Recent studies indicate that PIWI (P-element-induced WImpy testis) like proteins and their cognate PIWI-interacting RNAs (piRNAs), initially identified in germline cells for protecting genomic stability by transposon silencing, also exert multiple regulatory functions in somatic and immune systems. Additionally, PIWIL/piRNA pathways are linked to innate antiviral defense and immune signaling pathway regulation. This review systematically compiles the reports on the immunological functions of noncoding RNAs (ncRNAs) and delineates the potential molecular processes and functional characteristics of PIWIL/piRNA pathways. We propose that PIWIL/piRNAs function as a molecular link between adaptive and reproductive immunity and maintain barrier integrity in immune-privileged settings. Predictive bioinformatic analysis further revealed specific piRNAs that could interact with long noncoding RNAs (lncRNAs) and miRNAs to regulate immune response components within the TLR and JAK/STAT pathways, highlighting their potential role in antiviral and immunomodulatory signaling networks. We conclude by discussing the emerging opportunities to integrate ncRNA-mediated regulatory mechanisms into personalized medicine and targeted therapies while addressing the key hurdles in clinical application.

The prevailing view of biological evolution is not unlike bricolage/pastiche/tinkering-in sharp contrast with rational engineering. Yet, different paths often lead to solutions that coincide or converge whether they emerge from naturally-occurring evolution or rationally designed. Such a conjunction-often presented as an anecdote-reveals the ability of biological systems to explore solution spaces and gravitate toward information-rich attractors, which can be found through different routes. This scenario evokes one of embodied computing, a non-conventional type of data processing in which the solution to a problem is not delivered through numerical calculations but through its implementation in a material object. Once left to undergo a physical process the object manages a large number of parameters for reaching a multi objective optimum through thermodynamically-driven processes. The course of information is thus a physical flow and the outcome is a physical currency. The consequences of this notion for bioengineering are remarkable.

Where a transcript goes among a cell's membraneless compartments-stress granules, P-bodies, paraspeckles, nuclear speckles-is an addressable, rewritable property that this article proposes chemical modifications of RNA help write. The code's output depends on the transcript's role: for client messenger RNAs, an apparent partition coefficient (Kpart), its enrichment in a condensate; for the rare long noncoding RNAs acting as architectural scaffolds, the saturation concentration that decides whether the compartment forms at all. This client/scaffold asymmetry is the framework's central proposal, its scaffold arm as yet untested. Only m6A has cellular partitioning evidence; A-to-I editing sets nuclear address by a related route, and the remaining marks are candidates or structure-based predictions. The value is a variable and a falsifiable test: perturb a mark at fixed sequence and state, and ask whether the address moves. It reframes scattered epitranscriptomic and condensate biology as one control problem.

The concept of 'metabolic structure', which considers metabolism as a stable, genetically encoded architecture with enzymes occupying fixed control positions, is indispensable but incomplete, and it obscures metabolism's true nature. I propose redefining metabolism as a dynamic field of emergent biochemical fluxes, governed by six fundamental parameters: time, water, entropy, quantum effects, space, and electrostatic potential, shaping the thermodynamic trajectories of living matter. Metabolic control analysis already supports this view: flux control coefficients are state- and time-dependent coordinates within a thermodynamic field, not intrinsic enzyme properties. This perspective manifests across scales: electrostatics govern fructose 1,6-bisphosphate cleavage in aldolase; hepatic zonation shows spatial reorganization through a single parameter; glucose deprivation quantitatively redirects intestinal cancer cell metabolism from glycolytic to oxidative flux, driving differentiation into an enterocyte-like state; post-meal walking redirects glucose flux from storage to oxidation without pharmacological intervention; inherited metabolic diseases can sometimes be managed without correcting the causal mutation. These examples converge into a new framework: metabolism possesses not only a sophisticated architecture but also states that shape its fluxes. And states, unlike static structures, can be reconfigured.

Microtubules and motor proteins are components of a cytoskeleton that influence each other to maintain cellular functions. Microtubules act as tracks for motor protein-driven intracellular transport of organelles, vesicles, and macromolecules; therefore, their structural organization and stability are important. Kinesin and dynein motor proteins function not only as cargo transporters but also as contributors to the regulation of microtubule organization, stability, and interactions. The interaction of motor proteins and microtubules is essential for cellular homeostasis, and dysregulations can affect motility-dependent cellular processes such as intracellular trafficking and cell division. In this review, we summarize current knowledge on the relationship between motor proteins and factors associated with microtubule stability, particularly tubulin post-translational modifications and microtubule-associated proteins and discuss how alterations in these processes associate with disease.

Cellular function is frequently interpreted in terms of gene presence, protein abundance, and dose-response relationships. Yet interacting proteins operate within binding and assembly regimes in which relative abundance can alter which molecular complexes predominate. We propose a protein-ratio rheostat framework in which functional output depends jointly on component ratios, absolute concentrations relative to binding affinities, interaction stoichiometry, and in multivalent systems, valency and cooperativity. The same protein ratio can therefore generate different molecular and functional states under different concentration or affinity regimes. We develop testable predictions of this framework, illustrate its application to competitive protein interactions and biomolecular condensates, and outline experimental strategies for identifying composition-sensitive behavior within defined abundance and affinity regimes.

The regulation of replication fork (RF) speed is essential for faithful genome duplication and the maintenance of genome stability, and its dysregulation contributes to carcinogenesis and developmental disorders. Although many anticancer therapies perturb DNA replication, the molecular mechanisms by which RF speed is controlled remain incompletely understood. A major limitation has been the frequent omission of direct measurements of cellular deoxynucleotide triphosphate (dNTP) pools, despite their strong and immediate influence on DNA polymerase kinetics. In this review, we first summarize how dNTP availability constrains RF progression under physiological and stress conditions. We then discuss how anticancer agents targeting DNA replication modulate RF speed through phosphorylation-dependent signaling pathways. Finally, we examine emerging roles of PARylation and UFMylation as rapid, replisome-centered regulatory mechanisms that fine-tune fork progression and stability, and we highlight their clinical implications, including a mechanistic link between aberrant replisome regulation and microcephalic primordial dwarfism.

A complex network of protein interactions promotes the cooperative assembly of biomolecular condensates that control the formation of meiotic DNA double-strand breaks (DSBs). In many species, programmed DSBs made by SPO11 are required for the faithful pairing and segregation of homologous chromosomes during meiosis I. DSBs must be tightly regulated to support their intended function but also to minimize the risk of genomic damage from mutation or defective DSB repair. Multiple chromosome axis-associated proteins are important for the control of meiotic DSB formation and recombination, but the underlying mechanisms of those proteins remain poorly understood. Here, we present a current view of how these proteins work together in mice, based on recent advances in the characterization of their function and structure.

Telomerase-free cancer cells use a recombination-based alternative lengthening of telomeres (ALT) pathway to maintain telomere length. ALT cancer cells exhibit extreme heterogeneity in telomere length, which requires the formation of a specialized nuclear condensate, the ALT telomere-associated PML bodies (APBs). Recent findings on APB assembly reveal that APBs form through two mechanistically and kinetically distinct pathways. These pathways modulate the strength of ALT activity. In this essay, I discuss how APB formation dynamics may contribute to telomere-length variability in ALT cells and consider the broader implications of these findings for other chromatin-associated nuclear condensates.

Advanced vertebrates (gnathostomes) differ from the rest of the animal tree of life by their use of an elaborate endoskeleton and the deployment of the catecholamine neurotransmitters epinephrine and norepinephrine. Here we propose that the coordinated origins of these seemingly unrelated signature traits are explained by the varied propensities of different catecholamines to oxidize and polymerize into the light absorbent and structurally stable biopolymer melanin. Compared to dopamine and its precursor DOPA (L-3,4-dihydroxyphenylalanine), norepinephrine and epinephrine are much less susceptible to polymerization. The latter were therefore likely adaptively favored for peripheral signaling in vertebrates. In addition to the chemical evidence, we explore how peripheral nervous system development correlated with changes in gene family content, immune response organization, and internal support structure elaboration during early vertebrate evolution.

Recent human genetic studies revealed that Alzheimer's disease risk loci are enriched in genes expressed in myeloid cells, including microglia, the brain's resident immune cells. Notably, several risk-associated genes, such as SPI1 and MEF2C, encode transcription factors (TFs) that control critical microglial functions, including phagocytosis, inflammatory responses, and neurotrophic support. The objective of this article is to review the recent progress in understanding these TFs and evaluate them as therapeutic targets rather than as markers of microglial state. We examine the genetic evidence implicating PU.1, MEF2C, IRF8, and BHLHE40/41, the in vivo evidence from animal models, the transcriptional network these factors regulate, and the barriers to clinical translation. Because these TFs orchestrate broad gene expression networks by regulating multiple disease-relevant downstream partners, targeting their expression level or activity could achieve greater therapeutic efficacy than targeting single genes, provided that the dose and disease stage of modulation are carefully considered.

The rapid, unprecedented rate of worldwide pressures organisms are currently exposed to, from climate instability to pollution, urges to expand research focus toward stress resilience. Here, our main goal is to call for an integrative effort to understand conserved processes underlying whole-organism stress resilience with a specific focus on the following questions: (i) How can stress resilience be defined? (ii) What are its main underlying metrics at the whole-organism level (focus on glucocorticoid hormones, oxidative stress, neural and behavioral metrics)? (iii) What is the role of stress inoculation- and hormetic-like effects to build resilience throughout an organism´s lifespan? By building up on emerging knowledge spanning from behavioral biology and ecophysiology to biomedicine, we explore conserved mechanisms of stress resilience that are relevant for both environmental and human health. Finally, we encourage for more research on wildlife study systems, which experience natural and cumulative stressors across ecologically relevant settings, and can thus help uncover functional mechanisms of stress resilience across vertebrates, including humans.

Transcription and three-dimensional (3D) genome organization are closely coupled, but their precise relationship remains unresolved. Evidence from perturbation, imaging, and modeling studies suggests that transcription is not strictly required for the establishment of large-scale genome features such as compartments and topologically associating domains (TADs). Instead, transcription seems to exert more prominent effects at finer spatial scales, where it influences enhancer-promoter interactions, local chromatin loops, and microcompartments. RNA molecules, polymerase-driven supercoiling, and R-loop formation may further modulate chromatin organization at the gene level. At the same time, many architectural proteins and transcriptional regulators operate with functional overlap, complicating efforts to disentangle cause and consequence. Together, these observations suggest that genome architecture provides a relatively stable framework for regulated gene expression, while transcription and associated factors refine chromatin organization in a context-dependent manner. Understanding how these processes are integrated will require systematic, multi-scale perturbations across different biological and biochemical systems.

Tetracycline destructases (TDases) pose an emerging global threat by enzymatically inactivating all generations of tetracycline (Tet) antibiotics, including last-resort agents such as tigecycline. Despite their recent identification, TDases have rapidly disseminated worldwide, largely driven by mobile genetic elements and environmental reservoirs. This review synthesizes current knowledge on TDase genomics, structural and catalytic mechanisms, ecological niches, and clinical impacts. We detail the mechanistic distinctions between type 1 and type 2 TDases, emphasizing their divergent structural configurations and substrate specificity profiles. Additionally, we examine strategies for therapeutic intervention, highlighting progress in structure-guided inhibitor development. Key gaps remain in understanding ancestral reservoirs, evolutionary trajectories, and effective surveillance strategies. Addressing these areas through integrative evolutionary, biochemical, and ecological studies is critical for mitigating the clinical spread and therapeutic impact of TDases globally.