WIREs Mechanisms of Disease最新文献

Nearly one-fourth of the global population is infected by Mycobacterium tuberculosis (Mtb), and approximately 90%-95% remain asymptomatic as latent tuberculosis infection (LTBI), an estimated 5%-10% of those with latent infections will eventually progress to active tuberculosis (ATB). Although it is widely accepted that LTBI transitioning to ATB results from a disruption of host immune balance and a weakening of protective immune responses, the exact underlying immunological mechanisms that promote this conversion are not well characterized. Thus, it is difficult to accurately predict tuberculosis (TB) progression in advance, leaving the LTBI population as a significant threat to TB prevention and control. This article systematically explores three aspects related to the immunoregulatory mechanisms and translational research about LTBI: (1) the distinct immunocytological characteristics of LTBI and ATB, (2) LTBI diagnostic markers discovery related to host anti-TB immunity and metabolic pathways, and (3) vaccine development focus on LTBI. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology Infectious Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Genetics/Genomics/Epigenetics.

Liver disease represents a significant global burden, placing individuals at a heightened risk of developing cirrhosis and liver cancer. Viral infections act as a primary cause of liver diseases on a worldwide scale. Infections involving hepatitis viruses, notably hepatitis B, C, and E viruses, stand out as the most prevalent contributors to acute and chronic intrahepatic adverse outcome, although the hepatitis C virus (HCV) can be effectively cured with antiviral drugs, but no preventative vaccination developed. Hepatitis B virus (HBV) and HCV can lead to both acute and chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC), which are principal causes of worldwide morbidity and mortality. Other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), are capable of causing liver damage. Therefore, it is essential to recognize that virus infections and liver diseases are intricate and interconnected processes. A profound understanding of the underlying relationship between virus infections and liver diseases proves pivotal in the effective prevention, diagnosis, and treatment of these conditions. In this review, we delve into the mechanisms by which virus infections induce liver diseases, as well as explore the pathogenesis, diagnosis, and treatment of liver diseases. This article is categorized under: Infectious Diseases > Biomedical Engineering.

Cardiac-coronary interaction is fundamental to the function of the heart. As one of the highest metabolic organs in the body, the cardiac oxygen demand is met by blood perfusion through the coronary vasculature. The coronary vasculature is largely embedded within the myocardial tissue which is continually contracting and hence squeezing the blood vessels. The myocardium-coronary vessel interaction is two-ways and complex. Here, we review the different types of cardiac-coronary interactions with a focus on insights gained from mathematical models. Specifically, we will consider the following: (1) myocardial-vessel mechanical interaction; (2) metabolic-flow interaction and regulation; (3) perfusion-contraction matching, and (4) chronic interactions between the myocardium and coronary vasculature. We also provide a discussion of the relevant experimental and clinical studies of different types of cardiac-coronary interactions. Finally, we highlight knowledge gaps, key challenges, and limitations of existing mathematical models along with future research directions to understand the unique myocardium-coronary coupling in the heart. This article is categorized under: Cardiovascular Diseases > Computational Models Cardiovascular Diseases > Biomedical Engineering Cardiovascular Diseases > Molecular and Cellular Physiology.

Fungi are the cause of more than a billion infections in humans every year, although their interactions with the host are still neglected compared to bacteria. Major systemic fungal infections are very unusual in the healthy population, due to the long history of coevolution with the human host. Humans are routinely exposed to environmental fungi and can host a commensal mycobiota, which is increasingly considered as a key player in health and disease. Here, we review the current knowledge on host-fungi coevolution and the factors that regulate their interaction. On one hand, fungi have learned to survive and inhabit the host organisms as a natural ecosystem, on the other hand, the host immune system finely tunes the response toward fungi. In turn, recognition of fungi as commensals or pathogens regulates the host immune balance in health and disease. In the human gut ecosystem, yeasts provide a fingerprint of the transient microbiota. Their status as passengers or colonizers is related to the integrity of the gut barrier and the risk of multiple disorders. Thus, the study of this less known component of the microbiota could unravel the rules of the transition from passengers to colonizers and invaders, as well as their dependence on the innate component of the host's immune response. This article is categorized under: Infectious Diseases > Environmental Factors Immune System Diseases > Environmental Factors Infectious Diseases > Molecular and Cellular Physiology.

The fungal component of the microbiota, the mycobiota, has been neglected for a long time due to its poor richness compared to bacteria. Limitations in fungal detection and taxonomic identification arise from using metagenomic approaches, often borrowed from bacteriome analyses. However, the relatively recent discoveries of the ability of fungi to modulate the host immune response and their involvement in human diseases have made mycobiota a fundamental component of the microbial communities inhabiting the human host, deserving some consideration in host-microbe interaction studies and in metagenomics. Here, we reviewed recent data on the identification of yeasts of the Ascomycota phylum across human body districts, focusing on the most representative genera, that is, Saccharomyces and Candida. Then, we explored the key factors involved in shaping the human mycobiota across the lifespan, ranging from host genetics to environment, diet, and lifestyle habits. Finally, we discussed the strengths and weaknesses of culture-dependent and independent methods for mycobiota characterization. Overall, there is still room for some improvements, especially regarding fungal-specific methodological approaches and bioinformatics challenges, which are still critical steps in mycobiota analysis, and to advance our knowledge on the role of the gut mycobiota in human health and disease. This article is categorized under: Immune System Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Environmental Factors Infectious Diseases > Environmental Factors.

In multicellular organisms, sexed gonads have evolved that facilitate release of sperm versus eggs, and bilaterian animals purposefully combine their gametes via mating behaviors. Distinct neural circuits have evolved that control these physically different mating events for animals producing eggs from ovaries versus sperm from testis. In this review, we will describe the developmental mechanisms that sexually differentiate neural circuits across three major clades of bilaterian animals-Ecdysozoa, Deuterosomia, and Lophotrochozoa. While many of the mechanisms inducing somatic and neuronal sex differentiation across these diverse organisms are clade-specific rather than evolutionarily conserved, we develop a common framework for considering the developmental logic of these events and the types of neuronal differences that produce sex-differentiated behaviors. This article is categorized under: Congenital Diseases > Stem Cells and Development Neurological Diseases > Stem Cells and Development.

Angiogenesis is the process wherein endothelial cells (ECs) form sprouts that elongate from the pre-existing vasculature to create new vascular networks. In addition to its essential role in normal development, angiogenesis plays a vital role in pathologies such as cancer, diabetes and atherosclerosis. Mathematical and computational modeling has contributed to unraveling its complexity. Many existing theoretical models of angiogenic sprouting are based on the "snail-trail" hypothesis. This framework assumes that leading ECs positioned at sprout tips migrate toward low-oxygen regions while other ECs in the sprout passively follow the leaders' trails and proliferate to maintain sprout integrity. However, experimental results indicate that, contrary to the snail-trail assumption, ECs exchange positions within developing vessels, and the elongation of sprouts is primarily driven by directed migration of ECs. The functional role of cell rearrangements remains unclear. This review of the theoretical modeling of angiogenesis is the first to focus on the phenomenon of cell mixing during early sprouting. We start by describing the biological processes that occur during early angiogenesis, such as phenotype specification, cell rearrangements and cell interactions with the microenvironment. Next, we provide an overview of various theoretical approaches that have been employed to model angiogenesis, with particular emphasis on recent in silico models that account for the phenomenon of cell mixing. Finally, we discuss when cell mixing should be incorporated into theoretical models and what essential modeling components such models should include in order to investigate its functional role. This article is categorized under: Cardiovascular Diseases > Computational Models Cancer > Computational Models.

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.

A number of blinding diseases caused by damage to the optic nerve result in progressive vision loss or loss of visual acuity. Secondary glaucoma results from traumatic injuries, pseudoexfoliation or pigmentary dispersion syndrome. Progressive peripheral vision loss is common to all secondary glaucoma irrespective of the initial event. Axon regeneration is a potential therapeutic avenue to restore lost vision in these patients. In contrast to the usual approach of having the worst possible patient population for initial therapies, axon regeneration may require consideration of appropriate patient population even for initial treatment trials. The current state of axon regeneration therapies, their potential future and suitable patient population when ready is discussed in this perspective. The selection of patients are important for adoption of axon regeneration specifically in the areas of central nervous system regenerative medicine. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Neurological Diseases > Biomedical Engineering Metabolic Diseases > Molecular and Cellular Physiology.

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.