Calcium ions (Ca) are essential second messengers intimately implicated in a variety of biological processes, ranging from short-term events such as muscle contraction to long-term effects like gene expression. Dysregulated Ca signaling can disrupt cellular function and contribute to the development of various human diseases, including developmental, neurological, immunoinflammatory, metabolic, and cardiovascular disorders. To study the mechanisms and biological consequences of Ca signaling, optogenetic approaches have proven invaluable, as they offer exceptional spatiotemporal resolution compared to traditional methods. Recent progress in non-opsin-based optogenetics, particularly those engineered from Ca release-activated Ca (CRAC) channels, has substantially advanced our understanding of Ca signaling mechanisms. These tools have enabled precise manipulation of downstream signaling events, opening new avenues for therapeutic interventions. In this review, we examine the principles behind the design and engineering of light-sensitive calcium actuators and modulators (designated LiCAMs) and the applications of representative LiCAMs in remote and noninvasive control of Ca-modulated physiological processes both in vitro and in vivo.

The ability of the cell to generate precise and sustained intracellular Ca signals is governed by multiple spatial and temporal restrictions. Ca flowing into the cell through plasma membrane channels activates multiple effectors but is limited to targets in the vicinity of the channel. To reach distant effectors, cells developed a mechanism termed "Ca tunneling" where extracellular Ca entering the cell through "store-operated Ca entry" is shuttled through the lumen of the cortical endoplasmic reticulum to be released by inositol 1,4,5-trisphosphate receptors toward distal targets. Here, we review the mechanisms and functions of Ca tunneling in light of recent findings linking the structure of the cortical endoplasmic reticulum at membrane contact sites and the organization of the tunneling machinery.

Neutrophils are highly motile white blood cells that protect our body against bacterial and fungal infections. Local and global cytosolic Ca elevations enhance the ability of neutrophils to phagocytose and kill microbes, but how Ca signals regulate neutrophil adhesion, spreading, and -endothelial migration is unclear. Following the detection of chemotactic cues, selectin and integrin adhesion molecules unfold to interact with their ligands on the endothelial wall, triggering an extensive remodeling of the actin-based cytoskeleton that drives neutrophil migration and extravasation. Multiple intracellular signaling cascades are engaged by the activation of chemokine receptors, selectins, and integrins that coordinate actin-based motility and actin turnover to ensure the efficient directed migration of neutrophils to their targets. Here, we review how selectin and integrin-mediated Ca elevations regulate neutrophil adhesion and spreading, the molecular and ultrastructural basis of localized Ca signals in neutrophils, and the pathways decoding the Ca signals that sustain actin-based neutrophil motility.

Inositol 1,4,5-trisphosphate (IP) receptors (IPRs) are ubiquitously expressed intracellular calcium (Ca) release channels predominantly localized to the endoplasmic reticulum. There are three IPR subtypes, which assemble as homo-/heterotetramers. The opening of IPRs requires binding of one IP per monomer and Ca Recent high-resolution cryogenic electron microscopy (cryo-EM) structures of IPRs in combination with functional assays have greatly increased our understanding of the structural basis for IPR channel opening and closing. IPR channel activation is facilitated by IP and Ca binding to the activation site. Channel inactivation occurs in the presence of IP and high Ca when Ca is bound to the low-affinity Ca-binding motif. Specifically, in the near atomic resolution structures of IPRs, densities corresponding to the primary agonists-IP and Ca-and the allosteric modulator adenosine triphosphate (ATP) were identified. In this article, we aim to provide a comprehensive overview of the current understanding of structure-function relationships for IPRs mediated by IP, Ca, and ATP.

The collection of articles on the theme explores how brains are built, diversified, and adapted in a variety of species, integrating perspectives from evolutionary biology, developmental neuroscience, and systems neurobiology. Recent advances in molecular genetics, neuroanatomy, physiology, imaging, and computational modeling have enabled unprecedented insights into the mechanisms that shape neural circuits. This collection brings together contributions from leading investigators who examine the architecture and function of neural circuits from multiple angles. Key themes include the evolutionary divergence and convergence of circuit motifs, the conserved molecular and developmental building blocks that underlie connectivity, and the selective pressures that sculpt neural systems to support behavior and cognition. Articles cover topics ranging from retinal mapping and interneuron diversity to thalamocortical connectivity, prefrontal circuit maturation, and the computational modeling of both normal and abnormal circuit development. Collectively, these essays reveal how molecular signaling, cellular variability, and theoretical principles converge to shape the formation and function of circuits across vertebrate and invertebrate brains.

Many cell types migrate collectively, a process critical for animal development and co-opted in some medical disorders. Thus, uncovering the molecular regulation of collective cell migration is of broad interest, yet this process remains understudied as compared to individual cell motility. Both collective and individual cell movements rely on similar mechanisms to change cell shapes and adhesiveness. Although grouped cells face the added challenge of maintaining coordination and communication, they can then leverage group-level advantages, like animals in a pack. How motile cells work together to accomplish these feats is an active area of study. The border cells of the ovary provide an ideal case for investigating collective cell migration, because they can be imaged within their native tissue and are amenable to genetic manipulation. Here, we discuss how border cell movement is controlled genetically, including recent insights into group guidance, how these cells interact with their surroundings, and how they divide up functions and coordinate behaviors.

Plasticity of cell migration is a hallmark of cell movement during morphogenesis, tissue repair, and cancer metastasis. Interconversions of migration modes are tissue context-dependent and range from (1) collective migration of cohesive cells, migrating as epithelial sheets and strands; (2) multicellular networks of individualized cells moving while maintaining short-lived interactions; and (3) fully individualized cells moving by mesenchymal or amoeboid migration. Modes of cell migration, which are controlled by cell-cell adhesion, cell density, and active forces, can also be represented by physics-derived parameters, including temperature, applied stress, and volume fraction in classical passive jamming phase diagrams. Cell-packing density, cell-cell adhesion strength, and intrinsic migratory capacity have been defined as the key parameters driving jamming transitions in 2D sheet models, where extracellular matrix (ECM) is typically not considered. Here, we review how plasticity of cell migration programs intersects with jamming/unjamming principles and specifically focus on the impact of ECM architectures. In three-dimensional (3D) tissues, additional spatial parameters determine cell density and cell-cell interactions, including the degree of confinement forcing cells together versus the availability of free space. Integrating mechanisms of jamming/unjamming with actin-based active movement of cells in a 3D environment, similar to the motion of active nematic droplets in a passive nematic matrix, will enable building realistic models to predict cell behaviors in physiological and pathological contexts, including cancer metastasis.

Store-operated Ca entry (SOCE) is the primary Ca entry mechanism in nonexcitable cells such as endothelial cells (ECs). When the endoplasmic reticulum (ER)-resident stromal-interacting molecules 1 and 2 (STIM1/2) sense the depletion of Ca stores, they gain an extended conformation and move to interact with plasma membrane (PM) Orai channels within PM-ER junctions to trigger SOCE. Biophysically, SOCE is mediated by the Ca release-activated Ca (CRAC) current. SOCE was proposed to regulate many EC functions, including proliferation, migration, angiogenesis, and barrier permeability. Prior studies have provided evidence that dysregulation of endothelial SOCE underlies endothelial dysfunction in several vascular diseases. Here, we highlight the role of SOCE in regulating EC function and explore the potential of targeting Orai channels to treat vascular diseases.

Electric field-guided cell migration, known as galvanotaxis or electrotaxis, has garnered great interest as an engineering manipulation but has not been widely considered physiologically relevant. Here we provide experimental evidence proving galvanotaxis is a fundamental biological process, like chemotaxis, and show that the application of electric fields provides a powerful engineering approach. We will review our understanding of (1) endogenous electric fields naturally found in biological systems; (2) galvanotaxis of different cell types; and (3) sensing and signaling mechanisms of galvanotaxis. We reason that the bioelectrical mechanism is likely to be part of the environmental cues that cells and tissues integrate to make motility decisions.

Telomerase emerged in early eukaryotes as a highly specialized reverse transcriptase for maintaining chromosome integrity. The telomerase enzyme contains an integral RNA, providing the template for DNA repeat synthesis. This central telomerase RNA not only provides the template but also contributes to the enzyme's catalytic function and the biogenesis of the ribonucleoprotein. Remarkably, telomerase RNA exhibits significant diversity in sequence, structure, and biogenesis across eukaryotic lineages, a feature that sets it apart from other functional RNAs. In ciliates and plants, telomerase RNA is transcribed by RNA polymerase III, whereas in animals and fungi, it is predominantly transcribed by RNA polymerase II. These differences result in distinct pathways for RNA synthesis, maturation, and trafficking. This work highlights how the diversity in size and structure of telomerase RNAs impacts the complexity and evolution of telomerase ribonucleoproteins, spanning from unicellular eukaryotes to multicellular plants and animals, highlighting telomerase RNA's critical role in telomere biology.

Intracellular calcium (Ca) signaling is shaped by the coordinated action of pumps, channels, transporters, and Ca-binding proteins including the cytosolic annexins, which decode changes in cellular Ca levels and are crucial components of this intricate system. Here, we dissect overarching themes in annexin biology, detailing their structure, functional capabilities, and roles within the cellular context. We describe their bimodular structure consisting of the core domain with the Ca- and membrane-binding sites that classify the proteins and the amino-terminal domain containing sites for proteolytic cleavage, phosphorylation, and protein interaction including complex formation with S100 family Ca-binding proteins. We examine their Ca sensing and lipid/membrane binding properties and discuss experimental evidence toward their functions in building Ca-controlled platforms for dynamic assembly of functional machineries at specific membrane domains within the complex regulatory networks of cellular function.

One of the prime examples of the applicability of Mendel's laws to the animal world involves the characteristics of guinea pig coat color. The paper retraces the history of an especially illustrious example of Mendelian mechanisms in guinea pigs and analyzes its role in the dissemination of genetic theory. Its origins go back to William Castle's cross-breeding experiments conducted in the early 1900s, yet there is a substantial gap between Castle's results in that particular experiment and the canonized form into which they were subsequently molded: a concise chart that simultaneously demonstrates and reaffirms Mendel's laws. The extraordinary appeal of that chart stemmed from scientific, pedagogical, as well as cultural factors, the latter related to the sociopolitical significance of color differences in the context of racial discourse and of concerns about racial mixture. More generally, the guinea pigs chart analyzed here belonged to a family of standardized visualizations that purported to describe empirical findings while actually describing Mendelian theory.

Ribosomal frameshifting is a recoding mechanism that allows the ribosome to alter its reading frame during translation, often in response to specific messenger RNA (mRNA) elements or cellular conditions. While essential for the life cycle of many viruses, frameshifting also occurs spontaneously or in response to transfer RNA (tRNA) depletion, raising important questions about its regulation and biological relevance. This review explores the structural and kinetic principles that govern -1 frameshifting, highlighting the role of ribosome conformational dynamics, slippery sequences, and mRNA secondary structures. We discuss how programmed, hungry, and spontaneous frameshifting arise from distinct molecular pathways, yet converge on shared mechanistic features. The review also examines translational bypassing as a related form of recoding that involves large-scale ribosome sliding over noncoding regions and relies on a distinct set of RNA and ribosome conformational cues to ensure accurate take-off and landing. These insights expand our understanding of translation fidelity and recoding plasticity.

The calcium ion (Ca) is a pivotal second messenger orchestrating diverse cellular functions, including metabolism, signaling, and apoptosis. Membrane contact sites (MCSs) are critical hubs for Ca exchange, enabling rapid and localized signaling across cell compartments. Well-characterized interfaces, such as those between the endoplasmic reticulum (ER) and mitochondria and ER-plasma membrane (PM), mediate Ca flux through specialized channels. Less understood, yet significant, contacts involving Golgi, lysosomes, peroxisomes, and the nucleus further expand the landscape of intracellular Ca signaling. These organelles are engaged in Ca homeostasis mainly through their MCS, but the molecular players and the mechanisms regulating the process of Ca transfer remain incompletely elucidated. This review provides a comprehensive overview of Ca signaling across diverse MCS, emphasizing understudied organelles and the need for further investigation to uncover novel therapeutic opportunities.

Directed leukocyte motility is essential for immunity and host defense. Dysregulated leukocyte migration is implicated in clinical immunodeficiency and hyperinflammatory conditions. Leukocytes sense both chemical and physical cues within the environment to regulate internal migration machinery and thus coordinate the immune response and its resolution. In response to environmental cues, leukocytes cater migration strategies to both exert forces on surrounding tissues and alter the chemical environment through self-generated gradients. Here, we synthesize recent advances in our understanding of how chemical and physical cues within the tissue environment regulate leukocyte motility, with implications to develop therapeutic strategies to modulate the immune response in human disease.

-Translation is a recoding event in which a translating ribosome switches from the engaged messenger RNA (mRNA) to a specialized reading frame within transfer-messenger RNA (tmRNA) without releasing the nascent polypeptide, producing a protein that is encoded in two physically distinct RNA molecules. -Translation is the most abundant form of recoding and is found throughout the bacterial kingdom. In growing in liquid culture, ∼5% of newly synthesized proteins are recoded through -translation. The importance of this pathway for pathogenic bacteria makes it a potential target for antibiotic development. This review covers the role of -translation in pathogenesis, potential points for inhibition, and the progress in developing -translation inhibitors as antibiotics.

This perspective advocates for "evolutionary systems neuroscience" as a framework combining evolutionary biology with neural circuit analysis. Evolution creates natural circuit modifications that preserve essential functions while enabling new behaviors. Modern technologies now allow researchers to investigate causal connections from genes to circuits to behaviors with unprecedented precision. By studying both convergent and divergent evolution, we can uncover both broad computational principles and specific implementation mechanisms. Across diverse examples-from insect courtship to rodent communication-we explore how targeted circuit changes drive behavioral innovation without disrupting core functions. This framework may reveal "deep homologies" in neural mechanisms, similar to how evolutionary developmental biology (evo-devo) identified conserved genetic toolkits in morphological development. This evolutionary lens promises not just to reveal how brains work, but why they work the way they do-providing insights that extend beyond neuroscience to complex adaptive systems more broadly.

Cell migration is greatly affected by both the physical properties of the motile cell itself and the environment through which the cell is moving. In addition to studying cellular and extracellular mechanical properties in the context of cell migration, there is a growing interest in understanding the intersection between migration, mechanics, and metabolism. In this work, we discuss the many techniques and approaches researchers are currently using to study cellular mechanics, extracellular mechanics, and metabolism in the context of cell migration. Our goal is to bring exposure to new approaches in the fields of mechanobiology and mechanometabolism and highlight the importance of studying cell migration through a mechanical lens.

Cell migration is a fundamental biological process critical for development, immune response, and wound healing, but its dysregulation contributes to pathological conditions such as cancer metastasis. Recent research has demonstrated that migration is driven by excitable signal transduction and cytoskeletal networks, which function as separate but coupled systems. The signal transduction excitable network (STEN) propagates excitatory signals, while the cytoskeletal excitable network (CEN) generates cytoskeletal protrusions. Although distinct, these networks interact dynamically: STEN regulates CEN, while CEN provides feedback to STEN, influencing cell polarization and directionality. Computational models incorporating nonlinear dynamics and reaction-diffusion systems have successfully recapitulated these interactions, shedding light on their role in pseudopod formation, chemotaxis, and mechanosensation. This review discusses recent experimental and theoretical advances, highlighting how excitable systems underlie cell motility and how mathematical modeling helps to understand their role.

During development and homeostasis, tissues move and rearrange to form organs, seal wounds, or-in the case of cancer-spread in the body. To accomplish this, cells in tissues need to communicate with each other, generate force to push themselves forward, and know where to go to-all of this with little to no error. Here, we discuss how a migrating tissue-the zebrafish posterior lateral line primordium-solves these challenges. We focus on the strategies that ensure signaling within the tissue, enable the tissue to generate and transmit force to its substrate for propulsion, and allow robust directional sensing and migration by the tissue. These strategies include facilitated diffusion and ligand trapping for focal signaling, a self-generated attractant gradient for long-distance migration, clamping of the attractant concentration to the attractant receptor's for most sensitive signaling, mechanical coupling among cells for averaging directional sensing in a tissue, and large rear traction stresses to propel the tissue forward. Many of these strategies likely apply to collectively migrating cells in other contexts and should thus provide insights with direct relevance to human health.

Although cell migration has been extensively investigated using in vitro model systems, the mechanisms underlying mammalian cell migration in native tissue environments remain underexplored. Moreover, efforts to directly manipulate and visualize molecular regulators in live mammalian tissues have been scarce. In this article, we first review the current insights into various single-cell migration phenomena, including stem cell types, observed in mammalian tissues under homeostatic and pathophysiological conditions. Thereafter, we discuss intravital subcellular microscopy (ISMic) as a tool to unravel membrane remodeling mechanisms underlying cell migration in live animal tissues. Lastly, we emphasize the need for innovative microscopy and complementary advanced approaches to achieve a deeper fundamental understanding of cell migration modalities and their impact on mammalian tissue in homeostasis and pathophysiology.