metabolism is crucial for identifying individual risk factors and tailoring strategies to reduce alcohol-related harm. This comprehensive review offers a current perspective on alcohol pharmacokinetics, valuable insights into its implications for health, behavior, and potential innovative therapeutic targets.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"147 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1152/physrev.00005.2024
Sabrina Altendorf,Marta Bertolini,Alizée Le Riche,Antonella Tosti,Ralf Paus
Male pattern androgenetic alopecia (mpAGA), the most common form of hair loss in men, represents a heritable, androgen-dependent complex trait distinct from female pattern hair loss. Despite the psychosocial burden of mpAGA in some affected individuals and associations with other morbidities, we portray mpAGA as an essentially physiological phenomenon in which defined hair follicle (HF) populations in developmentally preprogrammed scalp skin regions undergo a dramatic, but reversible (mini-)organ transformation in genetically predisposed individuals. Histologically, mpAGA exhibits progressive HF miniaturization (terminal-to-vellus conversion) and anagen shortening. Clinically, this results in a characteristic balding pattern of frontotemporal and vertex scalp skin, associated with telogen effluvium. It remains unclear how exactly androgens induce this phenotype, since neither androgen receptor polymorphisms nor changes in androgen serum or local androgen skin levels persuasively explain it. It also is as yet unresolved if mpAGA-associated HF transformation and hair cycle changes are primarily driven by the HF mesenchyme, e.g. by excessive emigration and/or reduced inductive potential of dermal papilla fibroblasts, or by intraepithelial events such as prostaglandin D2-dependent reduced HF epithelial stem cell progenitor generation. While critically revisiting our limited current understanding of mpAGA physiology and the role of mpAGA-associated genes we discuss potential targets for future therapeutic intervention beyond androgens and highlight selected dysregulated signaling pathways in mpAGA. We underscore mpAGA as an instructive, accessible model for interrogating under-investigated physiological roles of immune cells, oxidative stress, aging/senescence, and the microbiome in human organ remodeling and hair cycle regulation, and define major open research questions beyond androgen receptor- mediated signaling.
{"title":"Frontiers in the physiology of male pattern androgenetic alopecia: Beyond the androgen horizon.","authors":"Sabrina Altendorf,Marta Bertolini,Alizée Le Riche,Antonella Tosti,Ralf Paus","doi":"10.1152/physrev.00005.2024","DOIUrl":"https://doi.org/10.1152/physrev.00005.2024","url":null,"abstract":"Male pattern androgenetic alopecia (mpAGA), the most common form of hair loss in men, represents a heritable, androgen-dependent complex trait distinct from female pattern hair loss. Despite the psychosocial burden of mpAGA in some affected individuals and associations with other morbidities, we portray mpAGA as an essentially physiological phenomenon in which defined hair follicle (HF) populations in developmentally preprogrammed scalp skin regions undergo a dramatic, but reversible (mini-)organ transformation in genetically predisposed individuals. Histologically, mpAGA exhibits progressive HF miniaturization (terminal-to-vellus conversion) and anagen shortening. Clinically, this results in a characteristic balding pattern of frontotemporal and vertex scalp skin, associated with telogen effluvium. It remains unclear how exactly androgens induce this phenotype, since neither androgen receptor polymorphisms nor changes in androgen serum or local androgen skin levels persuasively explain it. It also is as yet unresolved if mpAGA-associated HF transformation and hair cycle changes are primarily driven by the HF mesenchyme, e.g. by excessive emigration and/or reduced inductive potential of dermal papilla fibroblasts, or by intraepithelial events such as prostaglandin D2-dependent reduced HF epithelial stem cell progenitor generation. While critically revisiting our limited current understanding of mpAGA physiology and the role of mpAGA-associated genes we discuss potential targets for future therapeutic intervention beyond androgens and highlight selected dysregulated signaling pathways in mpAGA. We underscore mpAGA as an instructive, accessible model for interrogating under-investigated physiological roles of immune cells, oxidative stress, aging/senescence, and the microbiome in human organ remodeling and hair cycle regulation, and define major open research questions beyond androgen receptor- mediated signaling.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"111 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-10DOI: 10.1152/physrev.00047.2024
Clio P Mavragani,Mary K Crow
Type I interferons (IFNs), particularly IFNα and IFNβ, play a crucial role in the human immune response against viral infections. This review delves into the multifaceted antiviral, immunomodulatory and antitumor physiological roles of type I IFNs, while describing their contribution to the pathogenesis of various disease pathologies including cancer, systemic and organ specific autoimmunity, neuroinflammation and atherosclerosis. Genetic determinants influencing activation of type I IFN pathways and therapeutic interventions either targeting or stimulating these pathways in the context of autoimmunity and cancer respectively are also discussed. Ultimately, the current understanding of the role of type I IFNs as biomarkers indicative of distinct clinical and serological phenotypes, their correlation with disease activity, their predictive role in therapeutic outcomes across diverse clinical scenarios, as well as the challenges associated with their implementation in clinical practice, are thoroughly addressed. Together, these insights underscore the significant potential of type I IFNs, as mediators and therapeutic targets, to reshape clinical decision-making, while highlighting the urgent need for robust, standardized methodologies for assessment of type I IFNs and their integration into routine practice.
{"title":"Type I Interferons in health and disease-Molecular aspects and clinical implications.","authors":"Clio P Mavragani,Mary K Crow","doi":"10.1152/physrev.00047.2024","DOIUrl":"https://doi.org/10.1152/physrev.00047.2024","url":null,"abstract":"Type I interferons (IFNs), particularly IFNα and IFNβ, play a crucial role in the human immune response against viral infections. This review delves into the multifaceted antiviral, immunomodulatory and antitumor physiological roles of type I IFNs, while describing their contribution to the pathogenesis of various disease pathologies including cancer, systemic and organ specific autoimmunity, neuroinflammation and atherosclerosis. Genetic determinants influencing activation of type I IFN pathways and therapeutic interventions either targeting or stimulating these pathways in the context of autoimmunity and cancer respectively are also discussed. Ultimately, the current understanding of the role of type I IFNs as biomarkers indicative of distinct clinical and serological phenotypes, their correlation with disease activity, their predictive role in therapeutic outcomes across diverse clinical scenarios, as well as the challenges associated with their implementation in clinical practice, are thoroughly addressed. Together, these insights underscore the significant potential of type I IFNs, as mediators and therapeutic targets, to reshape clinical decision-making, while highlighting the urgent need for robust, standardized methodologies for assessment of type I IFNs and their integration into routine practice.","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":"4 1","pages":""},"PeriodicalIF":33.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01Epub Date: 2025-02-21DOI: 10.1152/physrev.00019.2024
Enrique Bastón, Juan García-Agulló, Héctor Peinado
Disruption of cellular communication that regulates normal physiology is often a key factor in the development of disease, including cancer. Extracellular vesicles (EVs) are mediators of cell-cell communication, modulating local and distant microenvironments and playing an important role influencing tumor progression at both early and late stages. Indeed, EV-mediated communication participates in the initial steps of primary tumor transformation and proliferation as well as the preparation of the premetastatic niche and subsequent metastasis. In this context, the presence of DNA in EVs (EV-DNA) is particularly intriguing, with important biological implications and significant potential as a biomarker in liquid biopsies. In this review we discuss the mechanisms involved in EV-shed DNA and the potential impact in tumor evolution. In addition, it has become apparent in recent years that the secretion of EVs also influences the behavior of the surrounding microenvironment. An important unresolved challenge in oncology is the resistance of tumors to treatment, one of the primary causes of high cancer mortality. The role of EVs in therapy resistance has garnered considerable interest. In the latter part of this review, we also examine the potential involvement of EVs in resistance to therapy.
{"title":"The influence of extracellular vesicles on tumor evolution and resistance to therapy.","authors":"Enrique Bastón, Juan García-Agulló, Héctor Peinado","doi":"10.1152/physrev.00019.2024","DOIUrl":"10.1152/physrev.00019.2024","url":null,"abstract":"<p><p>Disruption of cellular communication that regulates normal physiology is often a key factor in the development of disease, including cancer. Extracellular vesicles (EVs) are mediators of cell-cell communication, modulating local and distant microenvironments and playing an important role influencing tumor progression at both early and late stages. Indeed, EV-mediated communication participates in the initial steps of primary tumor transformation and proliferation as well as the preparation of the premetastatic niche and subsequent metastasis. In this context, the presence of DNA in EVs (EV-DNA) is particularly intriguing, with important biological implications and significant potential as a biomarker in liquid biopsies. In this review we discuss the mechanisms involved in EV-shed DNA and the potential impact in tumor evolution. In addition, it has become apparent in recent years that the secretion of EVs also influences the behavior of the surrounding microenvironment. An important unresolved challenge in oncology is the resistance of tumors to treatment, one of the primary causes of high cancer mortality. The role of EVs in therapy resistance has garnered considerable interest. In the latter part of this review, we also examine the potential involvement of EVs in resistance to therapy.</p>","PeriodicalId":20193,"journal":{"name":"Physiological reviews","volume":" ","pages":"1173-1212"},"PeriodicalIF":29.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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