WIREs Mechanisms of Disease最新文献

{"title":"A perspective on translating genomic discoveries into targets for brain-machine interface and deep brain stimulation devices.","authors":"Wander L Valentim, Daniel S Tylee, Renato Polimanti","doi":"10.1002/wsbm.1635","DOIUrl":"10.1002/wsbm.1635","url":null,"abstract":"<p><p>Mental illnesses have a huge impact on individuals, families, and society, so there is a growing need for more efficient treatments. In this context, brain-computer interface (BCI) technology has the potential to revolutionize the options for neuropsychiatric therapies. However, the development of BCI-based therapies faces enormous challenges, such as power dissipation constraints, lack of credible feedback mechanisms, uncertainty of which brain areas and frequencies to target, and even which patients to treat. Some of these setbacks are due to the large gap in our understanding of brain function. In recent years, large-scale genomic analyses uncovered an unprecedented amount of information regarding the biology of the altered brain function observed across the psychopathology spectrum. We believe findings from genetic studies can be useful to refine BCI technology to develop novel treatment options for mental illnesses. Here, we assess the latest advancements in both fields, the possibilities that can be generated from their intersection, and the challenges that these research areas will need to address to ensure that translational efforts can lead to effective and reliable interventions. Specifically, starting from highlighting the overlap between mechanisms uncovered by large-scale genetic studies and the current targets of deep brain stimulation treatments, we describe the steps that could help to translate genomic discoveries into BCI targets. Because these two research areas have not been previously presented together, the present article can provide a novel perspective for scientists with different research backgrounds. This article is categorized under: Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Biomedical Engineering.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1635"},"PeriodicalIF":3.1,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138499610","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":"Walking with giants: The challenges of variant impact assessment in the giant sarcomeric protein titin.","authors":"Timir G R Weston, Martin Rees, Mathias Gautel, Franca Fraternali","doi":"10.1002/wsbm.1638","DOIUrl":"10.1002/wsbm.1638","url":null,"abstract":"<p><p>Titin, the so-called \"third filament\" of the sarcomere, represents a difficult challenge for the determination of damaging genetic variants. A single titin molecule extends across half the length of a sarcomere in striated muscle, fulfilling a variety of vital structural and signaling roles, and has been linked to an equally varied range of myopathies, resulting in a significant burden on individuals and healthcare systems alike. While the consequences of truncating variants of titin are well-documented, the ramifications of the missense variants prevalent in the general population are less so. We here present a compendium of titin missense variants-those that result in a single amino-acid substitution in coding regions-reported to be pathogenic and discuss these in light of the nature of titin and the variant position within the sarcomere and their domain, the structural, pathological, and biophysical characteristics that define them, and the methods used for characterization. Finally, we discuss the current knowledge and integration of the multiple fields that have contributed to our understanding of titin-related pathology and offer suggestions as to how these concurrent methodologies may aid the further development in our understanding of titin and hopefully extend to other, less well-studied giant proteins. This article is categorized under: Cardiovascular Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1638"},"PeriodicalIF":3.1,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139058840","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":"MHC class III lymphocyte antigens 6 as endogenous immunotoxins: Unlocking immunotherapy in proficient mismatch repair colorectal cancer.","authors":"Guido Giordano, Massimo Pancione","doi":"10.1002/wsbm.1631","DOIUrl":"10.1002/wsbm.1631","url":null,"abstract":"<p><p>A majority of cancers, including colorectal cancer (CRC) with intact DNA mismatch repair, exhibit a paralyzed antitumor immune response and resistance to immune checkpoint inhibitors. Members of MHC class III lymphocyte antigen 6G (LY6G) encode glycosylphosphatidylinositol (GPI) proteins anchored to the membrane. Snake venom neurotoxins and LY6G proteins share a three-finger (3F) folding domain. LY6 proteins such as LY6G6D are gaining a reputation as excellent tumor-associated antigens that can potently inhibit anti-tumor immunity in cancers with proficient mismatch repair. Thus, we called MHC class III LY6G endogenous immunotoxins. Since the discovery of LY6G6D as a tumor-associated antigen, T-cell engagers (TcEs) have been developed to simultaneously bind LY6G6D on cancer cells and CD3 on T cells, improving the treatment of metastatic solid tumors that are resistant to ICIs. We present a current understanding of how alterations in MHC class III genes inhibit antitumor immunity, and how these understandings can be turned into effective treatments for patients who are refractory to standard immunotherapy. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Cancer > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1631"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41214661","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":"Rationalizing a prospective coupling effect of cannabinoids with the current pharmacotherapy for melanoma treatment.","authors":"Ava Bachari, Nazim Nassar, Ellen Schanknecht, Srinivasareddy Telukutla, Terrence Jerald Piva, Nitin Mantri","doi":"10.1002/wsbm.1633","DOIUrl":"10.1002/wsbm.1633","url":null,"abstract":"<p><p>Melanoma is one of the leading fatal forms of cancer, yet from a treatment perspective, we have minimal control over its reoccurrence and resistance to current pharmacotherapies. The endocannabinoid system (ECS) has recently been accepted as a multifaceted homeostatic regulator, influencing various physiological processes across different biological compartments, including the skin. This review presents an overview of the pathophysiology of melanoma, current pharmacotherapy used for treatment, and the challenges associated with the different pharmacological approaches. Furthermore, it highlights the utility of cannabinoids as an additive remedy for melanoma by restoring the balance between downregulated immunomodulatory pathways and elevated inflammatory cytokines during chronic skin conditions as one of the suggested critical approaches in treating this immunogenic tumor. This article is categorized under: Cancer > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1633"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71427417","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":"Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond.","authors":"Herman Huang, Guo N Huang, Alexander Y Payumo","doi":"10.1002/wsbm.1629","DOIUrl":"10.1002/wsbm.1629","url":null,"abstract":"<p><p>Interest in vertebrate cardiac regeneration has exploded over the past two decades since the discovery that adult zebrafish are capable of complete heart regeneration, contrasting the limited regenerative potential typically observed in adult mammalian hearts. Undercovering the mechanisms that both support and limit cardiac regeneration across the animal kingdom may provide unique insights in how we may unlock this capacity in adult humans. In this review, we discuss key discoveries in the heart regeneration field over the last 20 years. Initially, seminal findings revealed that pre-existing cardiomyocytes are the major source of regenerated cardiac muscle, drawing interest into the intrinsic mechanisms regulating cardiomyocyte proliferation. Moreover, recent studies have identified the importance of intercellular interactions and physiological adaptations, which highlight the vast complexity of the cardiac regenerative process. Finally, we compare strategies that have been tested to increase the regenerative capacity of the adult mammalian heart. This article is categorized under: Cardiovascular Diseases > Stem Cells and Development.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1629"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10840678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226809","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":"Synaptic plasticity and the role of astrocytes in central metabolic circuits.","authors":"Dominique Ameroso, Maribel Rios","doi":"10.1002/wsbm.1632","DOIUrl":"10.1002/wsbm.1632","url":null,"abstract":"<p><p>Neural circuits in the brain, primarily in the hypothalamus, are paramount to the homeostatic control of feeding and energy utilization. They integrate hunger, satiety, and body adiposity cues from the periphery and mediate the appropriate behavioral and physiological responses to satisfy the energy demands of the animal. Notably, perturbations in central homeostatic circuits have been linked to the etiology of excessive feeding and obesity. Considering the ever-changing energy requirements of the animal and required adaptations, it is not surprising that brain-feeding circuits remain plastic in adulthood and are subject to changes in synaptic strength as a consequence of nutritional status. Indeed, synapse density, probability of presynaptic transmitter release, and postsynaptic responses in hypothalamic energy balance centers are tailored to behavioral and physiological responses required to sustain survival. Mounting evidence supports key roles of astrocytes facilitating some of this plasticity. Here we discuss these synaptic plasticity mechanisms and the emerging roles of astrocytes influencing energy and glucose balance control in health and disease. This article is categorized under: Cancer > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1632"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10842964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41214662","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":"Secondary glaucoma: Toward interventions based on molecular underpinnings.","authors":"Anna Mueller, Isabel Lam, Krishna Kishor, Richard K Lee, Sanjoy Bhattacharya","doi":"10.1002/wsbm.1628","DOIUrl":"10.1002/wsbm.1628","url":null,"abstract":"<p><p>Glaucoma is a heterogeneous group of progressive diseases that leads to irreversible blindness. Secondary glaucoma refers to glaucoma caused by a known underlying condition. Pseudoexfoliation and pigment dispersion syndromes are common causes of secondary glaucoma. Their respective deposits may obstruct the trabecular meshwork, leading to aqueous humor outflow resistance, ocular hypertension, and optic neuropathy. There are no disease-specific interventions available for either. Pseudoexfoliation syndrome is characterized by fibrillar deposits (pseudoexfoliative material) on anterior segment structures. Over a decade of multiomics analyses taken together with the current knowledge on pseudoexfoliative glaucoma warrant a re-think of mechanistic possibilities. We propose that the presence of nucleation centers (e.g., vitamin D binding protein), crosslinking enzymes (e.g., transglutaminase 2), aberrant extracellular matrix, flawed endocytosis, and abnormal aqueous-blood barrier contribute to the formation of proteolytically resistant pseudoexfoliative material. Pigment dispersion syndrome is characterized by abnormal iridolenticular contact that disrupts iris pigment epithelium and liberates melanin granules. Iris melanogenesis is aberrant in this condition. Cytotoxic melanogenesis intermediates leak out of melanosomes and cause iris melanocyte and pigment epithelium cell death. Targeting melanogenesis can likely decrease the risk of pigmentary glaucoma. Skin and melanoma research provides insights into potential therapeutics. We propose that specific prostanoid agonists and fenofibrates may reduce melanogenesis by inhibiting cholesterol internalization and de novo synthesis. Additionally, melatonin is a potent melanogenesis suppressor, antioxidant, and hypotensive agent, rendering it a valuable agent for pigmentary glaucoma. In pseudoexfoliative glaucoma, where environmental insults drive pseudoexfoliative material formation, melatonin's antioxidant and hypotensive properties may offer adjunct therapeutic benefits. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1628"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10217842","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":"iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy.","authors":"Paola Rispoli, Tatiana Scandiuzzi Piovesan, Giuliana Decorti, Gabriele Stocco, Marianna Lucafò","doi":"10.1002/wsbm.1630","DOIUrl":"10.1002/wsbm.1630","url":null,"abstract":"<p><p>Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC-derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs-derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC-derived 2D models, iPSC-derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC-derived organoids present advantages in terms of versatility, patient-specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs. This article is categorized under: Cancer > Stem Cells and Development.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1630"},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41157974","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":"Network medicine for patients' stratification: From single-layer to multi-omics.","authors":"Manuela Petti, Lorenzo Farina","doi":"10.1002/wsbm.1623","DOIUrl":"10.1002/wsbm.1623","url":null,"abstract":"Precision medicine research increasingly relies on the integrated analysis of multiple types of omics. In the era of big data, the large availability of different health-related information represents a great, but at the same time untapped, chance with a potentially fundamental role in the prevention, diagnosis and prognosis of diseases. Computational methods are needed to combine this data to create a comprehensive view of a given disease. Network science can model biomedical data in terms of relationships among molecular players of different nature and has been successfully proposed as a new paradigm for studying human diseases. Patient stratification is an open challenge aimed at identifying subtypes with different disease manifestations, severity, and expected survival time. Several stratification approaches based on high-throughput gene expression measurements have been successfully applied. However, few attempts have been proposed to exploit the integration of various genotypic and phenotypic data to discover novel sub-types or improve the detection of known groupings. This article is categorized under: Cancer > Biomedical Engineering Cancer > Computational Models Cancer > Genetics/Genomics/Epigenetics.","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1623"},"PeriodicalIF":3.1,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9631281","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":"An update on the roles of transcription factor Ets1 in autoimmune diseases.","authors":"Lee Ann Garrett-Sinha","doi":"10.1002/wsbm.1627","DOIUrl":"10.1002/wsbm.1627","url":null,"abstract":"<p><p>Transcription factors are crucial to regulate gene expression in immune cells and in other cell types. In lymphocytes, there are a large number of different transcription factors that are known to contribute to cell differentiation and the balance between quiescence and activation. One such transcription factor is E26 oncogene homolog 1 (Ets1). Ets1 expression is high in quiescent B and T lymphocytes and its levels are decreased upon activation. The human ETS1 gene has been identified as a susceptibility locus for many autoimmune and inflammatory diseases. In accord with this, gene knockout of Ets1 in mice leads to development of a lupus-like autoimmune disease, with enhanced activation and differentiation of both B cells and T cells. Prior reviews have summarized functional roles for Ets1 based on studies of Ets1 knockout mice. In recent years, numerous additional studies have been published that further validate ETS1 as a susceptibility locus for human diseases where immune dysregulation plays a causative role. In this update, new information that further links Ets1 to human autoimmune diseases is organized and collated to serve as a resource. This update also describes recent studies that seek to understand molecularly how Ets1 regulates immune cell activation, either using human cells and tissues or mouse models. This resource is expected to be useful to investigators seeking to understand how Ets1 may regulate the human immune response, particularly in terms of its roles in autoimmunity and inflammation. This article is categorized under: Immune System Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Molecular and Cellular Physiology.</p>","PeriodicalId":29896,"journal":{"name":"WIREs Mechanisms of Disease","volume":" ","pages":"e1627"},"PeriodicalIF":4.6,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10842644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10215657","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}