Yu C J Chey, Jayshen Arudkumar, Annemieke Aartsma-Rus, Fatwa Adikusuma, Paul Q Thomas
{"title":"CRISPR applications for Duchenne muscular dystrophy: From animal models to potential therapies.","authors":"Yu C J Chey, Jayshen Arudkumar, Annemieke Aartsma-Rus, Fatwa Adikusuma, Paul Q Thomas","doi":"10.1002/wsbm.1580","DOIUrl":"https://doi.org/10.1002/wsbm.1580","url":null,"abstract":"<p><p>CRISPR gene-editing technology creates precise and permanent modifications to DNA. It has significantly advanced our ability to generate animal disease models for use in biomedical research and also has potential to revolutionize the treatment of genetic disorders. Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disease that could potentially benefit from the development of CRISPR therapy. It is commonly associated with mutations that disrupt the reading frame of the DMD gene that encodes dystrophin, an essential scaffolding protein that stabilizes striated muscles and protects them from contractile-induced damage. CRISPR enables the rapid generation of various animal models harboring mutations that closely simulates the wide variety of mutations observed in DMD patients. These models provide a platform for the testing of sequence-specific interventions like CRISPR therapy that aim to reframe or skip DMD mutations to restore functional dystrophin expression. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"15 1","pages":"e1580"},"PeriodicalIF":3.1,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/8b/3e/WSBM-15-0.PMC10078488.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9319968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gülizar Saritas, Ailsa Maria Main, Sofia Boeg Winge, Nina Mørup, Kristian Almstrup
{"title":"PIWI-interacting RNAs and human testicular function.","authors":"Gülizar Saritas, Ailsa Maria Main, Sofia Boeg Winge, Nina Mørup, Kristian Almstrup","doi":"10.1002/wsbm.1572","DOIUrl":"https://doi.org/10.1002/wsbm.1572","url":null,"abstract":"<p><p>Small noncoding RNAs (sncRNAs) are pieces of RNA with a length below 200 bp and represent a diverse group of RNAs having many different biological functions. The best described subtype is the microRNAs which primarily function in posttranscriptional gene regulation and appear essential for most physiological processes. Of particular interest for the germline is the PIWI-interacting RNAs (piRNAs) which are a class of sncRNA of 21-35 bp in length that are almost exclusively found in germ cells. Recently, it has become clear that piRNAs are essential for testicular function, and in this perspective, we outline the current knowledge of piRNAs in humans. Although piRNAs appear unique to germ cells, they have also been described in various somatic cancers and biofluids. Here, we discuss the potential function of piRNAs in somatic tissues and whether detection in biofluids may be used as a biomarker for testicular function. This article is categorized under: Reproductive System Diseases > Genetics/Genomics/Epigenetics Reproductive System Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"14 6","pages":"e1572"},"PeriodicalIF":3.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10436816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tianning Gu, Kejia Hu, Xiaohui Si, Yongxian Hu, He Huang
{"title":"Mechanisms of immune effector cell-associated neurotoxicity syndrome after CAR-T treatment.","authors":"Tianning Gu, Kejia Hu, Xiaohui Si, Yongxian Hu, He Huang","doi":"10.1002/wsbm.1576","DOIUrl":"https://doi.org/10.1002/wsbm.1576","url":null,"abstract":"<p><p>Chimeric antigen receptor T-cell (CAR-T) treatment has revolutionized the landscape of cancer therapy with significant efficacy on hematologic malignancy, especially in relapsed and refractory B cell malignancies. However, unexpected serious toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) still hamper its broad application. Clinical trials using CAR-T cells targeting specific antigens on tumor cell surface have provided valuable information about the characteristics of ICANS. With unclear mechanism of ICANS after CAR-T treatment, unremitting efforts have been devoted to further exploration. Clinical findings from patients with ICANS strongly indicated existence of overactivated peripheral immune response followed by endothelial activation-induced blood-brain barrier (BBB) dysfunction, which triggers subsequent central nervous system (CNS) inflammation and neurotoxicity. Several animal models have been built but failed to fully replicate the whole spectrum of ICANS in human. Hopefully, novel and powerful technologies like single-cell analysis may help decipher the precise cellular response within CNS from a different perspective when ICANS happens. Moreover, multidisciplinary cooperation among the subjects of immunology, hematology, and neurology will facilitate better understanding about the complex immune interaction between the peripheral, protective barriers, and CNS in ICANS. This review elaborates recent findings about ICANS after CAR-T treatment from bed to bench, and discusses the potential cellular and molecular mechanisms that may promote effective management in the future. This article is categorized under: Cancer > Biomedical Engineering Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"14 6","pages":"e1576"},"PeriodicalIF":3.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1b/d8/WSBM-14-e1576.PMC9787013.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10446991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular mechanisms underlying bacterial resistance to ceftazidime/avibactam.","authors":"Luying Xiong, Xueting Wang, Yuan Wang, Wei Yu, Yanzi Zhou, Xiaohui Chi, Tingting Xiao, Yonghong Xiao","doi":"10.1002/wsbm.1571","DOIUrl":"https://doi.org/10.1002/wsbm.1571","url":null,"abstract":"<p><p>Ceftazidime/avibactam (CAZ/AVI), a combination of ceftazidime and a novel β-lactamase inhibitor (avibactam) that has been approved by the U.S. Food and Drug Administration, the European Union, and the National Regulatory Administration in China. CAZ/AVI is used mainly to treat complicated urinary tract infections and complicated intra-abdominal infections in adults, as well as to treat patients infected with Carbapenem-resistant Enterobacteriaceae (CRE) susceptible to CAZ/AVI. However, increased clinical application of CAZ/AVI has resulted in the development of resistant strains. Mechanisms of resistance in most of these strains have been attributed to bla<sub>KPC</sub> mutations, which lead to amino acid substitutions in β-lactamase and changes in gene expression. Resistance to CAZ/AVI is also associated with reduced expression and loss of outer membrane proteins or overexpression of efflux pumps. In this review, the prevalence of CAZ/AVI-resistance bacteria, resistance mechanisms, and selection of detection methods of CAZ/AVI are demonstrated, aiming to provide scientific evidence for the clinical prevention and treatment of CAZ/AVI resistant strains, and provide guidance for the development of new drugs. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"14 6","pages":"e1571"},"PeriodicalIF":3.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10445244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eric Wistrom, Rebecca Chase, Patrick R Smith, Zachary T Campbell
{"title":"A compendium of validated pain genes.","authors":"Eric Wistrom, Rebecca Chase, Patrick R Smith, Zachary T Campbell","doi":"10.1002/wsbm.1570","DOIUrl":"https://doi.org/10.1002/wsbm.1570","url":null,"abstract":"<p><p>The development of novel pain therapeutics hinges on the identification and rigorous validation of potential targets. Model organisms provide a means to test the involvement of specific genes and regulatory elements in pain. Here we provide a list of genes linked to pain-associated behaviors. We capitalize on results spanning over three decades to identify a set of 242 genes. They support a remarkable diversity of functions spanning action potential propagation, immune response, GPCR signaling, enzymatic catalysis, nucleic acid regulation, and intercellular signaling. Making use of existing tissue and single-cell high-throughput RNA sequencing datasets, we examine their patterns of expression. For each gene class, we discuss archetypal members, with an emphasis on opportunities for additional experimentation. Finally, we discuss how powerful and increasingly ubiquitous forward genetic screening approaches could be used to improve our ability to identify pain genes. This article is categorized under: Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"14 6","pages":"e1570"},"PeriodicalIF":3.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9787016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10436299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pathogenesis of neural tube defects: The regulation and disruption of cellular processes underlying neural tube closure.","authors":"David M Engelhardt, Cara A Martyr, Lee Niswander","doi":"10.1002/wsbm.1559","DOIUrl":"https://doi.org/10.1002/wsbm.1559","url":null,"abstract":"<p><p>Neural tube closure (NTC) is crucial for proper development of the brain and spinal cord and requires precise morphogenesis from a sheet of cells to an intact three-dimensional structure. NTC is dependent on successful regulation of hundreds of genes, a myriad of signaling pathways, concentration gradients, and is influenced by epigenetic and environmental cues. Failure of NTC is termed a neural tube defect (NTD) and is a leading class of congenital defects in the United States and worldwide. Though NTDs are all defined as incomplete closure of the neural tube, the pathogenesis of an NTD determines the type, severity, positioning, and accompanying phenotypes. In this review, we survey pathogenesis of NTDs relating to disruption of cellular processes arising from genetic mutations, altered epigenetic regulation, and environmental influences by micronutrients and maternal condition. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Stem Cells and Development.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"14 5","pages":"e1559"},"PeriodicalIF":3.1,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9605354/pdf/nihms-1799087.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10134712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"New developments in the biology of fibroblast growth factors.","authors":"David M Ornitz, Nobuyuki Itoh","doi":"10.1002/wsbm.1549","DOIUrl":"https://doi.org/10.1002/wsbm.1549","url":null,"abstract":"<p><p>The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltage-gated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology Congenital Diseases > Stem Cells and Development Cancer > Stem Cells and Development.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"14 4","pages":"e1549"},"PeriodicalIF":3.1,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10115509/pdf/nihms-1890656.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9732920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Transition to extrauterine life and the modeling of perinatal asphyxia in rats.","authors":"M. Ortiz, F. Loidl, Pablo Vázquez-Borsetti","doi":"10.1002/wsbm.1568","DOIUrl":"https://doi.org/10.1002/wsbm.1568","url":null,"abstract":"Generation of murine models for the study of birth-related pathologies has proven to be a complex and controversial problem. Differences in the relative timing of developmental events of both species have led some researchers to suggest that the rat is born comparatively less developed than the human. The solution proposed to this problem would consist in the delay of the experiments of perinatal asphyxia (PA), usually up to 7-10 days, allowing developmental levels to \"equalize\" with the human at birth. This solution generates a new set of problems. The developmental milestones in both species follow a divergent temporal pattern. Increasing the age of the rat not only can improve resemblance with humans but also will make the model miss a crucial set of milestones related to birth. During this process, there are specific mechanisms to protect the fetus from neuronal damage, especially those caused by asphyxia. These factors are not present in models where the asphyxia is delayed. In these models, there will be more false positives and more damage that would not be present in humans exposed to PA. This article is categorized under: Cancer > Stem Cells and Development Congenital Diseases > Environmental Factors Neurological Diseases > Environmental Factors.","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"1 1","pages":"e1568"},"PeriodicalIF":3.1,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49363888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Energy metabolism in mammalian sperm motility.","authors":"A. Amaral","doi":"10.1002/wsbm.1569","DOIUrl":"https://doi.org/10.1002/wsbm.1569","url":null,"abstract":"Mammalian sperm, the only cells that achieve their purpose outside their organism of origin, have to swim vigorously within the female reproductive tract to reach an oocyte. Flagellar dyneins drive sperm motility, which accounts for the consumption of high amounts of ATP. The two main ATP-producing metabolic pathways are compartmentalized in sperm: oxidative phosphorylation in the midpiece and glycolysis in the principal piece. The relative preponderance of these pathways has been discussed for decades (the so-called sperm energy debate). The debate has been muddled by species-specific variances and by technical constraints. But recent findings suggest that sperm from most mammalian species employ a versatile metabolic strategy to maintain motility according to the physiological environment. Different metabolic pathways likely coordinate by using exogenous and/or endogenous substrates in order to produce ATP efficiently. Defects in any of these pathways (glycolysis, mitochondrial oxidative phosphorylation, Krebs cycle, fatty acids oxidation, and ketone bodies oxidation, among others) may disturb sperm motility and be at the origin of male infertility. Understanding sperm bioenergetics is thus crucial for building new diagnostic tools, and for the development of treatments for patients presenting with low sperm motility. Some of these patients may benefit from personalized metabolic supplementations and dietary interventions. This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology.","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"1 1","pages":"e1569"},"PeriodicalIF":3.1,"publicationDate":"2022-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43956095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martin Mawhinney, Amelia Kulle, Ajitha Thanabalasuriar
{"title":"From infection to repair: Understanding the workings of our innate immune cells.","authors":"Martin Mawhinney, Amelia Kulle, Ajitha Thanabalasuriar","doi":"10.1002/wsbm.1567","DOIUrl":"https://doi.org/10.1002/wsbm.1567","url":null,"abstract":"In a world filled with microbes, some posing a threat to our body, our immune system is key to living a healthy life. The innate immune system is made of various cell types that act to guard our bodies. Unlike the adaptive immune system that has a specific response, our innate immune system encompasses cells that elicit unspecific immune responses, triggered whenever the right signals are detected. Our understanding of immunity started with the concept of our immune system only responding to \"nonself\" like the pathogens that invade our body. However, over the past few decades, we have learned that the immune system is more than an on/off switch that recognizes nonself. The innate immune system regularly patrols our bodies for pathogens and tissue damage. Our innate immune system not only seeks to resolve infection but also repair tissue injury, through phagocytosing debris and initiating the release of growth factors. Recently, we are starting to see that it is not just recognizing danger, our innate immune system plays a crucial role in repair. Innate immune cells phenotypically change during repair. In the context of severe injury or trauma, our innate immune system is modified quite drastically to help repair, resulting in reduced infection control. Moreover, these changes in immune cell function can be modified by sex as a biological variable. From past to present, in this overview, we provide a summary of the innate immune cells and pathways in infection and tissue repair. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology.","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":"1 1","pages":"e1567"},"PeriodicalIF":3.1,"publicationDate":"2022-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46244774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}