Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. In addition to generating genomic heterogeneity that acts as a substrate for natural selection, CIN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway. These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.

Innate lymphoid cells (ILCs) are lymphocytes that do not express the type of diversified antigen receptors expressed on T cells and B cells. ILCs are largely tissue-resident cells and are deeply integrated into the fabric of tissues. The discovery and investigation of ILCs over the past decade has changed our perception of immune regulation and how the immune system contributes to the maintenance of tissue homeostasis. We now know that cytokine-producing ILCs contribute to multiple immune pathways by, for example, sustaining appropriate immune responses to commensals and pathogens at mucosal barriers, potentiating adaptive immunity, and regulating tissue inflammation. Critically, the biology of ILCs also extends beyond classical immunology to metabolic homeostasis, tissue remodeling, and dialog with the nervous system. The last 10 years have also contributed to our greater understanding of the transcriptional networks that regulate lymphocyte commitment and delineation. This, in conjunction with the recent advances in our understanding of the influence of local tissue microenvironments on the plasticity and function of ILCs, has led to a re-evaluation of their existing categorization. In this review, we distill the advances in ILC biology over the past decade to refine the nomenclature of ILCs and highlight the importance of ILCs in tissue homeostasis, morphogenesis, metabolism, repair, and regeneration.

Eukaryotic cells contain large assemblies of RNA and protein, referred to as ribonucleoprotein (RNP) granules, which include cytoplasmic P-bodies, stress granules, and neuronal and germinal granules, as well as nuclear paraspeckles, Cajal bodies, and RNA foci formed from repeat expansion RNAs. Recent evidence argues that intermolecular RNA-RNA interactions play a role in forming and determining the composition of certain RNP granules. We hypothesize that intermolecular RNA-RNA interactions are favored in cells yet are limited by RNA-binding proteins, helicases, and ribosomes, thereby allowing normal RNA function. An over-abundance of intermolecular RNA-RNA interactions may be toxic since perturbations that increase RNA-RNA interactions such as long repeat expansion RNAs, arginine-containing dipeptide repeat polypeptides, and sequestration or loss of abundant RNA-binding proteins can contribute to degenerative diseases.

There is tremendous enthusiasm for the microbiome in academia and industry. This Perspective argues that in order to realize its potential, the field needs to focus on establishing causation and molecular mechanism with an emphasis on phenotypes that are large in magnitude, easy to measure, and unambiguously driven by the microbiota.

Krebs cycle intermediates traditionally link to oxidative phosphorylation whilst also making key cell components. It is now clear that some of these metabolites also act as signals. Succinate plays an important role in inflammatory, hypoxic, and metabolic signaling, while itaconate (from another Krebs cycle intermediate, cis-aconitate) has an anti-inflammatory role.

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.

mRNA modifications are defining a novel layer of complexity that is becoming widely appreciated as the epitranscriptome. This SnapShot summarizes the major breakthroughs in the burgeoning field of mRNA modifications to provide an overview of the molecular players involved and insights gained into the functional consequences of the growing number of modifications occurring within mRNA transcripts.

The evidence that most adult-onset common diseases have a polygenic genetic architecture fully consistent with robust biological systems supported by multiple back-up mechanisms is now overwhelming. In this context, we consider the recent "omnigenic" or "core genes" model. A key assumption of the model is that there is a relatively small number of core genes relevant to any disease. While intuitively appealing, this model may underestimate the biological complexity of common disease, and therefore, the goal to discover core genes should not guide experimental design. We consider other implications of polygenicity, concluding that a focus on patient stratification is needed to achieve the goals of precision medicine.

Machine learning, a collection of data-analytical techniques aimed at building predictive models from multi-dimensional datasets, is becoming integral to modern biological research. By enabling one to generate models that learn from large datasets and make predictions on likely outcomes, machine learning can be used to study complex cellular systems such as biological networks. Here, we provide a primer on machine learning for life scientists, including an introduction to deep learning. We discuss opportunities and challenges at the intersection of machine learning and network biology, which could impact disease biology, drug discovery, microbiome research, and synthetic biology.

Tubulin posttranslational modifications are currently emerging as important regulators of the microtubule cytoskeleton and thus have a strong potential to be implicated in a number of disorders. Here, we review the latest advances in understanding the physiological roles of tubulin modifications and their links to a variety of pathologies.

A major challenge in the field of neurodegenerative diseases and brain aging is to identify the body's intrinsic mechanism that could sense the central nervous system (CNS) damage early and protect the brain from neurodegeneration. Accumulating evidence suggests that disease-associated microglia (DAM), a recently identified subset of CNS resident macrophages found at sites of neurodegeneration, might play such a protective role. Here, we propose that microglia are endowed with a dedicated sensory mechanism, which includes the Trem2 signaling pathway, to detect damage within the CNS in the form of neurodegeneration-associated molecular patterns (NAMPs). Combining data from transcriptional analysis of DAM at single-cell level and from human genome-wide association studies (GWASs), we discuss potential function of different DAM pathways in the diseased brain and outline how manipulating DAM may create new therapeutic opportunities.

Great strides have been made over the past decade toward comprehensive study of metabolism. Mass spectrometry (MS) has played a central role by enabling measurement of many metabolites simultaneously. Tracking metabolite labeling from stable isotope tracers can in addition reveal pathway activities. Here, we describe the basics of metabolite measurement by MS, including sample preparation, metabolomic analysis, and data interpretation. In addition, drawing on examples of successful experiments, we highlight the ways in which metabolomics and isotope tracing can illuminate biology.

The essential roles played by the immune system in the discrimination between self- versus non/altered-self and its integral role in promoting host defense against invading microbes and tumors have been extensively studied for many years. In these contexts, significant advances have been made in defining the molecular and cellular networks that orchestrate cell-cell communication to mediate host defense and pathogen expulsion. Notably, recent studies indicate that in addition to these classical immune functions, cells of the innate and adaptive immune system also sense complex tissue- and environment-derived signals, including those from the nervous system and the diet. In turn these responses regulate physiologic processes in multiple tissues throughout the body, including nervous system function, metabolic state, thermogenesis, and tissue repair. In this review we propose an integrated view of how the mammalian immune system senses and interacts with other complex organ systems to maintain tissue and whole-body homeostasis.

Nuclear import receptors are central players in transporting protein cargoes into the nucleus. Moving beyond this role, four newly published articles describe a function in regulating supramolecular assemblies by fine-tuning the phase separating properties of RNA-binding proteins, which has implications for a variety of devastating neurodegenerative disorders.

This SnapShot provides a list of the tumor types characterized by The Cancer Genome Atlas (TCGA) program. Key findings shown are the most relevant discoveries described in each marker paper for the tumor type.

Biallelic mutations in the RPE65 gene are associated with inherited retinal degenerations/dystrophies (IRD) and disrupt the visual cycle, leading to loss of vision. A new adenoviral vector-based gene therapy surgically delivered to retinal cells provides normal human RPE65 protein that can restore the visual cycle and some vision. To view this Bench to Bedside, open or download the PDF.

CGAS responds to cytosolic DNA by initiating a STING-dependent response that ultimately engages innate immune effectors to ensure the preservation of organismal homeostasis.

MicroRNAs (miRNAs) are ∼22 nt RNAs that direct posttranscriptional repression of mRNA targets in diverse eukaryotic lineages. In humans and other mammals, these small RNAs help sculpt the expression of most mRNAs. This article reviews advances in our understanding of the defining features of metazoan miRNAs and their biogenesis, genomics, and evolution. It then reviews how metazoan miRNAs are regulated, how they recognize and cause repression of their targets, and the biological functions of this repression, with a compilation of knockout phenotypes that shows that important biological functions have been identified for most of the broadly conserved miRNAs of mammals.

The construction of a predictive model of an entire eukaryotic cell that describes its dynamic structure from atomic to cellular scales is a grand challenge at the intersection of biology, chemistry, physics, and computer science. Having such a model will open new dimensions in biological research and accelerate healthcare advancements. Developing the necessary experimental and modeling methods presents abundant opportunities for a community effort to realize this goal. Here, we present a vision for creation of a spatiotemporal multi-scale model of the pancreatic β-cell, a relevant target for understanding and modulating the pathogenesis of diabetes.

Enveloped viruses enter cells by inducing fusion of viral and cellular membranes, a process catalyzed by a specialized membrane-fusion protein expressed on their surface. This review focuses on recent structural studies of viral fusion proteins with an emphasis on their metastable prefusion form and on interactions with neutralizing antibodies. The fusion glycoproteins have been difficult to study because they are present in a labile, metastable form at the surface of infectious virions. Such metastability is a functional requirement, allowing these proteins to refold into a lower energy conformation while transferring the difference in energy to catalyze the membrane fusion reaction. Structural studies have shown that stable immunogens presenting the same antigenic sites as the labile wild-type proteins efficiently elicit potently neutralizing antibodies, providing a framework with which to engineer the antigens for stability, as well as identifying key vulnerability sites that can be used in next-generation subunit vaccine design.