WIREs Mechanisms of Disease最新文献

A systematic review of several acute inflammatory diseases ranging from sepsis and trauma/hemorrhagic shock to the relevant pathology of the decade, COVID-19, points to the cytokine interleukin (IL)-17A as being centrally involved in the propagation of inflammation. We summarize the role of IL-17A in acute inflammation, leveraging insights made possible by biological network analysis and novel computational methodologies aimed at defining the spatiotemporal spread of inflammation in both experimental animal models and humans. These studies implicate IL-17A in the cross-tissue spread of inflammation, a process that appears to be in part regulated through neural mechanisms. Although acute inflammatory diseases are currently considered distinct from chronic inflammatory pathologies, we suggest that chronic inflammation may represent repeated, cyclical episodes of acute inflammation driven by mechanisms involving IL-17A. Thus, insights from computational modeling of acute inflammatory diseases may improve diagnosis and treatment of chronic inflammation; in turn, therapeutics developed for chronic/autoimmune disease may be of benefit in acute inflammation. This article is categorized under: Immune System Diseases > Computational Models.

The mammalian acrosome is a secretory vesicle attached to the sperm nucleus whose fusion with the overlying plasma membrane is required to achieve fertilization. Acrosome biogenesis starts during meiosis, but it lasts through the entire process of haploid cell differentiation (spermiogenesis). Acrosome biogenesis is a stepwise process that involves membrane traffic from the Golgi apparatus, but it also seems that the lysosome/endosome system participates in this process. Defective sperm head morphology is accompanied by defective acrosome shape and function, and patients with these characteristics are infertile or subfertile. The most extreme case of acrosome biogenesis failure is globozoospermia syndrome, which is primarily characterized by the presence of round-headed spermatozoa without acrosomes with cytoskeleton defects around the nucleus and infertility. Several genes participating in acrosome biogenesis have been uncovered using genetic deletions in mice, but only a few of them have been found to be deleted or modified in patients with globozoospermia. Understanding acrosome biogenesis is crucial to uncovering the molecular basis of male infertility and developing new diagnostic tools and assisted reproductive technologies that may help infertile patients through more effective treatment techniques. This article is categorized under: Reproductive System Diseases > Environmental Factors Infectious Diseases > Stem Cells and Development Reproductive System Diseases > Molecular and Cellular Physiology.

Plants commonly face the threat of invasion by a wide variety of pathogens and have developed sophisticated immune mechanisms to defend against infectious diseases. However, successful pathogens have evolved diverse mechanisms to overcome host immunity and cause diseases. Different cell structures and unique cellular organelles carried by plant cells endow plant-specific defense mechanisms, in addition to the common framework of innate immune system shared by both plants and animals. Effectors serve as crucial virulence weapons employed by phytopathogens to disarm the plant immune system and promote infection. Here we summarized the many diverse strategies by which phytopathogen effectors overcome plant defense and prospected future perspectives. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.

Drug therapies for treating peripheral nerve injury repair have shown significant promise in preclinical studies. Despite this, drug treatments are not used routinely clinically to treat patients with peripheral nerve injuries. Drugs delivered systemically are often associated with adverse effects to other tissues and organs; it remains challenging to predict the effective concentration needed at an injured nerve and the appropriate delivery strategy. Local drug delivery approaches are being developed to mitigate this, for example via injections or biomaterial-mediated release. We propose the integration of mathematical modeling into the development of local drug delivery protocols for peripheral nerve injury repair. Mathematical models have the potential to inform understanding of the different transport mechanisms at play, as well as quantitative predictions around the efficacy of individual local delivery protocols. We discuss existing approaches in the literature, including drawing from other research fields, and present a process for taking forward an integrated mathematical-experimental approach to accelerate local drug delivery approaches for peripheral nerve injury repair. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Neurological Diseases > Computational Models Neurological Diseases > Biomedical Engineering.

Male germ cells undergo an extreme but fascinating process of chromatin remodeling that begins in the testis during the last phase of spermatogenesis and continues through epididymal sperm maturation. Most of the histones are replaced by small proteins named protamines, whose high basicity leads to a tight genomic compaction. This process is epigenetically regulated at many levels, not only by posttranslational modifications, but also by readers, writers, and erasers, in a context of a highly coordinated postmeiotic gene expression program. Protamines are key proteins for acquiring this highly specialized chromatin conformation, needed for sperm functionality. Interestingly, and contrary to what could be inferred from its very specific DNA-packaging function across protamine-containing species, human sperm chromatin contains a wide spectrum of protamine proteoforms, including truncated and posttranslationally modified proteoforms. The generation of protamine knock-out models revealed not only chromatin compaction defects, but also collateral sperm alterations contributing to infertile phenotypes, evidencing the importance of sperm chromatin protamination toward the generation of a new individual. The unique features of sperm chromatin have motivated its study, applying from conventional to the most ground-breaking techniques to disentangle its peculiarities and the cellular mechanisms governing its successful conferment, especially relevant from the protein point of view due to the important epigenetic role of sperm nuclear proteins. Gathering and contextualizing the most striking discoveries will provide a global understanding of the importance and complexity of achieving a proper chromatin compaction and exploring its implications on postfertilization events and beyond. This article is categorized under: Reproductive System Diseases > Genetics/Genomics/Epigenetics Reproductive System Diseases > Molecular and Cellular Physiology.

Alzheimer's disease (AD) is one of the progressive neurodegenerative disorders and the most common cause of dementia in the elderly worldwide causing difficulties in the daily life of the patient. AD is characterized by the aberrant accumulation of β-amyloid plaques and tau protein-containing neurofibrillary tangles (NFTs) in the brain giving rise to neuroinflammation, oxidative stress, synaptic failure, and eventual neuronal cell death. The total cost of care in AD treatment and related health care activities is enormous and pharmaceutical drugs approved by Food and Drug Administration have not manifested sufficient efficacy in protection and therapy. In recent years, there are growing studies that contribute a fundamental understanding to AD pathogenesis, AD-associated risk factors, and pharmacological intervention. However, greater molecular process-oriented research in company with suitable experimental models is still of the essence to enhance the prospects for AD therapy and cell lines as a disease model are still the major part of this milestone. In this review, we provide an insight into molecular mechanisms, particularly the recent concept in gut-brain axis, vascular dysfunction and autophagy, and current models used in the study of AD. Here, we emphasized the importance of therapeutic strategy targeting multiple mechanisms together with utilizing appropriate models for the discovery of novel effective AD therapy. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.

Central nervous system (CNS) inflammation is a key factor in multiple sclerosis (MS). Invasion of peripheral immune cells into the CNS resulting from an unknown signal or combination of signals results in activation of resident immune cells and the hallmark feature of the disease: demyelinating lesions. These lesion sites are an amalgam of reactive peripheral and central immune cells, astrocytes, damaged and dying oligodendrocytes, and injured neurons and axons. Sustained inflammation affects cells directly located within the lesion site and further abnormalities are apparent diffusely throughout normal-appearing white matter and grey matter. It is only relatively recently, using animal models, new tissue sampling techniques, and next-generation sequencing, that molecular changes occurring in CNS resident cells have been broadly captured. Advances in cell isolation through Fluorescence Activated Cell Sorting (FACS) and laser-capture microdissection together with the emergence of single-cell sequencing have enabled researchers to investigate changes in gene expression in astrocytes, microglia, and oligodendrocytes derived from animal models of MS as well as from primary patient tissue. The contribution of some dysregulated pathways has been followed up in individual studies; however, corroborating results often go unreported between sequencing studies. To this end, we have consolidated results from numerous RNA-sequencing studies to identify and review novel patterns of differentially regulated genes and pathways occurring within CNS glial cells in MS. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.

The function of the liver depends critically on its blood supply. Numerous in silico models have been developed to study various aspects of the hepatic circulation, including not only the macro-hemodynamics at the organ level, but also the microcirculation at the lobular level. In addition, computational models of blood flow and bile flow have been used to study the transport, metabolism, and clearance of drugs in pharmacokinetic studies. These in silico models aim to provide insights into the liver organ function under both healthy and diseased states, and to assist quantitative analysis for surgical planning and postsurgery treatment. The purpose of this review is to provide an update on state-of-the-art in silico models of the hepatic circulation and transport processes. We introduce the numerical methods and the physiological background of these models. We also discuss multiscale frameworks that have been proposed for the liver, and their linkage with the large context of systems biology, systems pharmacology, and the Physiome project. This article is categorized under: Metabolic Diseases > Computational Models Metabolic Diseases > Biomedical Engineering Cardiovascular Diseases > Computational Models.

Organoids are units of function of a given organ able to reproduce, in culture, a biological structure similar in architecture and function to its counterpart in vivo. Today, it is possible to develop an organoid from a fragment of tissue, a stem cell located in an adult organ, an embryonic stem cell, or an induced pluripotent stem cell. In the past decade, many organoids have been developed which mimic stomach, pancreas, liver and brain tissues, optic cups, among many others. Additionally, different male reproductive system organs have already been developed as organoids, including the prostate and testis. These 3D cultures may be of great importance for urological cancer research and have the potential to be used in fertility research for the study of spermatozoa production and maturation, germ cells-somatic cells interactions, and mechanisms of disease. They also provide an accurate preclinical pipeline for drug testing and discovery, as well as for the study of drug resistance. In this work, we revise the current knowledge on organoid technology and its use in healthcare and research, describe the male reproductive system organoids and other biomaterials already developed, and discuss their current application. Finally, we highlight the research gaps, challenges, and opportunities in the field and propose strategies to improve the use of organoids for the study of male infertility situations. This article is categorized under: Reproductive System Diseases > Stem Cells and Development Reproductive System Diseases > Biomedical Engineering.