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Understanding how cells sense temperature is a fundamental question in biology and is pivotal for the evolution of life. In numerous organisms, temperature is not only sensed but also generated due to cellular processes. Consequently, the mechanisms governing temperature sensation in various organisms have been experimentally elucidated. Extending upon others’ proposals and demonstration of protein- and nucleic acid-based thermosensors, and utilizing a colonial India ‘punkah-wallahs’ analogy, I present my rationale for the necessity of temperature sensing in every organelle in a cell. Finally, I propose temperature-sensing riboceptors (ribonucleic acid receptors) to integrate all the RNA molecules (mRNA, non-coding RNA, and so forth) capable of sensing temperature and triggering a signaling event, which I call as thermocrine signaling. This approach could enable the identification of riboceptors in every cell of almost every organism, not only for temperature but also for other classes of ligands, including gaseous solutes, and water.

Understanding how cells sense gases or gaseous solutes is a fundamental question in biology and is pivotal for the evolution of molecular and organismal life. In numerous organisms, gases can diffuse into cells, be transported, generated, and sensed. Controlling gases in the cellular environment is essential to prevent cellular and molecular damage due to interactions with gas-dependent free radicals. Consequently, the mechanisms governing acute gas sensing are evolutionarily conserved and have been experimentally elucidated in various organisms. However, the scientific literature on direct gas sensing is largely based on hemoprotein-based gasoreceptors (or sensors). As RNA-based G-quadruplex (G4) structures can also bind to heme, I propose that some ribozymes that contain or associated with heme-binding G4 can act as gas-sensing riboceptors (ribonucleic acid receptors). Additionally, I present a few other ideas for non-heme metal ion- or metal cluster-based gas-sensing riboceptors. Studying riboceptors can help understand the evolutionary origins of environmental gas sensing, cellular and gasocrine signaling, and interspecies communication.

Abstract The current restrictive criteria for gasotransmitters exclude oxygen (O2) as a gasotransmitter in vertebrates. In this manuscript, I propose a revision of gasotransmitter criteria to include O2 per se as a signaling molecule and 'essential gasotransmitter' for vertebrates. This revision would enable us to search for protein‐based O2‐binding sensors (gasoreceptors) in all cells in the brain or other tissues rather than specialized tissues such as the carotid body or gills. If microorganisms have protein‐based O2‐binding sensors or gasoreceptors such as DosP or FixL or FNR with diverse signaling domains, then eukaryotic cells must also have O2‐binding sensors or gasoreceptors. Just as there are protein‐based receptor(s) for nitric oxide (GUCY1A, GUCY1B, CLOCK, NR1D2) in cells of diverse tissues, it is reasonable to consider that there are protein‐based receptors for O2 in cells of diverse tissues as well. In mammals, O2 must be acting as a gasotransmitter or gaseous signaling molecule via protein‐based gasoreceptors such as androglobin that very likely mediate acute sensing of O2. Accepting O2 as an essential gasotransmitter will enable us to search for gasoreceptors not only for O2 but also for other nonessential gasotransmitters such as hydrogen sulfide, ammonia, methane, and ethylene. It will also allow us to investigate the role of environment‐derived metal ions in acute gas (or solute) sensing within and between organisms. Finally, accepting O2 per se as a signaling molecule acting via gasoreceptors will open up the field of gasocrinology.

Abstract Animal‐based research and drug safety studies are essential to understanding the mysteries of nature and the long‐term survival of humans. Due to the rapid increase in the global human population, conflict‐ and economically driven human migration, tourism‐related activities, densely populated metropolitan areas, and local policies, humans will be affected by a multitude of novel disease‐causing microorganisms and civilizational diseases. Despite disparities among countries, recent and planned changes in regulations concerning animal research and drug safety studies could have detrimental effects on both the animal research community and nations lacking sufficient social support systems. Based on existing scientific literature, I argue that we need animal research encompassing aspects such as animal development, behavior, drug safety studies, and for the understanding of future civilizational diseases. Depending on the nature of the research questions and local challenges, a suitable animal model organism should be made mandatory.

Summary: Studies in zebrafish can unravel the functions of cellular communication and thus identify novel bench-to-bedside drugs targeting cellular communication signaling molecules. Due to the incomplete annotation of zebrafish proteome, the knowledge of zebrafish receptors, ligands, and tools to explore their interactome is limited. To address this gap, we de novo predicted the cellular localization of zebrafish reference proteome using deep learning algorithm. We combined the predicted and existing annotations on cellular localization of zebrafish proteins and created repositories of zebrafish ligands, membrane receptome, and interactome as well as associated diseases and targeting drugs. Unlike other tools, our interactome atlas is based on both the physical interaction data of zebrafish proteome and existing human ligand-receptor pair databases. The resources are available as R and Python scripts. DanioTalk provides a novel resource for researchers interested in targeting cellular communication in zebrafish, as we demonstrate in applications studying synapse and axo-glial interactome. DanioTalk methodology can be applied to build and explore the ligand-receptor atlas of other non-mammalian model organisms.

Summary: Individuals in a population respond differently to stressful situations. While resilient individuals recover efficiently, others are susceptible to the same stressors. However, it remains challenging to determine if resilience is established as a trait during development or acquired later in life. Using a behavioral paradigm in zebrafish larvae, we show that resilience is a stable and heritable trait, which is determined and exhibited early in life. Resilient larvae show unique stress-induced transcriptional response, and larvae with mutations in resilience-associated genes, such as neuropeptide Y and miR218, are less resilient. Transcriptome analysis shows that resilient larvae downregulate multiple factors of the innate immune complement cascade in response to stress. Perturbation of critical complement factors leads to an increase in resilience. We conclude that resilience is established as a stable trait early during development and that neuropeptides and the complement pathway play positive and negative roles in determining resilience, respectively.