The Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has revealed the virus's ability to induce multi-organ damage, including significant liver injury. The molecular mechanisms of liver dysfunction in COVID-19 patients are explored, focusing on direct viral infection, immune-mediated damage, and the gut–liver axis. SARS-CoV-2 enters liver cells through the Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) receptors, but alternative pathways, such as CD209/Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) and AXL receptors, can also contribute to viral entry. Additionally, immune responses, particularly the cytokine storm, exacerbate liver inflammation, leading to hepatocyte damage. Pre-existing liver conditions, such as metabolic-associated fatty liver disease (MAFLD), alcohol-related liver disease (ALD), and liver fibrosis, heighten the risk of severe outcomes in COVID-19 patients. Post-COVID-19 liver complications, including fibrosis progression and persistent liver damage, have been reported, with emerging evidence suggesting chronic inflammation, viral persistence, and autoimmune reactions as potential contributors. Furthermore, Drug-Induced Liver Injury (DILI) from COVID-19 treatments remains a concern, highlighting the need for careful management. Consequently, understanding the interplay between SARS-CoV-2 and the liver is critical for improving patient outcomes and developing targeted therapies to mitigate liver-related complications in both acute and Long COVID-19 phases. This article is categorized under:
The immune-oncology-microbiome (IOM) trio highlights the significant role of microbiomes in cancer progression by modulating immune evasion, genomic instability, and inflammation-key hallmarks of cancer. While microbiomes can exert both protective and detrimental effects on tumor development and treatment response, the mechanistic underpinnings-particularly those involving intratumoral microbiomes-remain poorly understood. To elucidate these dynamics, we frame the interplay between cancer, immune cells, and microbiomes through the lens of the Anna Karenina Principle (AKP)-using Leo Tolstoy's aphorism: "All happy families are alike; each unhappy family is unhappy in its own way." In biomedical terms, this translates to: all healthy systems including intratumoral microbiomes are alike, but each dysfunctional system fails in its own way. We hypothesize that either AKP or its inverse (anti-AKP) may govern microbial interactions that influence cancer progression. Analyzing four published cancer tissue microbiome datasets (Nejman 2020, Science), we identified two distinct patterns: AKP-driven increased microbial heterogeneity in lung and ovarian cancers, and anti-AKP-driven decreased heterogeneity in breast and colon cancers. We further propose cancer microbiome therapy (CMT) as an emerging frontier in microbiome-based therapeutics. The CMT may include the following strategies: (i) Restoring a healthy microbiome (including barrier tissue, tumor, blood microbiomes) to enhance immune function through ecosystem engineering; (ii) Developing specific microbial agents (species or their metabolites) to modulate crossroads of cancer immunotherapy; (iii) Engineering microbial agents to suppress cancer-causing microbes (oncomicrobes and complicit) and halt cancer progression; (iv) Reviving historical approaches like Coley's toxin and oncolytic viruses for direct cancer cell targeting. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Cancer > Computational Models.
The nucleolus, traditionally known for its role in ribosome biogenesis, is now recognized for its broader functions, including cellular stress adaptation and its involvement in various pathological processes, such as ribosomal alterations, viral infections, autoimmune disorders, and age-related diseases. Disruptions in nucleolar function can impair protein synthesis, cellular homeostasis, and immune responses, leading to multisystem disorders and increased susceptibility to neoplasms. This review classifies nucleolus-associated diseases into seven categories: deficiencies in protein synthesis, ribosomal and non-ribosomal alterations, cancer and nucleolar alterations, diseases related to aging and cellular stress, autoimmune diseases, and viral diseases. Understanding the complexity of the nucleolus and its dysfunctions represents a fundamental step toward advancing knowledge of the molecular basis of these pathologies, laying the groundwork for future research addressing its implications in cell biology and the development of human diseases. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.
Molecular research has gradually revealed the biological significance of genetically encoded information and how this information is transmitted and utilized in a cell. The scientific advances of the last few decades have brought about paradigm shifts in the strategies traditionally used to decipher biological information. From unidirectional approaches, we now have multidirectional model-system-based integrated OMICs that aim to describe the pathophysiology of diseases through a combination of genetic, transcriptomic, proteomic, and metabolomic data. Compared to other vertebrate models, zebrafish have a wealth of advantages that make them a powerful tool with a wide range of applications in biomedical research. The high degree of genetic conservation with humans, coupled with the availability of various gene manipulation techniques, has made zebrafish an immensely popular multi-utility genetic toolbox. This review describes the advances in the field of zebrafish-based biomedical research with a focus on its applications in disease modeling, functional omics, toxicology, and pharmacology. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Infectious Diseases > Molecular and Cellular Physiology Congenital Diseases > Molecular and Cellular Physiology.
Noncanonical proteins, encoded by previously overlooked genomic regions (part of the "dark genome"), are emerging as crucial players in human health and disease, expanding our understanding of the "dark proteome." This review explores their landscape, including proteins derived from long non-coding RNAs, circular RNAs, and alternative open reading frames. Recent advances in ribosome profiling, mass spectrometry, and proteogenomics have unveiled their involvement in critical cellular processes. We examine their roles in cancer, neurological disorders, cardiovascular diseases, and infectious diseases, highlighting their potential as novel biomarkers and therapeutic targets. The review addresses challenges in identifying and characterizing these proteins, particularly recently evolved ones, and discusses implications for drug discovery, including cancer immunotherapy and neoantigen sources. By synthesizing recent findings, we underscore the significance of noncanonical proteins in expanding our understanding of the human genome and proteome, and their promise in developing innovative diagnostic tools and targeted therapies. This overview aims to stimulate further research into this unexplored biological space, potentially revolutionizing approaches to disease treatment and personalized medicine.
AbstractAxonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure. Data from patients with MS, post‐mortem histological analysis, and animal models of demyelinating disease have elucidated patterns of MS pathogenesis and underlying mechanisms of neurodegeneration. MRI and molecular biomarkers have been proposed to identify predictors of neurodegeneration and risk factors for disease progression. Early signs of axonal dysfunction have come to light including impaired mitochondrial trafficking, structural axonal changes, and synaptic alterations. With sustained inflammation as well as impaired remyelination, axons succumb to degeneration contributing to CNS atrophy and worsening of disease. These studies highlight the role of chronic demyelination in the CNS in perpetuating axonal loss, and the difficulty in promoting remyelination and repair amidst persistent inflammatory insult. Regenerative and neuroprotective strategies are essential to overcome this barrier, with early intervention being critical to rescue axonal integrity and function. The clinical and basic research studies discussed in this review have set the stage for identifying key propagators of neurodegeneration in MS, leading the way for neuroprotective therapeutic development.This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology
Morphological scaling relationships, or allometries, describe how traits grow coordinately and covary among individuals in a population. The developmental regulation of scaling is essential to generate correctly proportioned adults across a range of body sizes, while the mis-regulation of scaling may result in congenital birth defects. Research over several decades has identified the developmental mechanisms that regulate the size of individual traits. Nevertheless, we still have poor understanding of how these mechanisms work together to generate correlated size variation among traits in response to environmental and genetic variation. Conceptually, morphological scaling can be generated by size-regulatory factors that act directly on multiple growing traits (trait-autonomous scaling), or indirectly via hormones produced by central endocrine organs (systemically regulated scaling), and there are a number of well-established examples of such mechanisms. There is much less evidence, however, that genetic and environmental variation actually acts on these mechanisms to generate morphological scaling in natural populations. More recent studies indicate that growing organs can themselves regulate the growth of other organs in the body. This suggests that covariation in trait size can be generated by network-regulated scaling mechanisms that respond to changes in the growth of individual traits. Testing this hypothesis, and one of the main challenges of understanding morphological scaling, requires connecting mechanisms elucidated in the laboratory with patterns of scaling observed in the natural world. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Comparative Development and Evolution > Organ System Comparisons Between Species.
Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool for investigating cell states and functions at the single-cell level. It has greatly revolutionized transcriptomic studies in many life science research fields, such as neurobiology, immunology, and developmental biology. With the fast development of both experimental platforms and bioinformatics approaches over the past decade, scRNA-seq is becoming economically feasible and experimentally practical for many biomedical laboratories.Drosophilahas served as an excellent model organism for dissecting cellular and molecular mechanisms that underlie tissue development, adult cell function, disease, and aging. The recent application of scRNA-seq methods toDrosophilatissues has led to a number of exciting discoveries. In this review, I will provide a summary of recent scRNA-seq studies inDrosophila, focusing on technical approaches and biological applications. I will also discuss current challenges and future opportunities of making new discoveries using scRNA-seq inDrosophila. This article is categorized under: Technologies > Analysis of the Transcriptome
Vertebrate nervous system function requires glial cells, including myelinating glia that insulate axons and provide trophic support that allows for efficient signal propagation by neurons. In vertebrate peripheral nervous systems, neural crest-derived glial cells known as Schwann cells (SCs) generate myelin by encompassing and iteratively wrapping membrane around single axon segments. SC gliogenesis and neurogenesis are intimately linked and governed by a complex molecular environment that shapes their developmental trajectory. Changes in this external milieu drive developing SCs through a series of distinct morphological and transcriptional stages from the neural crest to a variety of glial derivatives, including the myelinating sublineage. Cues originate from the extracellular matrix, adjacent axons, and the developing SC basal lamina to trigger intracellular signaling cascades and gene expression changes that specify stages and transitions in SC development. Here, we integrate the findings from in vitro neuron-glia co-culture experiments with in vivo studies investigating SC development, particularly in zebrafish and mouse, to highlight critical factors that specify SC fate. Ultimately, we connect classic biochemical and mutant studies with modern genetic and visualization tools that have elucidated the dynamics of SC development. This article is categorized under: Signaling Pathways > Cell Fate Signaling Nervous System Development > Vertebrates: Regional Development
Characterizing the proteome composition of organelles and subcellular regions of living cells can facilitate the understanding of cellular organization as well as protein interactome networks. Proximity labeling-based methods coupled with mass spectrometry (MS) offer a high-throughput approach for systematic analysis of spatially restricted proteomes. Proximity labeling utilizes enzymes that generate reactive radicals to covalently tag neighboring proteins. The tagged endogenous proteins can then be isolated for further analysis by MS. To analyze protein-protein interactions or identify components that localize to discrete subcellular compartments, spatial expression is achieved by fusing the enzyme to specific proteins or signal peptides that target to particular subcellular regions. Although these technologies have only been introduced recently, they have already provided deep insights into a wide range of biological processes. Here, we provide an updated description and comparison of proximity labeling methods, as well as their applications and improvements. As each method has its own unique features, the goal of this review is to describe how different proximity labeling methods can be used to answer different biological questions. This article is categorized under: Technologies > Analysis of Proteins.
The pulmonary system is comprised of two main compartments, airways and alveolar space. Their tissue and cellular complexity ensure lung function and protection from external agents, for example, virus. Two-dimensional (2D) in vitro systems and animal models have been largely employed to elucidate the molecular mechanisms underlying human lung development, physiology, and pathogenesis. However, neither of these models accurately recapitulate the human lung environment and cellular crosstalk. More recently, human-derived three-dimensional (3D) models have been generated allowing for a deeper understanding of cell-to-cell communication. However, the availability and accessibility of primary human cell sources from which generate the 2D and 3D models may be limited. In the past few years, protocols have been developed to successfully employ human pluripotent stem cells (hPSCs) and differentiate them toward pulmonary fate in vitro. In the present review, we discuss the advantages and pitfalls of hPSC-derived lung 2D and 3D models, including the main characteristics and potentials for these models and their current and future applications for modeling development and diseases. Lung organoids currently represent the closest model to the human pulmonary system. We further focus on the applications of lung organoids for the study of human diseases such as pulmonary fibrosis, infectious diseases, and lung cancer. Finally, we discuss the present limitations and potential future applications of 3D lung organoids. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion.
Acute myeloid leukemias (AML) and acute lymphoid leukemias (ALL) are heterogenous diseases encompassing a wide array of genetic mutations with both loss and gain of function phenotypes. Ultimately, these both result in the clonal overgrowth of blast cells in the bone marrow, peripheral blood, and other tissues. As a consequence of this, normal hematopoietic stem cell function is severely hampered. Technologies allowing for the early detection of genetic alterations and understanding of these varied molecular pathologies have helped to advance our treatment regimens toward personalized targeted therapies. In spite of this, both AML and ALL continue to be a major cause of morbidity and mortality worldwide, in part because molecular therapies for the plethora of genetic abnormalities have not been developed. This underscores the current need for better model systems for therapy development. This article reviews the current zebrafish models of AML and ALL and discusses how novel gene editing tools can be implemented to generate better models of acute leukemias. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Technologies > Perturbing Genes and Generating Modified Animals
The 3D organization of the genome facilitates gene regulation, replication, and repair, making it a key feature of genomic function and one that remains to be properly understood. Over the past two decades, a variety of chromosome conformation capture (3C) methods have delineated genome folding from megabase-scale compartments and topologically associating domains (TADs) down to kilobase-scale enhancer-promoter interactions. Understanding the functional role of each layer of genome organization is a gateway to understanding cell state, development, and disease. Here, we discuss the evolution of 3C-based technologies for mapping 3D genome organization. We focus on genomics methods and provide a historical account of the development from 3C to Hi-C. We also discuss ChIP-based techniques that focus on 3D genome organization mediated by specific proteins, capture-based methods that focus on particular regions or regulatory elements, 3C-orthogonal methods that do not rely on restriction digestion and proximity ligation, and methods for mapping the DNA-RNA and RNA-RNA interactomes. We consider the biological discoveries that have come from these methods, examine the mechanistic contributions of CTCF, cohesin, and loop extrusion to genomic folding, and detail the 3D genome field's current understanding of nuclear architecture. Finally, we give special consideration to Micro-C as an emerging frontier in chromosome conformation capture and discuss recent Micro-C findings uncovering fine-scale chromatin organization in unprecedented detail. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics
Studies in model organisms have demonstrated that extensive communication occurs between distant organs both during development and in diseases such as cancer. Organs communicate with each other to coordinate growth and reach the correct size, while the fate of tumor cells depend on the outcome of their interaction with the immune system and peripheral tissues. In this review, we outline recent studies inDrosophila, which have enabled an improved understanding of the complex crosstalk between organs in the context of both organismal and tumor growth. We argue thatDrosophilais a powerful model organism for studying these interactions, and these studies have the potential for improving our understanding of signaling pathways and candidate factors that mediate this conserved interorgan crosstalk. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Early Embryonic Development > Development to the Basic Body Plan Invertebrate Organogenesis > Flies
The study of the mechanisms controlling organ size during development and regeneration is critical to understanding how complex life arises from cooperating single cells. Long bones are powerful models in this regard, as their size depends on a scaffold made from another tissue (cartilage, composed of chondrocytes), and both tissues interact during the growth period. Investigating long bone growth offers a valuable window into the processes that integrate internal and external cues to yield finely controlled size of organs. Within the cellular and molecular pathways that control bone growth, the regulation of stem-cell renewal, along with amplification and differentiation of their progeny, are key to understanding normal and perturbed long-bone development. The phenomenon of "catch-up" growth-where cellular hyperproliferation occurs following injury to restore a normal growth trajectory-reveals key aspects of this regulation, such as the fact that bone growth is target-seeking. The control mechanisms that lead to this behavior are either bottom-up or top-down, and the interaction between these modes is likely critical to achieve a highly nuanced, yet flexible, degree of control. The role of cartilage-intrinsic mechanisms has been well studied, establishing a very solid groundwork for this field. However, addressing the unanswered questions of bone growth arguably requires new hypotheses and approaches. Future research could for example address to what extent extrinsic signals and cells, as well as communication with other tissues, modulate intra-limb and inter-organ growth coordination.This article is categorized under:Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and NichesEstablishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and TimingVertebrate Organogenesis > Musculoskeletal and Vascular
The compound eyes of flies exhibit striking variation in size, which has contributed to the adaptation of these animals to different habitats and their evolution of specialist behaviors. These differences in size are caused by differences in the number and/or size of ommatidia, which are specified during the development of the retinal field in the eye imaginal disc. While the genes and developmental mechanisms that regulate the formation of compound eyes are understood in great detail in the fruit fly Drosophila melanogaster, we know very little about the genetic changes and mechanistic alterations that lead to natural variation in ommatidia number and/or size, and thus overall eye size, within and between fly species. Understanding the genetic and developmental bases for this natural variation in eye size not only has great potential to help us understand adaptations in fly vision but also determine how eye size and organ size more generally are regulated. Here we explore the genetic and developmental mechanisms that could underlie natural differences in compound eye size within and among fly species based on our knowledge of eye development in D. melanogaster and the few cases where the causative genes and mechanisms have already been identified. We suggest that the fly eye provides an evolutionary and developmental framework to better understand the regulation and diversification of this crucial sensory organ globally at a systems level as well as the gene regulatory networks and mechanisms acting at the tissue, cellular and molecular levels. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Invertebrate Organogenesis > Flies Comparative Development and Evolution > Regulation of Organ Diversity.
All vertebrates have a spinal cord with dimensions and shape specific to their species. Yet how species-specific organ size and shape are achieved is a fundamental unresolved question in biology. The formation and sculpting of organs begins during embryonic development. As it develops, the spinal cord extends in anterior-posterior direction in synchrony with the overall growth of the body. The dorsoventral (DV) and apicobasal lengths of the spinal cord neuroepithelium also change, while at the same time a characteristic pattern of neural progenitor subtypes along the DV axis is established and elaborated. At the basis of these changes in tissue size and shape are biophysical determinants, such as the change in cell number, cell size and shape, and anisotropic tissue growth. These processes are controlled by global tissue-scale regulators, such as morphogen signaling gradients as well as mechanical forces. Current challenges in the field are to uncover how these tissue-scale regulatory mechanisms are translated to the cellular and molecular level, and how regulation of distinct cellular processes gives rise to an overall defined size. Addressing these questions will help not only to achieve a better understanding of how size is controlled, but also of how tissue size is coordinated with the specification of pattern. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Signaling Pathways > Global Signaling Mechanisms Nervous System Development > Vertebrates: General Principles
Nervous system development proceeds via well-orchestrated processes involving a balance between progressive and regressive events including stabilization or elimination of axons, synapses, and even entire neurons. These progressive and regressive events are driven by functionally antagonistic signaling pathways with the dominant pathway eventually determining whether a neural element is retained or removed. Many of these developmental sculpting events are triggered by final target innervation necessitating a long-distance mode of communication. While long-distance progressive signaling has been well characterized, particularly for neurotrophic factors, there remains relatively little known about how regressive events are triggered from a distance. Here we discuss the emergent phenomenon of long-distance regressive signaling pathways. In particular, we will cover (a) progressive and regressive cues known to be employed after target innervation, (b) the mechanisms of long-distance signaling from an endosomal platform, (c) recent evidence that long-distance regressive cues emanate from platforms like death receptors or repulsive axon guidance receptors, and (d) evidence that these pathways are exploited in pathological scenarios. This article is categorized under: Nervous System Development > Vertebrates: General Principles Signaling Pathways > Global Signaling Mechanisms Establishment of Spatial and Temporal Patterns > Cytoplasmic Localization.
Faithful establishment and maintenance of proportion is seen across biological systems and provides a glimpse at fundamental rules of scaling that underlie development and evolution. Dysregulation of proportion is observed in a range of human diseases and growth disorders, indicating that proper scaling is an essential component of normal anatomy and physiology. However, when viewed through an evolutionary lens, shifts in the regulation of relative proportion are one of the most striking sources of morphological diversity among organisms. To date, the mechanisms via which relative proportion is specified and maintained remain unclear. Through the application of powerful experimental, genetic and molecular approaches, the teleost fin has provided an effective model to investigate the regulation of scaling, size, and relative growth in vertebrate organisms.This article is categorized under:Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and TimingAdult Stem Cells, Tissue Renewal, and Regeneration > RegenerationComparative Development and Evolution > Regulation of Organ Diversity
