Cold Spring Harbor perspectives in biology最新文献

The PIEZO1 and PIEZO2 membrane proteins form uniquely structured calcium permeable nonselective cation channels dedicated to mechanical force sensing in eukaryotic cells. In this review of the scientific literature, we address PIEZOs in the heart. PIEZOs enable the formation of the aortic valve, cardiac vasculature, and pericardial drainage. In the established heart, they enable baroreceptor pressure sensing and reflex regulation of the heart rate and influence the heart's size and stiffness through roles in cardiac myocytes and cardiac fibroblasts. Therefore, mechanical force sensing by PIEZOs participates in normal cardiac development and function. There is also interest in PIEZOs in pathophysiology, when the structure and mechanical properties of the heart often change. Studies in rats and mice suggest that experimentally induced cardiac stress and injury cause PIEZO upregulation that is adverse. Similar changes may occur in human heart disease, creating potential for therapeutic benefit through PIEZO modulation. This is a productive, accelerating, and exciting new research topic with importance for our understanding of the heart and its diseases.

Cell migration phenomenon has inspired and benefited from computational modeling for decades. Here, we review recent applications of traditional bottom-up modeling to three aspects of cell migration: the role of membrane tension (MT) in organizing directional cell motility, the role of the electric field (EF) as the directional cue for migration, and the mechanics of three-dimensional migration. We then discuss nascent applications of machine learning (ML) to cell migration and galvanotaxis. We focus on the migratory mechanisms of the single cell and highlight the feedback between theory and experiment.

Over the years, the fission yeast has become a reference model for telomere biology studies as this organism shares with mammals a highly conserved telomere composition. Here, we highlight the latest discoveries in telomere replication in fission yeast and show how this research brings new insights into the understanding of the replication and maintenance of mammalian telomeres.

Skeletal muscle owes its plasticity and ability to regenerate following severe injury to the resident somatic stem cells, termed satellite cells, of which a subset represent multipotent muscle stem cells (MuSCs). Adult MuSCs originate from mesoderm-derived somitic cells during embryonic development and are necessary for the maintenance and regeneration of skeletal muscle throughout life. In adult muscle, MuSCs reside under the basal lamina where extrinsic cues modulate their quiescence in resting conditions and activation in response to injury. The process of MuSC activation is highly regulated by the niche microenvironment, and perturbations that impact the MuSC-niche interaction can have deleterious effects on muscle regeneration. Here, we discuss the embryonic origin of skeletal muscle and MuSCs; the regulation of MuSC activation, self-renewal, and commitment; and myopathies that impact MuSC function.

Beyond their well-known roles in chromosome end protection, telomeres play critical roles in ensuring the fidelity of meiosis, the specialized cell division underlying sexual reproduction. Central to this process is the conserved telomere bouquet, a polarized nuclear arrangement in which telomeres cluster beneath the centrosome. The telomere bouquet orchestrates movements of meiotic chromosomes that facilitate pairing and recombination between homologous chromosomes, the defining events of meiosis. Here, we review both this canonical function and newly discovered meiotic telomere functions. We focus on three species-fission yeast, budding yeast, and mouse-that highlight both general principles and novel insights likely to be broadly applicable across eukaryotes. We propose that these diverse telomere functions provided early eukaryotes with a powerful adaptive advantage, contributing to the evolutionary success of linear chromosomes.

How biological systems obtain their shape and structure is a fundamental question with many practical implications. Like much of biology, over the last several decades, tissue and organ morphogenesis has focused on uncovering regulatory mechanisms at the cellular and subcellular scales. Such studies have either implicitly or explicitly reified the view that the creation of form is instructed or controlled by a combination of genetic and molecular processes. However, pioneering early twentieth century biological theorists such as Conrad Waddington cautioned against the total subsummation of biology by, for instance, biochemistry and molecular biology. Through the coining of terms such as "epigenotype," it was argued that processes at every scale between genotype and phenotype were necessary to organize morphogenesis. Thus, organizing processes exist that are not reducible merely to the sum of inputs from "genes" and "environment." Here, we argue that uncovering generative epigenetic processes beyond the cell yet within the organism requires a holistically oriented use of physical concepts involving mechanics and material phases. To uncover and clearly articulate such "supracellular" processes, we discuss how relations between mesenchymal cells and extracellular matrix (ECM) serve as a powerful model system. Based on the study of mesenchymal-ECM systems, we suggest that it may not be possible to understand the ultimate functional role of gene products such as signaling molecules without an appreciation of supracellular processes in their own right.

Cell migration is a fundamental biological process central to a number of physiological and pathophysiological events. Traditional genetic and pharmacological approaches have identified crucial molecular regulators of migration, yet they often lack the spatial and temporal resolution required to interrogate the highly dynamic signaling events that govern cell locomotion. Chemogenetic and optogenetic platforms-genetically encoded inducible systems activated by chemical or light stimuli, respectively-have emerged as powerful tools for achieving precise, on-demand control over protein function in living cells. These systems enable researchers to dissect molecular signaling pathways in real time and with subcellular precision, even as cells are actively migrating. Together with advances in de novo protein design, biosensors, and live-cell imaging, inducible molecular tools are transforming our ability to manipulate and elucidate the intricate mechanisms underlying cell motility. Looking forward, the application of these technologies in animal models will be crucial for gaining deeper physiological and pathophysiological insights.

Calcium signaling is a key controller of numerous cellular events and is intricately linked to many processes that are critical pathways in cancer progression. This review revisits the calcium signaling toolkit in cancer, with a focus on calcium regulation of processes that go beyond the originally defined "classic" hallmarks of cancer such as those associated with proliferation, metastasis, and resistance to cell death pathways. We will consider calcium signaling in the context of the more recently proposed hallmarks of cancer, emerging hallmarks, and cancer-enabling characteristics. This broader examination of calcium signaling and its toolkit members will encompass processes such as metabolic reprogramming, evasion of immune destruction, cellular phenotypic plasticity, senescence, genome instability, and nonmutational epigenetic reprogramming. These cancer features and their interactions with calcium signaling will frequently be analyzed through the lenses of therapy resistance and the complexities of the tumor microenvironment.

Cancers that rely on activation of the alternative lengthening of telomeres (ALT) pathway predominantly affect children and adolescents, and are associated with catastrophic outcomes due to a lack of clinically effective, targeted therapeutics. The exponential rise in our understanding of the ALT mechanism in recent years has led to the identification of many therapeutic targets and strategies for patients suffering from these cancers. These include targeting replication fork remodelers and DNA damage response pathways to exacerbate telomere-specific replication stress, inhibiting ALT-mediated telomere synthesis to induce telomere dysfunction, and using oncolytic viruses to selectively kill ALT cancer cells. Herein we will evaluate the advantages and shortfalls of these therapeutic strategies, and discuss current diagnostic opportunities that are a necessary accompaniment to direct ALT therapeutics to patients.

Recent years have seen significant breakthroughs at the intersection of machine learning and protein science. Tools such as AlphaFold have revolutionized protein structure prediction. They are also enabling variant effect prediction and functional annotation of proteins, as well as opening up new possibilities for protein design. However, these technological advances must be balanced with sustainable computing practices.